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  • 201.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Johnsson, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Maric, C.
    Department of Medicine, Georgetown University Medical Centre, Washington, DC, USA.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hormonal regulation of renomedullary hyaluronan2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 193, no 2, p. 191-198Article in journal (Refereed)
    Abstract [en]

    AIM

    Hyaluronan (HA) is involved in renomedullary water handling through its water-binding capacity. This study addressed the effect of hormones involved in regulating fluid-electrolyte homeostasis on renomedullary HA content in vivo and in vitro.

    METHODS

    The kidneys from rats treated with L-NAME, indomethacin, vasopressin (AVP) or methylprednisolone (MP) during euvolaemia or water loading were analysed for HA by RIA, ELISA and histochemical staining. HA was measured in renomedullary interstitial cells treated with AVP, angiotensin II (Ang II) or a combination of AVP and Ang II.

    RESULTS

     Baseline renal cortical and medullary HA content was unaffected by 2 h of intravenous treatment with L-NAME (NOS inhibitor) or indomethacin (cyclo-oxygenase inhibitor), whereas AVP reduced medullary HA by 33%. During 2 h of acute water loading, diuresis was accompanied by an increase in renomedullary HA (+45%), but cortical HA was unaffected. In both L-NAME- and indomethacin-treated animals, the water loading-induced increase in renomedullary HA was absent, indicating involvement of NO and prostaglandins. After 7 days of MP treatment, medullary HA was reduced by 40%, but the water loading-induced elevation in HA remained. In cultured renomedullary interstitial cells, AVP reduced the HA content in the supernatant by 63%, and simultaneous treatment with Ang II reduced the HA content even further (95%).

    CONCLUSION

     AVP reduces HA content, and NO and prostaglandins are needed for the increase in HA during water loading.

  • 202.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Takahashi, Tomoko
    School of Pharmaceutical Sciences, Ohu University, Koriyama, Japan.
    Shimizu, Kei
    School of Pharmaceutical Sciences, Ohu University, Koriyama, Japan.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hyaluronan synthases and hyaluronidases in the kidney during changes in hydration status2009In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 28, no 7, p. 390-395Article in journal (Refereed)
    Abstract [en]

    Hyaluronan is a large glycosaminoglycan that is abundant in the   interstitium of the renal medulla/papilla. Papillary hyaluronan   increases during hydration and decreases during dehydration. Due to its   gel properties and ability to retain large volumes of water, hyaluronan   plays a role in renal water handling by affecting the permeability   characteristics of the papillary interstitium. The focus of the present   investigation was the regulation of hyaluronan metabolism in the   kidney, especially during variations in hydration status.   In control papillas, HAS 2 mRNA was heavily expressed and HAS 1 and 3   mRNA were weakly distributed. HYALs 1-3 mRNA were found at high   expression and HYAL 4 was only weakly expressed. in hydrated animals,   the diuretic response (12-fold) was followed by a 58% elevation in   papillary hyaluronan and a 45% reduction in the excreted urinary   hyaluronidase activity. No difference was determined in HAS 1-3 mRNA or   HYAL 1, 3-4 mRNA expression, suggesting a change in activity rather   than amount of protein. In dehydrated animals, antidiuresis was   followed by a 22% reduction in papillary hyaluronan and a 62% elevation   in excreted urinary hyaluronidase activity. Plasma vasopressin was   2.8-fold higher in dehydrated vs. hydrated rats.   In conclusion, HAS 2 appears a major contributor to the baseline levels   of hyaluronan. Reduced HAS 2 gene expression and increased excreted   urinary hyaluronidase activity during dehydration contribute to the   reduced amount of hyaluronan and to antidiuretic response.

  • 203.
    Schiffer, Tomas A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christensen, Michael
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Gustafsson, Hakan
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The effect of inactin on kidney mitochondrial function and production of reactive oxygen species2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0207728Article in journal (Refereed)
    Abstract [en]

    Inactin is a long lasting anesthetic agent commonly used in rat studies, but is also shown to exert physiological effects such as reducing renal blood flow, glomerular filtration rate and depressing tubular transport capacity. The effect of inactin on isolated kidney mitochondria is unknown and may be important when studying related topics in anaesthetized animals. The aim of this study was to determine whether inactin exerts effects on mitochondrial function and production of reactive oxygen species. Kidney mitochondrial function and production of reactive oxygen after acutely (5 min) or longer (1.5 hour) anesthetizing rats with inactin was evaluated using high-resolution respirometry. The results demonstrate that inactin significantly improves respiratory control ratio, inhibits complex I in the mitochondrial respiratory chain, reduce both unregulated proton leak and time dependently reduce the regulated proton leak via uncoupling protein-2 and adenine nucleotide translocase. Inactin also contributes to increased mitochondrial hydrogen peroxide production. In conclusion, inactin exerts persistent effects on mitochondrial function and these profound effects on mitochondrial function should to be considered when studying mitochondria isolated from animals anesthesized with inactin.

  • 204.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Microcirculation, Mucus and Microbiota in Inflammatory Bowel Disease2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Inflammatory bowel diseases, (IBD), are a group of chronic disorders of the gastro-intestinal tract, and include Crohn’s disease (CD) and Ulcerative Colitis (UC). The pathogenesis is not known, but involves at least in part a loss of tolerance towards the commensal colonic microbiota. In this thesis, we show in animal models of CD and UC that the colonic mucosal blood flow increased compared to healthy animals. This blood flow increase is due to an up regulation of endothelial nitric oxide synthase (NOS). Further, we show in the UC model that the thickness of the firmly adherent colonic mucus layer increased compared to healthy animals. This increase is due to an up regulation of inducible NOS in the epithelium. Both the blood flow and mucus thickness increase appear to be protective mechanisms.  We demonstrate that the firmly adherent colonic mucus layer acts as a partial barrier towards luminal bacteria. In the UC model, this barrier is destroyed, causing increased bacterial translocation. The adhesion molecule P-selectin was up regulated in the UC model, leading to increased interactions between leukocytes and the endothelium, but also increased interactions between platelets and the endothelium. This indicates that not only leukocytes, but also platelets are involved in colonic inflammation. The addition of the probiotic bacterial strain Lactobacillus reuteri prevented disease by normalizing P-selectin levels and endothelial interactions with leukocytes and platelets. Lactobacillus reuteri also decreased bacterial translocation over the epithelium. In summary, this thesis highlights the importance of colonic barrier functions, and investigates the role of the microbiota in experimental IBD.

    List of papers
    1. eNOS involved in colitis-induced mucosal blood flow increase
    Open this publication in new window or tab >>eNOS involved in colitis-induced mucosal blood flow increase
    Show others...
    2007 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 293, no 6, p. G1281-G1287Article in journal (Refereed) Published
    Abstract [en]

    The role of NO in inflammatory bowel disease is controversial. Studies indicate that endothelial nitric oxide synthase (eNOS) might be involved in protecting the mucosa against colonic inflammation. The aim of this study was to investigate the involvement of nitric oxide (NO) in regulating colonic mucosal blood flow in two different colitis models in rats. In anesthetized control and colitic rats, the distal colon was exteriorized and the mucosa visualized. Blood flow (laser-Doppler flowmetry) and arterial blood pressure were continuously monitored throughout the experiments, and vascular resistance was calculated. Trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) was used to induce colitis. All groups were given the NOS inhibitor N-omega-nitro-Larginine (L-NNA) or the inducible NOS (iNOS) inhibitor L-N-6-(1-iminoethyl)- lysine (L-NIL). iNOS, eNOS, and neuronal NOS (nNOS) mRNA in colonic samples were investigated with real-time RT-PCR. Before NOS inhibition, colonic mucosal blood flow, expressed as perfusion units, was higher in both colitis models compared with the controls. The blood flow was reduced in the TNBS- and DSS-treated rats during L-NNA administration but was not altered in the control group. Vascular resistance increased more in the TNBS- and DSS-treated rats than in the control rats, indicating a higher level of vasodilating NO in the colitis models. L-NIL did not alter blood pressure or blood flow in any of the groups. iNOS and eNOS mRNA increased in both colitis models, whereas nNOS remained at the control level. TNBS- and DSS-induced colitis results in increased colonic mucosal blood flow, most probably due to increased eNOS activity.

    Keywords
    trinitrobenzene sulfonic acid, dextran sulfate sodium, inducible nitric oxide synthase, neuronal nitric oxide synthase
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13069 (URN)10.1152/ajpgi.00357.2007 (DOI)000251510500020 ()17947450 (PubMedID)
    Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2017-12-11Bibliographically approved
    2. iNOS-dependent increase in colonic mucus thickness in DSS-colitic rats
    Open this publication in new window or tab >>iNOS-dependent increase in colonic mucus thickness in DSS-colitic rats
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To investigate colonic mucus thickness in vivo in health and during experimental inflammatory bowel disease.

    Methods: Colitis was induced with 5% DSS for 9 days. The colon of anesthetized rats was mounted mucosal side up and studied with intravital microscopy. Using a micropipette, attached to a micromanipulator and a digimatic indicator, mucus thickness was measured. The unselective NOS inhibitor L-NNA, the selective iNOS inhibitor L-NIL and the unselective COX inhibitor diclofenac were used to assess the contributions of NOS and prostaglandins in the regulation of mucus thickness. C57Bl/6 and iNOS -/- mice were used to further investigate the role of iNOS in mucus regulation.

    Results: Colitic rats had a thicker firmly adherent mucus layer than untreated control rats 9 days after the start of the experiment (88 ± 2 µm vs 76 ± 1 µm). During the course of the colitis-induction the thickness of the mucus layer first decreased, but from day 4 the mucus thickness was significantly thicker than in untreated rats. Diclofenac (5 mg/kg i.v.) reduced the mucus thickness comparably in colitic and untreated rats (-17 ± 6 µm vs -14 ± 2 µm). While L-NNA had no effect on mucus thickness in either DSS or untreated controls (+3 ± 2 µm vs +3 ± 1 µm), L-NIL reduced the mucus thickness significantly more in colitic rats than in untreated controls (-33 ± 4 µm vs -12 ± 1 µm). The importance of iNOS in maintaining mucus thickness was confirmed in iNOS -/- mice which had a thinner mucus thickness than control mice (35 ± 3 µm vs 50 ± 2 µm).

    Conclusion: Colitic rats have a thicker firmly adherent colonic mucus layer and this effect is mediated by iNOS. Prostaglandins are involved in the regulation of base line mucus secretion.

     

     

    Keywords
    Experimental colitis, DSS, mucus thickness, MUC2, iNOS, prostaglandins
    National Category
    Physiology
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-112500 (URN)
    Available from: 2010-01-19 Created: 2010-01-14 Last updated: 2018-01-12
    3. Lactobacillus reuteri prevents colitis by reducing P-selectin-associated leukocyte- and platelet-endothelial cell interactions
    Open this publication in new window or tab >>Lactobacillus reuteri prevents colitis by reducing P-selectin-associated leukocyte- and platelet-endothelial cell interactions
    Show others...
    2009 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 296, no 3, p. G534-G542Article in journal (Refereed) Published
    Abstract [en]

    Recent findings indicate that dextran sodium sulfate (DSS)-induced colitis is associated with a prothrombogenic phenotype, with P-selectin playing a major role in platelet recruitment. It has been suggested that probiotics may ameliorate colonic inflammation. We therefore investigated how treatment with Lactobacillus reuteri influenced P-selectin expression, leukocyte and platelet endothelial cell interactions, and colitis severity in DSS-treated rats. Rats were divided into the following four groups: nontreated, DSS treated (5% in drinking water for 9 days), L. reuteri, and L. reuteri and DSS treated. The rats were anesthetized with Inactin (120 mg/kg ip), and the dual radiolabeled monoclonal antibody technique was used to quantify P-selectin expression. Leukocyte-endothelial and platelet-endothelial cell interactions were studied in colonic venules with intravital microscopy. Colitis severity was assessed using a disease activity index. Disease activity index increased, as did the expression of P-selectin in the entire colon after DSS treatment, but both were reduced to control levels with L. reuteri pretreatment. The increased platelet- and leukocyte-endothelial cell interactions after DSS treatment were abolished by pretreatment with L. reuteri. L. reuteri protects against DSS-induced colitis in rats. The protection is associated with reduced P-selectin expression and a decrease in leukocyte- and platelet-endothelial cell interactions.

    Keywords
    dextran sulfate sodium, disease activity index
    National Category
    Medical and Health Sciences Medical and Health Sciences Physiology
    Identifiers
    urn:nbn:se:uu:diva-104355 (URN)10.1152/ajpgi.90470.2008 (DOI)000263900800010 ()19147805 (PubMedID)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2018-01-13Bibliographically approved
    4. Influence of Lactobacillus reuteri on the colonic microbiota in health and DSS-induced colitis
    Open this publication in new window or tab >>Influence of Lactobacillus reuteri on the colonic microbiota in health and DSS-induced colitis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To investigate the impact of Lactobacillus reuteri and Dextran Sulphate Sodium (DSS) on the colonic microbiota by investigating bacterial content and composition in the individual colonic mucus layers and mesenteric lymph nodes.

    Methods: Rats were divided into 4 groups: control, L. reuteri, DSS and L. reuteri+DSS.     L. reuteri was given as a cocktail containing 109 cfu of four different strains of L. reuteri by gavage daily for 16 days. Colitis was induced by 5% DSS in the drinking water for 9 days. The firmly and loosely mucus layers and mesenteric lymph nodes were collected, homogenized and its bacterial content was monitored using both culturing as well as the molecular method terminal restriction fragment length polymorphism (TRFLP).

    Results: In controls, the number of bacteria was significantly lower in the inner firmly adherent mucus layer than the outer loosely adherent layer, indicating a barrier function of the inner mucus layer. The composition of the microbiota was also different between layers. L. reuteri prevented colitis but did not alter the microbiota. DSS obliterated the differences between mucus layers both in terms of number of bacteria, and bacterial composition, indicating that DSS destroys the mucus regardless of the addition of L. reuteri. L. reuteri did however significantly decrease bacterial translocation in the DSS-model.

    Conclusion: The firmly adherent mucus layer serves as a barrier towards luminal bacteria. DSS alters the colonic microbiota and destroys the mucus barrier. L. reuteri ameliorates DSS-colitis by decreasing bacterial translocation.

     

    Keywords
    Experimental colitis, DSS, probiotics, Lactobacillus reueteri, lactobacilli, colonic microbiota, colonic mucus, bacterial translocation, T-RFLP
    National Category
    Microbiology in the medical area
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-112501 (URN)
    Available from: 2010-01-19 Created: 2010-01-14 Last updated: 2018-01-12
  • 205.
    Schreiber, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Dicksved, Johan
    Institutionen för Mikrobiologi, Sveriges Lantbruksuniversitet.
    Willing, Ben
    Institutionen för Mikrobiologi, Sveriges Lantbruksuniversitet.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rang, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Siemiatkowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jonsson, Hans
    Institutionen för Mikrobiologi, Sveriges Lantbruksuniversitet.
    Lindgren, Sven
    Institutionen för Mikrobiologi, Sveriges Lantbruksuniversitet.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Roos, Stefan
    Institutionen för Mikrobiologi, Sveriges Lantbruksuniversitet.
    Influence of Lactobacillus reuteri on the colonic microbiota in health and DSS-induced colitisManuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To investigate the impact of Lactobacillus reuteri and Dextran Sulphate Sodium (DSS) on the colonic microbiota by investigating bacterial content and composition in the individual colonic mucus layers and mesenteric lymph nodes.

    Methods: Rats were divided into 4 groups: control, L. reuteri, DSS and L. reuteri+DSS.     L. reuteri was given as a cocktail containing 109 cfu of four different strains of L. reuteri by gavage daily for 16 days. Colitis was induced by 5% DSS in the drinking water for 9 days. The firmly and loosely mucus layers and mesenteric lymph nodes were collected, homogenized and its bacterial content was monitored using both culturing as well as the molecular method terminal restriction fragment length polymorphism (TRFLP).

    Results: In controls, the number of bacteria was significantly lower in the inner firmly adherent mucus layer than the outer loosely adherent layer, indicating a barrier function of the inner mucus layer. The composition of the microbiota was also different between layers. L. reuteri prevented colitis but did not alter the microbiota. DSS obliterated the differences between mucus layers both in terms of number of bacteria, and bacterial composition, indicating that DSS destroys the mucus regardless of the addition of L. reuteri. L. reuteri did however significantly decrease bacterial translocation in the DSS-model.

    Conclusion: The firmly adherent mucus layer serves as a barrier towards luminal bacteria. DSS alters the colonic microbiota and destroys the mucus barrier. L. reuteri ameliorates DSS-colitis by decreasing bacterial translocation.

     

  • 206.
    Schreiber, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jägare, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon
    Inst. för Fysiologi och Farmakologi, Karolinska Institutet, Stockholm.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    iNOS-dependent increase in colonic mucus thickness in DSS-colitic ratsManuscript (preprint) (Other academic)
    Abstract [en]

    Aim: To investigate colonic mucus thickness in vivo in health and during experimental inflammatory bowel disease.

    Methods: Colitis was induced with 5% DSS for 9 days. The colon of anesthetized rats was mounted mucosal side up and studied with intravital microscopy. Using a micropipette, attached to a micromanipulator and a digimatic indicator, mucus thickness was measured. The unselective NOS inhibitor L-NNA, the selective iNOS inhibitor L-NIL and the unselective COX inhibitor diclofenac were used to assess the contributions of NOS and prostaglandins in the regulation of mucus thickness. C57Bl/6 and iNOS -/- mice were used to further investigate the role of iNOS in mucus regulation.

    Results: Colitic rats had a thicker firmly adherent mucus layer than untreated control rats 9 days after the start of the experiment (88 ± 2 µm vs 76 ± 1 µm). During the course of the colitis-induction the thickness of the mucus layer first decreased, but from day 4 the mucus thickness was significantly thicker than in untreated rats. Diclofenac (5 mg/kg i.v.) reduced the mucus thickness comparably in colitic and untreated rats (-17 ± 6 µm vs -14 ± 2 µm). While L-NNA had no effect on mucus thickness in either DSS or untreated controls (+3 ± 2 µm vs +3 ± 1 µm), L-NIL reduced the mucus thickness significantly more in colitic rats than in untreated controls (-33 ± 4 µm vs -12 ± 1 µm). The importance of iNOS in maintaining mucus thickness was confirmed in iNOS -/- mice which had a thinner mucus thickness than control mice (35 ± 3 µm vs 50 ± 2 µm).

    Conclusion: Colitic rats have a thicker firmly adherent colonic mucus layer and this effect is mediated by iNOS. Prostaglandins are involved in the regulation of base line mucus secretion.

     

     

  • 207.
    Schreiber, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Perry, M.
    Roos, S.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lactobacillus reuteri prevents colitis by reducing P-selectin-associated leukocyte- and platelet-endothelial cell interactions2009In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 296, no 3, p. G534-G542Article in journal (Refereed)
    Abstract [en]

    Recent findings indicate that dextran sodium sulfate (DSS)-induced colitis is associated with a prothrombogenic phenotype, with P-selectin playing a major role in platelet recruitment. It has been suggested that probiotics may ameliorate colonic inflammation. We therefore investigated how treatment with Lactobacillus reuteri influenced P-selectin expression, leukocyte and platelet endothelial cell interactions, and colitis severity in DSS-treated rats. Rats were divided into the following four groups: nontreated, DSS treated (5% in drinking water for 9 days), L. reuteri, and L. reuteri and DSS treated. The rats were anesthetized with Inactin (120 mg/kg ip), and the dual radiolabeled monoclonal antibody technique was used to quantify P-selectin expression. Leukocyte-endothelial and platelet-endothelial cell interactions were studied in colonic venules with intravital microscopy. Colitis severity was assessed using a disease activity index. Disease activity index increased, as did the expression of P-selectin in the entire colon after DSS treatment, but both were reduced to control levels with L. reuteri pretreatment. The increased platelet- and leukocyte-endothelial cell interactions after DSS treatment were abolished by pretreatment with L. reuteri. L. reuteri protects against DSS-induced colitis in rats. The protection is associated with reduced P-selectin expression and a decrease in leukocyte- and platelet-endothelial cell interactions.

  • 208.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Implanted biomaterials: Neutrophil-mediated vascularization2017In: NATURE BIOMEDICAL ENGINEERING, ISSN 2157-846X, Vol. 1, no 6, article id UNSP 0086Article in journal (Other academic)
  • 209.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Tissue hypoxia induces the mobilisation from the spleen of pro-angiogenic neutrophils through the activation of sympathetic nerves2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 78-78Article in journal (Other academic)
  • 210.
    Sendeski, Mauricio
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Patzak, Andreas
    Pallone, Thomas L
    Cao, Chunhua
    Persson, A Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, Pontus B
    Iodixanol, Constriction of Medullary Descending Vasa Recta, and Risk for Contrast Medium-induced Nephropathy2009In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 251, no 3, p. 697-704Article in journal (Refereed)
    Abstract [en]

    Purpose: To determine whether a type of contrast medium (CM), iodixanol, modifies outer medullary descending vasa recta (DVR) vasoreactivity and nitric oxide (NO) production in isolated microperfused DVR. Materials and Methods: Animal handling conformed to the Animal Care Committee Guidelines of all participating institutions. Single specimens of DVR were isolated from rats and perfused with a buffered solution containing iodixanol. A concentration of 23 mg of iodine per milliliter was chosen to mimic that expected to be used in usual examinations in humans. Luminal diameter was determined by using video microscopy, and NO was measured by using fluorescent techniques. Results: Iodixanol led to 52% reduction of DVR luminal diameter, a narrowing that might interfere with passage of erythrocytes in vivo. Vasoconstriction induced by angiotensin II was enhanced by iodixanol. Moreover, iodixanol decreased NO bioavailability by more than 82%. Use of 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (a superoxide dismutase mimetic) prevented both vasoconstriction with iodixanol alone and increased constriction with angiotensin II caused by CM. Conclusion: Iodixanol in doses typically used for coronary interventions constricts DVR, intensifies angiotensin II-induced constriction, and reduces bioavailability of NO. CM-induced nephropathy may be related to these events and scavenging of reactive oxygen species might exert a therapeutic benefit by preventing the adverse effects that a CM has on medullary perfusion.

  • 211. Shepherd, C. E.
    et al.
    Goyette, J.
    Utter, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rahimi, F.
    Yang, Z.
    Geczy, C. L.
    Halliday, G. M.
    Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease2006In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 27, no 11, p. 1554-1563Article in journal (Refereed)
    Abstract [en]

    Inflammation, insoluble protein deposition and neuronal cell loss are important features of the Alzheimer's disease (AD) brain. S100B is associated with the neuropathological hallmarks of AD where it is thought to play a role in neuritic pathology. S100A8, S100A9 and S100A12 comprise anew group of inflammation-associated proteins that are constitutively expressed by neutrophils and inducible in numerous inflammatory cells. We investigated expression of S100B, S100A8, S100A9 and S100A12 in brain samples from sporadic and familial (PS-1) AD cases and controls using immunohistochemistry and Western blot analysis. S100B, S100A9 and S100A12, but not S100A8, were consistently associated with the neuropathological hallmarks of AD. Western blot analysis confirmed significant increases in soluble S100A9 in PS-1 AD compared to controls. S100A9 complexes that were resistant to reduction were also evident in brain extracts. A reactive component of a size consistent with hexameric S100A12 was seen in all cases. This study indicates a potential role for pro-inflammatory S100A9 and S100A12 in pathogenesis caused by inflammation and protein complex formation in AD.

  • 212.
    Shore, Richard
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp, Funct Perioperat Med & Intens Care, S-17176 Stockholm, Sweden..
    Bjorne, Hakan
    Karolinska Univ Hosp, Funct Perioperat Med & Intens Care, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Omoto, Yoko
    Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Endocrine & Breast Surg, Kamigyo Ku, 465 Kajii Cho, Kyoto 6020841, Japan..
    Siemiatkowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Gustafsson, Jan-Åke
    Univ Houston, Ctr Nucl Receptors & Cell Signalling, Houston, TX 77004 USA..
    Lindblad, Mats
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, S-14186 Stockholm, Sweden..
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Sex differences and effects of oestrogen in rat gastric mucosal defence2017In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 23, no 3, p. 426-436Article in journal (Refereed)
    Abstract [en]

    AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence. METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry. RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 +/- 0.12 mL/min.g in males and 0.51 +/- 0.03 mL/min.g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 +/- 1 mu m and 80 +/- 3 mu m respectively. After 60 min the mucus thickness increased to 113 +/- 3 mu m in males and 121 +/- 3 mu m in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 mu g/kg.min), mean blood flow in the gastric mucosa decreased by 31% [68 +/- 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 +/- 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 +/- 0.04 to 1.1 +/- 0.1 mL/min.100 g in males and 0.4 +/- 0.3 to 2.1 +/- 0.3 mL/min.100 g in females (P = 0.065)]. There were no significant differences between 17 beta-Estradiol treated males (mean ratio of positive staining +/- SEM) (0.06 +/- 0.07) and females (0.11 +/- 0.11) in the staining of ER alpha (P = 0.24). Also, there were no significant differences between 17 beta-Estradiol treated males (0.18 +/- 0.21) and females (0.06 +/- 0.12) in the staining of ER beta (P = 0.11). Finally, there were no significant differences between 17 beta-Estradiol treated males (0.04 +/- 0.05) and females (0.11 +/- 0.10) in the staining of CGRP (P = 0.14). CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.

  • 213. Singh, Prabhleen
    et al.
    Ricksten, Sven-Erik
    Bragadottir, Gudrun
    Redfors, Bengt
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 138-147Article, review/survey (Refereed)
    Abstract [en]

    Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.

  • 214.
    Sivertsson, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala Univ, Div Integrat Physiol, Dept Med Cell Biol, Uppsala, Sweden.
    Friederich Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Öberg, Carl M.
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Rippe, Bengt
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability2018In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 5, p. F864-F872Article in journal (Refereed)
    Abstract [en]

    An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

  • 215. Skogstrand, Trude
    et al.
    Leh, Sabine
    McClure, John
    Dashti, Mohammed
    Iversen, Bjarne M
    Graham, Delyth
    McBride, Martin W
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Identification of a common molecular pathway in hypertensive renal damage: comparison of rat and human gene expression profiles2015In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 33, no 3, p. 584-596Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex.

    METHOD: The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system. Gene-expression profiles were determined using microarrays and validated using a panel of 47 genes by quantitative real-time PCR.

    RESULTS: All groups showed kidney damage (SHRs: 0.32 ± 0.09 vs. Wistar-Kyoto rats: 0.06 ± 0.03; 2K1C: 0.27 ± 0.13 vs. pooled controls: 0.01 ± 0.01; SHRSP: 1.13 ± 0.14 vs. WKY: 0.04 ± 0.03; all P < 0.05). A total of 1614 genes were changed in the SHR experiment, 1323 in the SHRSP, and 576 in the 2K1C. Eighty-eight genes were similarly regulated in all three models. Gene ontology enrichment analysis identified 59 ontologies that were enriched in all three datasets. These included over-representation to extracellular matrix, response to oxidative stress, and immune system processes. Out of the 88 in-common genes, 40 could be connected in a common pathway that was compared to two gene-expression profiles from human kidneys with histologically verified fibrosis to identify a highly significant number of in-common genes that were also represented in the common genetic pathway.

    CONCLUSION: There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.

  • 216. Skogstrand, Trude
    et al.
    McBride, Martin
    McClure, John
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal extracellular matrix in three rat-models of hypertensive kidney damage: A microarray study of SHR, SHRSP and 2K1C2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 217. Smith, S M
    et al.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Perry, M A
    Grisham, M B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Arfors, K E
    Granger, D N
    Kvietys, P R
    Role of neutrophils in hemorrhagic shock-induced gastric mucosal injury in the rat1987In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 93, no 3, p. 466-471Article in journal (Refereed)
    Abstract [en]

    Gastric mucosal clearance of 51Cr-labeled red blood cells (51Cr-RBC) was measured in rats during a 30-min control period, a 30-min ischemic period (hemorrhage to 27 mmHg arterial pressure), and a 60-min reperfusion period (reinfusion of shed blood). In untreated (control) rats, a dramatic rise in the leakage of 51Cr-labeled red blood cells into the gastric lumen was observed during the reperfusion period. Treatment with neutrophil antiserum attenuated 51Cr-labeled red blood cell flux into the gastric lumen. Using the radioactive microsphere technique, neutrophil-depleted animals were shown to have higher blood flows in the ischemic period than the untreated rats. Bleeding of untreated rats to a mean arterial pressure of 40 mmHg resulted in blood flows that were not different from those in antiserum-treated rats bled to 27 mmHg and leakage of 51Cr-labeled red blood cells similar to that measured in antiserum-treated rats. The results of this study indicate that neutrophils play an important role in hemorrhagic shock-induced gastric bleeding.

  • 218.
    Stridh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Regulation of Renal Hyaluronan in Water Handling: Studies in vivo and in vitro2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hyaluronan (HA) is a negatively charged extracellular matrix (ECM) component with water-attracting properties. It is the dominating ECM component in the renal medullary interstitium, where the amount changes in relation to hydration status: it increases during hydration and decreases during dehydration. It has, therefore, been suggested that HA participates in the regulation of renal fluid handling by changing the permeability properties of the interstitial space. This thesis investigates potential mechanisms for such a role in renal fluid regulation.

    The results demonstrate that the high renal HA content of late nephrogenesis decreases during the completion of kidney development in the rat, which takes place in the neonatal period. The heterogenous distribution of HA is mainly established during the first three weeks after birth. On day 21, the HA content is similar to that in the adult rat. The process is dependent on normal Ang II function. It primarily involves a reduction of HA synthase 2 expression and an increase of medullary hyaluronidase 1. 

    The cortical accumulation of HA that results from neonatal ACE inhibition can partly explain the pathological condition of the adult kidney, which causes reduced urinary concentration ability and tubulointerstitial inflammation.

    It is possible to reduce renomedullary HA with the HA synthesis inhibitor 4-MU, and the kidney’s ability to respond to a hydration challenge will then be suppressed, without affecting GFR. 

    The investigation of renomedullary interstitial cells (RMIC) in culture, shows that media osmolality and hormones of central importance for body fluid homeostasis, such as angiotensin II, ADH and endothelin, affect HA turnover through their effect on the RMICs, in a manner comparable to that found in vivo during changes in hydration status. 

    In established streptozotocin-induced diabetes, HA is regionally accumulated in the kidney, proteinuria and polyuria, reduced urine osmolality, and reduced response to ADH V2 activation will occur. As opposed to the proteinuria, the HA accumulation is not sensitive to mTOR inhibition, suggesting an alternate pathway compared to other ECM components 

    Taken together, the data suggest that during normal physiological conditions, renomedullary interstitial HA participates in renal fluid handling by affecting the interstitial prerequisites for fluid flux across the interstitial space. This is possible due to the water-attracting and physicochemical properties of this glycosaminoglycan. During pathological conditions, such as diabetes, the elevated interstitial HA can contribute to the defective kidney function, due to the proinflammatory and water-attracting properties of HA.

    List of papers
    1. Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1
    Open this publication in new window or tab >>Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1
    Show others...
    2011 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 30, no 1, p. 62-69Article in journal (Refereed) Published
    Abstract [en]

    A functional renin-angiotensin system (RAS) is required for normal kidney development. Neonatal inhibition of the RAS in rats results in long-term pathological renal phenotype and causes hyaluronan (HA), which is involved in morphogenesis and inflammation, to accumulate. To elucidate the mechanisms, intrarenal HA content was followed during neonatal completion of nephrogenesis with or without angiotensin converting enzyme inhibition (ACEI) together with mRNA expression of hyaluronan synthases (HAS), hyaluronidases (Hyal), urinary hyaluronidase activity and cortical lymphatic vessels, which facilitate the drainage of HA from the tissue. In 6-8days old control rats cortical HA content was high and reduced by 93% on days 10-21, reaching adult low levels. Medullary HA content was high on days 6-8 and then reduced by 85% to 12-fold above cortical levels at day 21. In neonatally ACEI-treated rats the reduction in HA was abolished. Temporal expression of HAS2 corresponded with the reduction in HA content in the normal kidney. In ACEI-treated animals cortical HAS2 remained twice the expression of controls. Medullary Hyal1 increased in controls but decreased in ACEI-treated animals. Urine hyaluronidase activity decreased with time in control animals while in ACEI-treated animals it was initially 50% lower and did not change over time. Cells expressing the lymphatic endothelial mucoprotein podoplanin in ACEI-treated animals were increased 18-fold compared to controls suggesting compensation. In conclusion, the high renal HA content is rapidly reduced due to reduced HAS2 and increased Hyal1 mRNA expressions. Normal angiotensin II function is crucial for inducing these changes. Due to the extreme water-attracting and pro-inflammatory properties of HA, accumulation in the neonatally ACEI-treated kidneys may partly explain the pathological renal phenotype of the adult kidney, which include reduced urinary concentration ability and tubulointerstitial inflammation.

    Keywords
    Nephrogenesis, Lymphatic vessel, Podoplanin, HAS2, Hyal1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-151774 (URN)10.1016/j.matbio.2010.09.006 (DOI)000287548300008 ()20933085 (PubMedID)
    Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2017-12-11Bibliographically approved
    2. Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration
    Open this publication in new window or tab >>Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration
    2013 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 217-221Article in journal (Refereed) Published
    Abstract [en]

    Background. Hyaluronan (HA) is the dominant glycosaminoglycan in the renomedullary interstitium. Renomedullary HA has been implicated in tubular fluid handling due to its water-attracting properties and the changes occurring in parallel to acute variations in the body hydration status.

    Methods. HA production was inhibited by 4-methylumbelliferone (4-MU in drinking water for 5 days, 1.45 ± 0.07 g/day/kg body weight) in rats prior to hydration.

    Results. Following hypotonic hydration for 135 min in control animals, diuresis and osmotic excretion increased while sodium excretion and glomerular filtration rate (GFR) remained unchanged. The medullary and cortical HA contents were 7.85 ± 1.29 ng/mg protein and 0.08 ± 0.01 ng/mg protein, respectively. Medullary HA content after 4-MU was 38% of that in controls (2.98 ± 0.95 ng/g protein, p < 0.05), while the low cortical levels were unaffected. Baseline urine flow was not different from that in controls. The diuretic response to hydration was, however, only 51% of that in controls (157 ± 36 versus 306 ± 54 µl/g kidney weight/135 min, p < 0.05) and the osmolar excretion only 47% of that in controls (174 ± 47 versus 374 ± 41 µOsm/g kidney weight/135 min, p < 0.05). Sodium excretion, GFR, and arterial blood pressure were similar to that in control rats and unaltered during hydration.

    Conclusions. Reduction of renomedullary interstitial HA using 4-MU reduces the ability of the kidney to respond appropriately upon acute hydration. The results strengthen the concept of renomedullary HA as a modulator of tubular fluid handling by changing the physicochemical properties of the interstitial space.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-209756 (URN)10.3109/03009734.2013.834013 (DOI)000325527300002 ()
    Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2018-01-11Bibliographically approved
    3. Hyaluronan turnover by  renomedullary interstitial cells.  Influence of fluid regulating hormones
    Open this publication in new window or tab >>Hyaluronan turnover by  renomedullary interstitial cells.  Influence of fluid regulating hormones
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-209760 (URN)
    Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2018-01-11
    4. Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan
    Open this publication in new window or tab >>Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan
    Show others...
    2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 4, p. 233-240Article in journal (Refereed) Published
    Abstract [en]

    Objectives. Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation.Methods. Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested.Results. Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected.Conclusion. Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.

    Keywords
    Diabetes mellitus; hyaluronan; hyaluronidase; mTOR; nephropathy; rapamycin
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-209761 (URN)10.3109/03009734.2015.1062442 (DOI)000365684900002 ()26175092 (PubMedID)
    Funder
    Swedish Research Council, 10840
    Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2018-01-11
  • 219.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kerjaschki, D
    Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.
    Chen, Y
    Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rügheimer, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Åstrand, A B M
    Department of Physiology, Institute of Physiology and Pharmacology, Gothenburg University, Gothenburg, Sweden.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Friberg, P
    Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Takahashi, T
    Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
    Ikegami-Kawai, M
    Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 12011In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 30, no 1, p. 62-69Article in journal (Refereed)
    Abstract [en]

    A functional renin-angiotensin system (RAS) is required for normal kidney development. Neonatal inhibition of the RAS in rats results in long-term pathological renal phenotype and causes hyaluronan (HA), which is involved in morphogenesis and inflammation, to accumulate. To elucidate the mechanisms, intrarenal HA content was followed during neonatal completion of nephrogenesis with or without angiotensin converting enzyme inhibition (ACEI) together with mRNA expression of hyaluronan synthases (HAS), hyaluronidases (Hyal), urinary hyaluronidase activity and cortical lymphatic vessels, which facilitate the drainage of HA from the tissue. In 6-8days old control rats cortical HA content was high and reduced by 93% on days 10-21, reaching adult low levels. Medullary HA content was high on days 6-8 and then reduced by 85% to 12-fold above cortical levels at day 21. In neonatally ACEI-treated rats the reduction in HA was abolished. Temporal expression of HAS2 corresponded with the reduction in HA content in the normal kidney. In ACEI-treated animals cortical HAS2 remained twice the expression of controls. Medullary Hyal1 increased in controls but decreased in ACEI-treated animals. Urine hyaluronidase activity decreased with time in control animals while in ACEI-treated animals it was initially 50% lower and did not change over time. Cells expressing the lymphatic endothelial mucoprotein podoplanin in ACEI-treated animals were increased 18-fold compared to controls suggesting compensation. In conclusion, the high renal HA content is rapidly reduced due to reduced HAS2 and increased Hyal1 mRNA expressions. Normal angiotensin II function is crucial for inducing these changes. Due to the extreme water-attracting and pro-inflammatory properties of HA, accumulation in the neonatally ACEI-treated kidneys may partly explain the pathological renal phenotype of the adult kidney, which include reduced urinary concentration ability and tubulointerstitial inflammation.

  • 220.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Linköping university.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 217-221Article in journal (Refereed)
    Abstract [en]

    Background. Hyaluronan (HA) is the dominant glycosaminoglycan in the renomedullary interstitium. Renomedullary HA has been implicated in tubular fluid handling due to its water-attracting properties and the changes occurring in parallel to acute variations in the body hydration status.

    Methods. HA production was inhibited by 4-methylumbelliferone (4-MU in drinking water for 5 days, 1.45 ± 0.07 g/day/kg body weight) in rats prior to hydration.

    Results. Following hypotonic hydration for 135 min in control animals, diuresis and osmotic excretion increased while sodium excretion and glomerular filtration rate (GFR) remained unchanged. The medullary and cortical HA contents were 7.85 ± 1.29 ng/mg protein and 0.08 ± 0.01 ng/mg protein, respectively. Medullary HA content after 4-MU was 38% of that in controls (2.98 ± 0.95 ng/g protein, p < 0.05), while the low cortical levels were unaffected. Baseline urine flow was not different from that in controls. The diuretic response to hydration was, however, only 51% of that in controls (157 ± 36 versus 306 ± 54 µl/g kidney weight/135 min, p < 0.05) and the osmolar excretion only 47% of that in controls (174 ± 47 versus 374 ± 41 µOsm/g kidney weight/135 min, p < 0.05). Sodium excretion, GFR, and arterial blood pressure were similar to that in control rats and unaltered during hydration.

    Conclusions. Reduction of renomedullary interstitial HA using 4-MU reduces the ability of the kidney to respond appropriately upon acute hydration. The results strengthen the concept of renomedullary HA as a modulator of tubular fluid handling by changing the physicochemical properties of the interstitial space.

  • 221.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal interstitial hyaluronan: functional aspects during normal and pathological conditions2012In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 302, no 11, p. R1235-R1249Article, review/survey (Refereed)
    Abstract [en]

    The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physico-chemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the back-ground of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.

  • 222.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats2009In: Oxygen transport to tissue xxx / [ed] Per Liss, New York: Springer, 2009, Vol. 645, p. 219-225Chapter in book (Refereed)
    Abstract [en]

    Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.

  • 223. Sun, Zuyue
    et al.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kutschera, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sundvold-Gjerstad, Vibeke
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Choy, Wing Wen
    Zang, Guangxiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Abid, Md Ruhul
    Spurkland, Anne
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd2012In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 209, no 7, p. 1363-1377Article in journal (Refereed)
    Abstract [en]

    Regulation of vascular endothelial (VE) growth factor (VEGF)-induced permeability is critical in physiological and pathological processes. We show that tyrosine phosphorylation of VEGF receptor 2 (VEGFR2) at Y951 facilitates binding of VEGFR2 to the Rous sarcoma (Src) homology 2-domain of T cell-specific adaptor (TSAd), which in turn regulates VEGF-induced activation of the c-Src tyrosine kinase and vascular permeability. c-Src was activated in vivo and in vitro in a VEGF/TSAd-dependent manner, and was regulated via increased phosphorylation at pY418 and reduced phosphorylation at pY527. Tsad silencing blocked VEGF-induced c-Src activation, but did not affect pathways involving phospholipase C gamma, extracellular regulated kinase, and endothelial nitric oxide. VEGF-induced rearrangement of VE-cadherin-positive junctions in endothelial cells isolated from mouse lungs, or in mouse cremaster vessels, was dependent on TSAd expression, and TSAd formed a complex with VE-cadherin, VEGFR2, and c-Src at endothelial junctions. Vessels in tsad(-/-) mice showed undisturbed flow and pressure, but impaired VEGF-induced permeability, as measured by extravasation of Evans blue, dextran, and microspheres in the skin and the trachea. Histamine-induced extravasation was not affected by TSAd deficiency. We conclude that TSAd is required for VEGF-induced, c-Src-mediated regulation of endothelial cell junctions and for vascular permeability.

  • 224.
    Sundbom, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Almqvist, Catarina
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Insomnia symptoms and asthma control – interrelations and importance of comorbiditiesManuscript (preprint) (Other academic)
    Abstract [en]

    Background

     

    Insomnia symptoms are common with asthma. The aim of the study was to analyze the associations between insomnia symptoms and asthma control, asthma severity, and asthma-related comorbidity in a community-based population.

     

    Methods

    Adults (n=23,875, ages 18-45) from the community-based LifeGene study answered a questionnaire on insomnia symptoms, airway symptoms, asthma diagnosis, asthma medication, and asthma-related comorbidities (chronic rhinosinusitis, gastro-esophageal reflux, anxiety, depression, or obesity).

     

    Results

    Of the participants, 1,272 (5.3%) had asthma. The prevalence of any insomnia symptom was higher in participants with uncontrolled asthma (n=201) than with controlled or partially controlled asthma (32.2% vs. 19.9% and 20.1%, respectively, p<0.01). There was no significant difference in the prevalence of insomnia symptoms between subjects with controlled asthma and subjects without asthma. 

     

    Subjects with asthma and any asthma-related comorbidity reported more insomnia symptoms (29.0% vs. 22.4%, p<0.01) compared to asthmatics without comorbidity. Moreover, the prevalence was highest among subjects reporting both uncontrolled asthma and any asthma-related comorbidity (45.1%, p<0.01).

     

    Uncontrolled asthma remained significantly associated with insomnia symptoms (OR 1.72 (1.15-2.56)) after adjusting for age, sex, BMI, smoking history, comorbidities, physical activity, and educational level, while medication level was not. Among asthma-related comorbidities, chronic rhinosinusitis (OR 1.62 (1.20-2.19)), obesity (1.87 (1.07-3.25)), and depression (OR 1.85 (1.34-2.55)) were independently associated with insomnia symptoms. 

     

    Conclusion

     

    Uncontrolled asthma was significantly associated with insomnia symptoms, while controlled or partially controlled asthma was not. Asthma-related comorbidity is of great importance, and asthma control seems to be more important than asthma severity for sleep quality.

  • 225.
    Synnerstad, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Johansson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Intraluminal acid and gastric mucosal integrity: the importance of blood-borne bicarbonate.2001In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 280, no 1, p. G121-G129Article in journal (Refereed)
    Abstract [en]

    The acid-secreting gastric mucosa resists intraluminal acid better than the nonsecreting. Here we investigated pH at the epithelial cell surface, mucosal permeability, and blood flow during intraluminal administration of acid (100 mM) in acid-stimulated and nonstimulated gastric corpus mucosae. Surface pH (H(+)-selective microelectrodes), permeability (clearance of (51)Cr-EDTA), and mucosal blood flow (laser-Doppler flowmetry) were studied in Inactin-anesthetized rats. Acid secretion was stimulated with pentagastrin (40 microg. kg(-1). h(-1)) or impromidine (500 microg. kg(-1). h(-1)), or HCO(3)(-) (5 mmol. kg(-1). h(-1)) given intravenously. Surface pH was only slightly reduced by intraluminal acid in acid secretion-stimulated or HCO(3)(-)-treated rats but was substantially lowered in nonstimulated rats. Clearance increased threefold and blood flow increased by approximately 75% in nonstimulated rats. During stimulated acid secretion or intravenous infusion of HCO(3)(-), clearance was unchanged and blood flow increased by only approximately 30% during intraluminal acid. Increased epithelial transport of HCO(3)(-) buffering the mucus gel is most probably the explanation for the acid-secreting mucosa being less vulnerable to intraluminal acid than the nonsecreting.

  • 226.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jensen, Boye L
    Skøtt, Ole
    Brown, Russell D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Neuronal nitric oxide synthase-deficient mice have impaired renin release but normal blood pressure2008In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nitric oxide deficiency is involved in the development of hypertension, but the mechanisms are currently unclear. This study was conducted to further elucidate the role of neuronal nitric oxide synthase (nNOS) in blood pressure regulation and renin release in relation to different sodium loads. METHODS: Blood pressure and heart rate were measured telemetrically and assessed during periods of physical activity and inactivity. Urinary solute excretion was measured by metabolism cages and plasma renin concentration (PRC) was determined by radioimmunoassay; all in nNOS knockout (nNOS(-/-)) and wild-type (nNOS(+/+)) mice after 10 days of low (0.01% NaCl) and high (4% NaCl) sodium diets. RESULTS: The resting heart rate was reduced in nNOS(-/-) mice, but the two genotypes had similar blood pressure during the low (nNOS(+/+) 104 +/- 2 mm Hg; nNOS(-/-) 103 +/- 2 mm Hg) and high (nNOS(+/+) 107 +/- 3 mm Hg; nNOS(-/-) 108 +/- 2 mm Hg) sodium diets. During the high sodium diet, PRC did not differ between the genotypes (nNOS(+/+) 743 +/- 115 10(-5) Goldblatt units; nNOS(-/-) 822 +/- 63 10(-5) Goldblatt units), but during the low sodium diet, nNOS(-/-) mice failed to increase PRC (nNOS(+/+) 2164 +/- 220 10(-5) Goldblatt units; nNOS(-/-) 907 +/- 101 10(-5) Goldblatt units) and renal renin mRNA. On the low sodium diet, nNOS(-/-) mice also showed increased urine flow rate and osmolar excretion, observations not made during a high sodium diet. CONCLUSIONS: Our results show that nNOS is necessary for stimulation of renin in response to sodium restriction. Furthermore, nNOS(-/-) mice are normotensive, and their blood pressure responds normally to an increased dietary sodium intake, indicating that nNOS deficiency does not cause salt-sensitive hypertension.

  • 227.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fredholm, Bertil B.
    Kouzmine, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    High-protein-induced glomerular hyperfiltration is independent of the tubuloglomerular feedback mechanism and nitric oxide synthases2010In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 299, no 5, p. R1263-R1268Article in journal (Refereed)
    Abstract [en]

    A high protein intake is associated with increased glomerular filtration rate (GFR), which has been suggested to be mediated by reduced signaling of the tubuloglomerular feedback (TGF) mechanism. Nitric oxide (NO) has been shown to contribute to high protein-induced glomerular hyperfiltration, but the specific NO synthase (NOS) isoform responsible is not clear. In this study, a model for high-proteininduced hyperfiltration in conscious mice was developed. Using this model, we investigated the role of TGF using adenosine A(1)-receptor knockout mice lacking the TGF mechanism. Furthermore, the role of the different NOS isoforms was studied using neuronal-, inducible-, and endothelial-NOS knockout mice, and furthermore, wild-type mice acutely administered with the unspecific NOS inhibitor N-omega-nitro-L-arginine methyl ester (100 mg/kg). GFR was measured consecutively in mice given a low-protein diet (8% casein) for 10 days, followed by a high-protein diet (50% casein) for 10 days. All mice developed high protein-induced hyperfiltration to a similar degree. These results demonstrate that high protein-induced glomerular hyperfiltration is independent of the TGF mechanism and NOS isoforms.

  • 228.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Engström, Terese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fredholm, Bertil
    Fysiologi och Farmakologi, Karolinska Institutet.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inhibition of sodium-linked glucose reabsorption in the kidney normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor-deficient mice2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 2, p. 440-445Article in journal (Refereed)
    Abstract [en]

    Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. In this study, we investigated the role of the increased tubular sodium/glucose co-transport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback mechanism (TGF), we used adenosine A1-receptor deficient (A1AR-/-) mice known to lack a functional TGF mechanism, and compared the results to corresponding wild-type animals (A1AR+/+). Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose co-transporters were inhibited by phlorizin 30 minutes prior to GFR measurements. Normoglycemic animals had a similar GFR independent of genotype, and induction of diabetes resulted in similar glomerular hyperfiltration in both groups. Phlorizin had no effect on GFR in normoglycemic mice, whereas it reduced GFR in both genotypes during diabetes. Notably, the reduction was more pronounced in the A1AR-/-. This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

  • 229.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jensen, Boye
    Physiology and Pharmacology, University of Southern Denmark.
    Skøtt, Ole
    Physiology and Pharmacology, University of Southern Denmark.
    Xiang, Gao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 32010In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 23, no 11, p. 1241-1246Article in journal (Refereed)
    Abstract [en]

    Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells.

    Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3.

    Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively.

    Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.

    Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.

  • 230.
    Teerlink, Tom
    et al.
    VU Medisch Centrum, Amsterdam.
    Luo, Zaiming
    Georgetown University.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wilcox, Christopher S
    Georgetown University.
    Cellular ADMA: regulation and action.2009In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 60, no 6, p. 448-460Article, review/survey (Refereed)
    Abstract [en]

    Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.

  • 231.
    Thålin, Charlotte
    et al.
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Lundström, Staffan
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm; Karolinska Inst, Dept Oncol Pathol, Stockholm.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Daleskog, Maud
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Lundström, Annika
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Henriksson, Peter
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm.
    Helleday, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wallen, Håkan
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm.
    Demers, Melanie
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Internal Med, Stockholm.
    Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0191231Article in journal (Refereed)
    Abstract [en]

    Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

  • 232. Tiwari, Swasti
    et al.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Halagappa, Veerendra K Madala
    Ecelbarger, Carolyn A
    Trafficking of ENaC subunits in response to acute insulin in mouse kidney2007In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 293, no 1, p. F178-F185Article in journal (Refereed)
    Abstract [en]

    Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice (n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1-2 h) sodium excretion and kidney ENaC subunits (alpha, beta, and gamma) and serum and glucocorticoid-induced kinase (SGK-1) regulation. Insulin resulted in a significant reduction in urine sodium (by approximately 80%) that was restored by intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26-103%) for insulin- relative to vehicle-treated mice for alpha- and gamma-ENaC in the homogenate (H), and plasma membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly, beta-ENaC was significantly increased in MF (by 45%) but no change in the H. It was, however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of alpha-, beta-, and gamma-ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, Western blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.

  • 233.
    Tolf, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Integrin and VEGFR profiles of different neutrophil populations2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 234.
    Turner, Anita J.
    et al.
    Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia.;Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Brown, Russell D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia.
    Brandon, Amanda E.
    Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia.
    Gibson, Karen J.
    Univ New South Wales, Sch Med Sci, Dept Physiol, Sydney, NSW, Australia..
    Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 313, no 4, p. F864-F873Article in journal (Refereed)
    Abstract [en]

    Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomcrular.filtration rate. or electrolyte excretion rates between the.Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex treatedfetuses was significantly lower (12.9 +/- 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 +/- 1.0 til/min). This resetting of TOE sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TOE sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TOE response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.

  • 235. Turner, Anita J
    et al.
    Brown, Russell D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Gibson, Karen J
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Mechanisms of neonatal increase in glomerular filtration rate2008In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 295, no 3, p. R916-21Article in journal (Refereed)
    Abstract [en]

    To investigate the mechanisms responsible for the neonatal increase in glomerular filtration rate (GFR), renal function studies (whole kidney and micropuncture) were carried out in anesthesized fetal sheep (133-140 days gestation; term = 150 days) and lambs (12-18 days). Fetuses were delivered and placed in a water bath (39.5 degrees C), keeping the umbilical cord moist and intact. Lambs were studied on a thermostatically controlled heating pad. Animals were prepared for either blood flow studies or micropuncture measurements. Expected differences in blood composition and cardiovascular and renal function were observed between fetuses and lambs, and values obtained for most variables were similar to those measured in chronically catheterized unanesthetized animals. Fetal GFR was much lower than that of lambs (0.20 vs. 0.62 ml.min(-1).g kidney(-1), P < 0.001). Free-flow, stop-flow, and net filtration pressures (NFP) were lower in the fetuses than the lambs (NFP 20.8 vs. 23.8 mmHg, P < 0.001), as was the calculated ultrafiltration coefficient (0.014 vs. 0.022 ml.min(-1).g(-1).mmHg(-1), P < 0.001). Thus, we conclude that rises in both net filtration pressure and the ultrafiltration coefficient contribute to the large increase in GFR between fetal life and approximately 2 wk after birth.

  • 236. Tveitaras, Maria Kathrine
    et al.
    Skogstrand, Trude
    Helle, Frank
    Leh, Sabine
    Reed, Rolf K.
    Chatziantoniou, Christos
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    MMP2 deficient mice are protected from hydronephrosis after unilateral urethral obstruction2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 237. Tveitarås, Maria K
    et al.
    Skogstrand, Trude
    Leh, Sabine
    Helle, Frank
    Iversen, Bjarne M
    Chatziantoniou, Christos
    Reed, Rolf K
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0143390Article in journal (Refereed)
    Abstract [en]

    Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis.

  • 238. Vethe, Heidrun
    et al.
    Finne, Kenneth
    Skogstrand, Trude
    Vaudel, Marc
    Vikse, Bjørn E
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Placier, Sandrine
    Scherer, Andreas
    Tenstad, Olav
    Marti, Hans-Peter
    Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model2015In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 33, no 1, p. 126-135Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Hypertensive nephrosclerosis is one of the most frequent causes of chronic kidney failure. Proteome analysis potentially improves the pathophysiological understanding and diagnostic precision of this disorder. In the present exploratory study, we investigated experimental nephrosclerosis in the two-kidney, one-clip (2K1C) hypertensive rat model.

    METHODS:

    The renal cortex proteome from juxtamedullary cortex and outer cortex of 2K1C male Wistar-Hannover rats (n = 4) was compared with the sham-operated controls (n = 6), using mass spectrometry-based quantitative proteomics. We combined a high abundant plasma protein depletion strategy with an extended liquid chromatographic gradient to improve peptide and protein identification. Immunohistology was used for independent confirmation of abundance.

    RESULTS:

    We identified 1724 proteins, of which 1434 were quantified with at least two unique peptides. Comparative proteomics revealed 608 proteins, including the platelet-derived growth factor receptor-β signalling pathway, with different abundances between the non-clipped kidney of hypertensive 2K1C rats and the corresponding kidney of the normotensive controls (P < 0.05, absolute fold change ≥1.5). Among the most significantly altered proteins in the whole cortex were periostin, transgelin, and creatine kinase B-type. Relative abundance of periostin alone allowed clear classification of 2K1C and controls. Enrichment of periostin in 2K1C rats was verified by immunohistology, showing positivity especially around the fibrotic vessels.

    CONCLUSION:

    The proteome is altered in hypertension-induced kidney damage. We propose periostin, especially in combination with transgelin and creatine kinase B-type, as possible proteomic classifier to distinguish hypertensive nephrosclerosis from the normal tissue. This classifier needs to be further validated with respect to early diagnosis of fibrosis, prognosis, and its potential as a novel molecular target for pharmacological interventions.

  • 239.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Exploring immune cell functions and ways to make use of them2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In addition to host defense, alternative functions of immune cells are emerging. Immune cells are crucial during healing of injured tissue, in formation of new blood vessels, angiogenesis, and also in maintaining the balance in inflammation having immune regulating functions. Over the last decade a higher degree of heterogeneity and plasticity of immune cells have been reported and immune cells develop different characteristics in different situations in vivo.

    This thesis investigates roles for immune cells in situations of muscle hypoxia and reduced blood perfusion, wound healing in skin and at sites of transplantation of allogeneic islets of Langerhans and on top of this, ways to steer immune cell function for future therapeutic purposes. A specific neutrophil subset (CD49d+VEGFR1+CXCR4high) was found to be recruited to VEGF-A released at hypoxia and these neutrophils were crucial for functional angiogenesis. In muscle with restricted blood flow macrophages were detected in perivascular positions and started to express aSMA and PDGFR1b and were found to directly assist in blood flow regulation by iNOS-dependent NO production. This essential function in muscle regain of function could be boosted by plasmid overexpression of CXCL12 where the effect of these macrophages chaperoning the vasculature was amplified improving limb blood flow regulation. The effect on macrophages accelerating tissue regeneration being amplified by CXCL12 was tested in a model of cutaneous wound healing where the administration of CXCL12 was optimized for high bioavailability. In the skin, CXCL12-treatment induced accumulation of TGFb-expressing macrophages close to the wound driving the healing process, and subsequently the wounds healed with an efficiency never reported before. In the last study means to circumvent systemic immune suppressive therapy required in allogeneic transplantation was investigated. Allogeneic islets of Langerhans transplanted to muscle were immediately destroyed by the host immune system. Co-transplanting islets and CCL22-encoding plasmids we could curb this fast rejection for 10 days by accumulating CD4+CD25+FoxP3+ regulatory T lymphocytes at the site for transplantation preventing islet grafts from being attacked by the host cytotoxic T lymphocytes.

    In summary this thesis outlines distinct immune cell subsets being essential for regain of tissue function in hypoxia, ischemia and post injury and ways to amplify specific immune cell functions in these situations that are feasible for clinical use.

    List of papers
    1. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
    Open this publication in new window or tab >>Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
    Show others...
    2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, p. 2016-2026Article in journal (Refereed) Published
    Abstract [en]

    Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-265201 (URN)10.1182/blood-2015-03-631572 (DOI)000366389200012 ()26286848 (PubMedID)
    Funder
    Swedish Research CouncilThe Royal Swedish Academy of SciencesMagnus Bergvall FoundationSwedish Diabetes AssociationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
    Available from: 2015-10-25 Created: 2015-10-25 Last updated: 2018-01-10Bibliographically approved
    2. Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscle
    Open this publication in new window or tab >>Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscle
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-299682 (URN)
    Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2016-08-26Bibliographically approved
    3. Accelerated skin wound healing by CXCL12 1a delivered on site by lactic acid bacteria
    Open this publication in new window or tab >>Accelerated skin wound healing by CXCL12 1a delivered on site by lactic acid bacteria
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-299681 (URN)
    Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2016-08-26Bibliographically approved
    4. Immunological shielding by induced recruitment of regulatory T lymphocytes delays rejection of islets transplanted to muscle
    Open this publication in new window or tab >>Immunological shielding by induced recruitment of regulatory T lymphocytes delays rejection of islets transplanted to muscle
    Show others...
    2015 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, p. 263-276Article in journal (Refereed) Published
    Abstract [en]

    The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune-suppressive regulatory T lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of immunosuppressive therapy during engraftment. Islets were co-transplanted with a plasmid encoding the chemokine CCL22 into muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were co-transplanted with pCCL22, significantly fewer effector T lymphocytes wereobserved in close proximity to the islets, leading to delayed graft rejection.As a result, diabeticrecipients co-transplanted with islets and pCCL22 intramuscularly became normoglycemic for ten consecutive days, while grafts co-transplanted with control plasmid muscle were rejected immediately leaving recipients severely hyperglycemic. Here, we propose a simple method to initially shield MHC-mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-239507 (URN)10.3727/096368914X678535 (DOI)000351251400011 ()24480306 (PubMedID)
    Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-11Bibliographically approved
  • 240.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Strategical steering of the immune system: induction of leukocyte vascular chaperoning increases functional blood flow responses in ischemic muscle2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 670.6Article in journal (Other academic)
  • 241.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Waldén, Tomas B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Immunological Shielding by Induced Recruitment of Regulatory T-Lymphocytes Delays Rejection of Islets Transplanted in Muscle2015In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, p. 263-276Article in journal (Refereed)
    Abstract [en]

    The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune-suppressive regulatory T-lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of irnmunosuppressive therapy during engraftment. Islets were cotransplanted with a plasmid encoding the chemokine CCL22 into the muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were cotransplanted with pCCL22, significantly fewer effector T-lymphocytes were observed in close proximity to the islets, leading to delayed graft rejection. As a result, diabetic recipients cotransplanted with islets and pCCL22 intramuscularly became normoglycemic for 10 consecutive days, while grafts cotransplanted with control plasmid were rejected immediately, leaving recipients severely hyperglycemic. Here we propose a simple method to initially shield MHC-mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided.

  • 242.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, Annelenen
    Proost, Paul
    Huss, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Roos, Stefan
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Accelerated skin wound healing by CXCL12 1a delivered on site by lactic acid bacteriaManuscript (preprint) (Other academic)
  • 243.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscleManuscript (preprint) (Other academic)
  • 244.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Öhnstedt, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, Anneleen
    Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium..
    Lofton Tomenius, Hava
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Huss, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery. Uppsala Univ Hosp, Dept Plast & Maxillofacial Surg, Burn Ctr, S-75185 Uppsala, Sweden.
    Proost, Paul
    Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium..
    Roos, Stefan
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Mol Sci, S-75007 Uppsala, Sweden..
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 8, p. 1895-1900Article in journal (Refereed)
    Abstract [en]

    Impaired wound closure is a growing medical problem associated with metabolic diseases and aging. Immune cells play important roles in wound healing by following instructions from the microenvironment. Here, we developed a technology to bioengineer the wound microenvironment and enhance healing abilities of the immune cells. This resulted in strongly accelerated wound healing and was achieved by transforming Lactobacilli with a plasmid encoding CXCL12. CXCL12-delivering bacteria administrated topically to wounds in mice efficiently enhanced wound closure by increasing proliferation of dermal cells and macrophages, and led to increased TGF-beta expression in macrophages. Bacteria-produced lactic acid reduced the local pH, which inhibited the peptidase CD26 and consequently enhanced the availability of bioactive CXCL12. Importantly, treatment with CXCL12-delivering Lactobacilli also improved wound closure in mice with hyperglycemia or peripheral ischemia, conditions associated with chronic wounds, and in a human skin wound model. Further, initial safety studies demonstrated that the topically applied transformed bacteria exerted effects restricted to the wound, as neither bacteria nor the chemokine produced could be detected in systemic circulation. Development of drugs accelerating wound healing is limited by the proteolytic nature of wounds. Our technology overcomes this by on-site chemokine production and reduced degradation, which together ensure prolonged chemokine bioavailability that instructed local immune cells and enhanced wound healing.

  • 245.
    Wang, R
    et al.
    Jilin Normal Univ, Sch Life Sci, Dept Biotechnol, Siping, Peoples R China.
    Zhang, W
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China.
    Dong, Z
    Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin, Peoples R China.
    Qi, Y
    Jilin Normal Univ, Sch Life Sci, Dept Biosci, Siping, Peoples R China.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zhou, X
    Jilin Normal Univ, Sch Life Sci, Dept Biosci, Siping, Peoples R China.
    Lai, E Y
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China.
    c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 2, p. 494-509Article in journal (Refereed)
    Abstract [en]

    AIM: Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of this study was to investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signalling in PVN in CHF rats.

    METHODS: Chronic heart failure was induced by left coronary ligation in Wistar rats. Renal sympathetic nerve discharge (RSND) and mean arterial pressure (MAP) responses to the PVN infusion were determined in anaesthetized rats. Osmotic minipumps were used for chronic PVN infusion. PTGER3 expression was examined with immunofluorescence staining, quantitative real-time PCR and Western blot.

    RESULTS: Chronic heart failure rats had increased JNK activation and decreased glutamate decarboxylase 1 (GAD1) and GABAA receptor alpha 1 subunit (GABRA1) expression in the PVN. PVN infusion of the PTGER3 agonist SC-46275 caused sympathoexcitation in sham-operated control (Sham) rats and increased it further in CHF. The PTGER3 antagonist L798106 reduced sympathoexcitation and cardiac dysfunction in CHF. PVN infusion of EP1 receptor antagonist SC-19220, EP2 receptor antagonist AH6809 or EP4 receptor antagonist L-161982 had no effect on sympathoexcitation. The JNK inhibitor SP600125 normalized sympathoexcitation and GAD1 and GABRA1 expression in PVN in CHF rats. Both the p44/42 and p38 mitogen-activated protein kinase inhibitors PD98059 and SB203580 could not prevent the downregulation of GAD1 and GABRA1 expression in PVN in CHF. PTGER3 agonist activated JNK but downregulated GAD1 and GABRA1 expression in NG108 neuronal cells.

    CONCLUSION: Prostaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.

  • 246. Wang, Renjun
    et al.
    Huang, Qian
    Zhou, Rui
    Dong, Zengxiang
    Qi, Yunfeng
    Li, Hua
    Wei, Xiaowei
    Wu, Hui
    Wang, Huiping
    Wilcox, Christopher S
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zhou, Xiaofu
    Lai, En Yin
    Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus2016In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 9, no 1, article id e002261Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic heart failure (CHF) increases sympathoexcitation through angiotensin II (ANG II) receptors (AT1R) in the paraventricular nucleus (PVN). Recent publications indicate both γ-aminobutyric acid B-type receptor 1 (GABBR1) and microRNA-7b (miR-7b) are expressed in the PVN. We hypothesized that ANG II regulates sympathoexcitation through homeobox D10 (HoxD10), which regulates miR-7b in other tissues.

    METHODS AND RESULTS: Ligation of the left anterior descendent coronary artery in rats caused CHF and sympathoexcitation. PVN expression of AT1R, HoxD10, and miR-7b was increased, whereas GABBR1 was lower in CHF. Infusion of miR-7b in the PVN caused sympathoexcitation in control animals and enhanced the changes in CHF. Antisense miR-7b infused in PVN normalized GABBR1 expression while attenuating CHF symptoms, including sympathoexcitation. A luciferase reporter assay detected miR-7b binding to the 3' untranslated region of GABBR1 that was absent after targeted mutagenesis. ANG II induced HoxD10 and miR-7b in NG108 cells, effects blocked by AT1R blocker losartan and by HoxD10 silencing. miR-7b transfection into NG108 cells decreased GABBR1 expression, which was inhibited by miR-7b antisense. In vivo PVN knockdown of AT1R attenuated the symptoms of CHF, whereas HoxD10 overexpression exaggerated them. Finally, in vivo PVN ANG II infusion caused dose-dependent sympathoexcitation that was abrogated by miR-7b antisense and exaggerated by GABBR1 silencing.

    CONCLUSIONS: There is an ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway in the PVN that contributes to sympathoexcitation and deterioration of cardiac function in CHF.

  • 247. Wang, Zhongli
    et al.
    Xu, Ming
    Hu, Zhengguo
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lai, Enyin
    Sex-specific prevalence of fatty liver disease and associated metabolic factors in Wuhan, south central China2014In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 26, no 9, p. 1015-1021Article in journal (Refereed)
    Abstract [en]

    Background This study aimed to investigate the sex-specific prevalence and metabolic risk factors of fatty liver disease (FLD), and to predict the prevalence of steatohepatitis with liver fibrosis in Wuhan, south central China. Methods A cross-sectional study was conducted among 25 032 participants who underwent health checkups from 2010 to 2011 in Zhongnan hospital. Results The prevalence of FLD was higher among men than among women (31.8 vs. 12.9%, P<0.0001). However, it increased markedly with age among women, and in the age-groups above 60 years, the prevalence was similar between men and women (26.4 vs. 27.6%, P>0.05). FLD was associated with obesity, increased levels of total cholesterol, triglycerides (TG), low-density lipoproteins, serum uric acid, aspartate aminotransferase, alanine aminotransferase, and fasting blood sugar, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, and a decreased level of high-density lipoprotein in both sexes. Multiple regression analyses showed that obesity, elevated levels of fasting blood sugar, TG, total cholesterol, and alanine aminotransferase, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, serum uric acid levels, and decreased high-density lipoprotein levels were related to FLD in men, whereas age played a more prominent role in women. The prevalence of steatohepatitis with advanced fibrosis, estimated using the BMI, age, ALT, and TG index (BAAT index), was 2.5% in men and 1.4% in women; more women with FLD had a BAAT score of 3 or higher compared with men (9.0 vs. 6.6%). Conclusion The prevalence of FLD in China is high among men and elderly women and is mainly related to various metabolic parameters. The prevalence of steatohepatitis with advanced fibrosis is considerably high among individuals with FLD.

  • 248. Wang, Zhongli
    et al.
    Xu, Ming
    Peng, Jianhong
    Jiang, Li
    Hu, Zhengguo
    Wang, Hua
    Zhou, Shiqing
    Zhou, Rui
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lai, En Yin
    Prevalence and associated metabolic factors of fatty liver disease in the elderly2013In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 48, no 8, p. 705-709Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate the metabolic risk factors for fatty liver disease in the elderly, and determine the prevalence of fatty liver disease in the elderly in Wuhan, central China.

    METHODS: The study was a case-control study based on all 4226 adults above 60years of age from a cohort investigated in 2010-11 at the medical examination center of Zhongnan hospital, using 3145 randomly selected adults under 60years of age from the same cohort as controls. Fatty liver disease (FLD) was identified with ultrasound imaging. The risk factors measured were body mass index (BMI), and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) and serum uric acid (SUA). The probability of steatohepatitis with advanced fibrosis was predicted using a score based on BMI, age, ALT, and TG (BAAT),and using AST/ALT ratio (AAR).

    RESULTS: FLD was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, p>0.05). BMI, TC, TG, LDL, SUA, AST and ALT were all significantly higher in FLD, whereas the level of HDL was markedly lower. Multiple regression analyses showed that obesity, high TC, TG, SUA, low HDL, and elevated ALT, AAR<1 were closely related to the elderly FLD, while male sex, obesity, high TC, TG, low HDL, elevated ALT, AST and AAR<1 were closely related to the non-elderly FLD. The prevalence of steatohepatitis with advanced fibrosis estimated as BAAT index≥3 was 2.4% in all subjects, and was higher in the elderly FLD patients than in the non-elderly FLD patients.

    CONCLUSION: The prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the non-elderly FLD controls.

  • 249. Waterhouse, Christopher C M
    et al.
    Johnson, Steven
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Zbytnuik, Lori
    Petri, Björn
    Kelly, Margaret
    Lowe, John B
    Kubes, Paul
    Secretory cell hyperplasia and defects in Notch activity in a mouse model of leukocyte adhesion deficiency type II2010In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 138, no 3, p. 1079-1090.e5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS:

    Leukocyte adhesion deficiency II (LAD II) is a rare condition caused by defective protein fucosylation, causing decreased leukocyte rolling, psychomotor retardation, and poor growth. The ligand-binding activity of Notch, a gastrointestinal signaling protein, depends on O-fucosylation. We investigated Notch signaling and intestinal epithelial architecture in a mouse model of LAD II.

    METHODS:

    Mice lacking 3,5-epimerase/4-reductase (FX) or FX(-/-) bone marrow chimeras (with either wild-type or FX(-/-) bone marrow) were maintained on a fucose-free diet. Intestinal secretory epithelial cells were quantified by histology and immunohistochemistry. Reverse transcription-polymerase chain reaction and immunoblot analyses were used to detect Notch-regulated genes in isolated crypt epithelium. Intestinal leukocyte-endothelial interaction was quantified by intravital microscopy. The intestinal epithelium of 2-week-old FX(-/-) mice was transfected with an adenoviral vector expressing a constitutively active form of Notch.

    RESULTS:

    FX(-/-) mice rapidly exhibited secretory epithelial cell hyperplasia, reduced cell proliferation, and altered epithelial gene expression patterns consistent with reduced Notch signaling. These effects were reversed when mice were given dietary fucose or by adenoviral transfection of the intestinal epithelium with the Notch intracellular domain.

    CONCLUSIONS:

    In a mouse model of LAD II, secretory cell hyperplasia occurs in the small intestine and colon; these effects depend on Notch signaling. Defects in Notch signaling might therefore be involved in the pathogenesis of this rare pediatric condition.

  • 250.
    Weigl, Wojciech
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Adamski, Jan
    Satakunta Dist Hosp, Dept Anaesthesia & Intens Care, Pori, Finland..
    Gorynski, Pawel
    Natl Inst Publ Hlth, Natl Inst Hyg, Ctr Monitoring & Anal Populat Hlth Status, Warsaw, Poland..
    Kanski, Andrzej
    Med Univ Warsaw, Cent Teaching Hosp, Dept Anesthesiol & Intens Care 2, Warsaw, Poland..
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Comparison of ICU outcomes in Poland to other European countries: reasons for high mortality rates2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1022-1023Article in journal (Other academic)
23456 201 - 250 of 258
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