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  • 1.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Strugala, V
    Allen, A
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    The adherent gastrointestinal mucus gel layer: thickness and physicalstate in vivo2001In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 280, p. G922-G929Article in journal (Refereed)
    Abstract [en]

    Divergent results from in vitro studies on the thickness and appearance of the gastrointestinal mucus layer have previously been reported. With an in vivo model, we studied mucus gel thickness over time from stomach to colon. The gastrointestinal tissues of Inactin-anesthetized rats were mounted luminal side up for intravital microscopy. Mucus thickness was measured with a micropipette before and after mucus removal by suction. The mucus layer was translucent and continuous; it was thickest in the colon (∼830 μm) and thinnest in the jejunum (∼123 μm). On mucus removal, a continuous, firmly adherent mucus layer remained attached to the epithelial surface in the corpus (∼80 μm), antrum (∼154 μm), and colon (∼116 μm). In the small intestine, this layer was very thin (∼20 μm) or absent. After mucus removal, there was a continuous increase in mucus thickness with the highest rate in the colon and the lowest rate in the stomach. In conclusion, the adherent gastrointestinal mucus gel in vivo is continuous and can be divided into two layers: a loosely adherent layer removable by suction and a layer firmly attached to the mucosa.

  • 2.
    Bengtsson, Magnus W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Mäkelä, Kari
    Oulu University, Finland.
    Herzig, Karl-Heinz
    Oulu University, Finland.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Short food deprivation inhibits orexin receptor 1 expression and orexin-A induced intracellular calcium signaling in acutely isolated duodenal enterocytes2009In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 296, no 3, p. G651-G658Article in journal (Refereed)
    Abstract [en]

    Bengtsson MW, Makela K, Herzig KH, Flemstrom G. Short food deprivation   inhibits orexin receptor 1 expression and orexin-A induced   intracellular calcium signaling in acutely isolated duodenal   enterocytes. Am J Physiol Gastrointest Liver Physiol 296: G651-G658,   2009. First published December 31, 2008;   doi:10.1152/ajpgi.90387.2008.-Close intra-arterial infusion of the   appetite regulating peptide orexin-A stimulates bicarbonate secretion   from the duodenal mucosa. The aim of the present study was to elucidate   the ability of orexin-A to induce intracellular calcium signaling in   acutely isolated duodenal enterocytes. Freshly isolated clusters of   enterocytes, obtained from rat duodenal mucosa or human duodenal   biopsies, were loaded with fura 2-AM and mounted in a perfusion   chamber. Cryptlike enterocytes were selected (caged), and changes in   intracellular calcium concentration ([Ca2+](i)) were evaluated by   fluorescence imaging. Total RNA was extracted from pellets of   enterocytes and reverse transcribed to cDNA, and expression of orexin   receptors 1 and 2 (OX1R and OX2R) was measured by quantitative   real-time PCR. Orexin-A at all concentrations tested (1-100 nM)   increased [Ca2+](i) in enterocytes isolated from continuously fed rats,   and the OX1R-antagonist SB-334867 (10 nM) attenuated the response. The   primary [Ca2+](i) response was a slow increase to a sustained plateau   persisting after orexin-A removal, and a similar response was observed   in enterocytes from human biopsies. In contrast to orexin-A, the OX2R   agonist (Ala(11), D-Leu(15))orexin-B (1-10 nM) did not induce calcium   signaling. There were no significant [Ca2+](i) responses in enterocytes   from animals food deprived overnight, and overnight fasting decreased   (P < 0.01) enterocyte OX1R as well as OX2R mRNA. Induction of   intracellular calcium signaling in isolated duodenal enterocytes is   thus mediated primarily by OX1R receptors. Short (overnight) food   deprivation markedly depresses receptor expression and inhibits   orexin-A induced increases in [Ca2+](i). Studies of enterocyte   signaling and intestinal secretion requires particular evaluation   regarding feeding status.

  • 3.
    Bengtsson, Magnus W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Uotila, Sanna
    Åkerman, Karl E. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Herzig, Karl-Heinz
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Food-induced expression of orexin receptors in rat duodenal mucosa regulates the bicarbonate secretory response to orexin-A2007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 293, no 2, p. G501-G509Article in journal (Refereed)
    Abstract [en]

    Presence of appetite-regulating peptides orexin-A and orexin-B in mucosal endocrine cells suggests a role in physiological control of the intestine. Our aim was to characterize orexin-induced stimulation of duodenal bicarbonate secretion and modulation of secretory responses and mucosal orexin receptors by overnight food deprivation. Lewis x Dark Agouti rats were anesthetized and proximal duodenum cannulated in situ. Mucosal bicarbonate secretion (pH stat) and mean arterial blood pressure were continuously recorded. Orexin-A was administered intra-arterially close to the duodenum, intraluminally, or into the brain ventricles. Total RNA was extracted from mucosal specimens, reverse transcribed to cDNA and expression of orexin receptors 1 and 2 (OX1 and OX2) measured by quantitative real-time PCR. OX1 protein was measured by Western blot. Intra-arterial orexin-A (60–600 nmol·h–1·kg–1) increased (P < 0.01) the duodenal secretion in fed but not in fasted animals. The OX1 receptor antagonist SB-334867, which was also found to have a partial agonist action, abolished the orexin-induced secretory response but did not affect secretion induced by the muscarinic agonist bethanechol. Atropine, in contrast, inhibited bethanechol but not orexin-induced secretion. Orexin-A infused into the brain ventricles (2–20 nmol·kg–1·h–1) or added to luminal perfusate (1.0–100 nM) did not affect secretion, indicating that orexin-A acts peripherally and at basolateral receptors. Overnight fasting decreased mucosal OX1 and OX2 mRNA expression (P < 0.01) as well as OX1 protein expression (P < 0.05). We conclude that stimulation of secretion by orexin-A may involve both receptor types and is independent of cholinergic pathways. Intestinal OX receptors and secretory responses are markedly related to food intake.

  • 4.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Fysiologi.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Fysiologi.
    Epithelial Cells and Their Neighbors: II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells2005In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 289, no 3, p. G377-G380Article in journal (Refereed)
    Abstract [en]

    Surface sensory enteroendocrine cells are established mucosal taste cells that monitor luminal contents and provide an important link in transfer of information from gut epithelium to the central nervous system. Recent studies now show that these cells can also mediate efferent signaling from the brain to the gut. Centrally elicited stimulation of vagal and sympathetic pathways induces release of melatonin, which acts at MT(2) receptors to increase mucosal electrolyte secretion. Psychological factors as well mucosal endocrine cell hyperplasia are implicated in functional intestinal disorders. Central nervous influence on the release of transmitters from gut endocrine cells offers an exciting area of future gastrointestinal research with a clinical relevance.

  • 5.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Åkerman, Karl EO
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin2003In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 285, no 6, p. G1091-G1096Article in journal (Refereed)
    Abstract [en]

    Orexins are involved in the central nervous control of appetite and behavior, and in addition, they are present in endocrine cells and/or neurons in the intestine. The role of these peptides in peripheral regulation of intestinal secretion has not been investigated. We thus compared the effects of orexin A and some established secretagogues on duodenal HCO3- secretion in fed rats with effects in rats exposed to short (overnight) food deprivation. Rats were anesthetized with thiobarbiturate, a 12-mm segment of proximal duodenum with intact blood supply was cannulated in situ, and the alkaline secretion was titrated by pH stat. Secretagogues were supplied specifically to the duodenum by close intra-arterial infusion. Orexin A (60-600 pmol·kg-1·h-1) caused marked and dose-dependent stimulation of the duodenal secretion in fed animals but did not affect secretion in overnight food-deprived animals. Similarly, short fasting caused a 100-fold increase in the amount of the muscarinic agonist bethanechol (from 50 to 5,000 nmol·kg-1·h-1) required for stimulation of the secretion. In contrast, the secretory responses to VIP (50-1,000 pmol·kg-1·h-1) and melatonin (20-200 nmol·kg-1·h-1) were not affected. The appetite-regulating peptide orexin A is thus a stimulant of intestinal secretion, but the response to this peptide as well as the muscarinic agonist bethanechol is markedly dependent on previous intake of food. Overnight fasting is a standard experimental procedure in studies of gastrointestinal function and pathophysiology in humans and animals. Studies made on neuroendocrine control of intestinal secretion may require reevaluation with respect to feeding status.

  • 6.
    Henriksnäs, Johanna
    et al.
    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.
    Storm, Martin
    Engstrand, Lars
    Soleimani, Manoocher
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Impaired mucus-bicarbonate barrier in Helicobacter pylori-infected mice2006In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 291, no 3, p. G396-G403Article in journal (Refereed)
    Abstract [en]

    To resist the harsh intrinsic milieu, several lines of defense exist in the stomach. The aim of this study was to investigate the effect of the gastric pathogen Helicobacter pylori on these mechanisms in vivo. We used FVB/N mice expressing human alpha-1,3/4-fucosyl transferase ( producing Lewis b epitopes) and inoculated with H. pylori 1. Mice were anesthetized with isoflurane or Hypnorm-midazolam, the stomach was exteriorized, and the surface of the corpus mucosa was exposed. Mucus thickness was measured with micropipettes, juxtamucosal pH (pH(jm)) was measured with pH-sensitive microelectrodes, blood flow was measured with laser-Doppler flowmetry, and mRNA levels of the bicarbonate transporter SLC26A9 were quantified with real-time PCR. The increase in mucosal blood flow seen in response to luminal acid (pH 1.5) in control animals (140 +/- 9% of control) was abolished in infected mice. The firmly adherent mucus layer was significantly thinner in infected mice (31 +/- 2 mu m) than in control mice (46 +/- 5 mu m), and no mucus accumulation occurred in infected mice. pHjm decreased significantly more on exposure to luminal acid in infected mice ( luminal pH 1.5, pH(jm) 2.4 +/- 0.7) than in control mice (pH(jm) 6.4 +/- 0.5). Despite reduced pHjm, SLC26A9 mRNA expression was significantly, by increased 1.9-fold, in infected mice. The reduction in pH(jm) by infection with H. pylori might be due to a reduced firmly adherent mucus layer, increased mucus permeability to H+, and/or inhibition of bicarbonate transport. The upregulation of SLC26A9 in H. pylori-infected epithelium might be a result of continuous inhibition of the transporter, e. g., by ammonium, a H. pylori product, which has been previously shown to inhibit SLC26A9.

  • 7.
    Holm, Lena
    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.
    Perry, M A
    Department of Physiology and Pharmacology, University of New South Wales, Sydney, 2052, Australia.
    NO-flurbiprofen maintains duodenal blood flow, enhances mucus secretion contributing to lower mucosal injury2002In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 283, no 5, p. G1090-G1097Article in journal (Refereed)
    Abstract [en]

    This study investigates possible mechanisms behind the reduced gastrointestinal ulcerogenicity of nitric oxide (NO)-flurbiprofen compared with flurbiprofen. The duodenal mucosa of Inactin-anaesthetised rats was exteriorized for intravital microscopy. Blood flow was measured with laser-Doppler flowmetry (LDF), mucus thickness with micropipettes, ICAM-1 and P-selectin expression with dual-labeled antibody technique, and mucosal integrity by (51)Cr-EDTA permeability. Exposure of the duodenum to flurbiprofen (1.0 mg/ml) for 90 min significantly reduced LDF to 70 +/- 4%, whereas NO-flurbiprofen (1.3 mg/ml) had no significant effect. Mucus accumulation after 60-min exposure was 75 +/- 23 microm (control), -1 +/- 17 microm (flurbiprofen), and 104 +/- 35 microm (NO-flurbiprofen). Mucosal permeability to (51)Cr-EDTA was unchanged in the control and NO-flurbiprofen groups but increased significantly from 1.0 +/- 0.2 to 3.7 +/- 0.7 microl x min(-1) x g(-1) after 90-min exposure to flurbiprofen. Expression of ICAM-1 was significantly increased after oral flurbiprofen but not by NO-flurbiprofen. Positive effects of NO-flurbiprofen compared with flurbiprofen on mucus formation, blood flow, and adhesion molecule expression likely contribute to the reduced mucosal injury observed with NO-flurbiprofen.

  • 8. Kober, Olivia
    et al.
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pin, Carmen
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carding, Simon R
    Juge, Nathalie
    γδ T-cell-deficient mice show alterations in mucin expression, glycosylation and goblet cells but maintain an intact mucus layer.2014In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 306, no 7, p. G582-G593Article in journal (Refereed)
    Abstract [en]

    Intestinal homeostasis is maintained by a hierarchy of immune defences acting in concert to minimize contact between luminal microorganisms and the intestinal epithelial cell surface. The intestinal mucus layer, covering the gastrointestinal (GI) tract epithelial cells, contributes to mucosal homeostasis by limiting bacterial invasion. In this study, we used γδ T-cell-deficient (TCRδ(-/-)) mice to examine whether and how γδ T-cells modulate the properties of the intestinal mucus layer. Increased susceptibility of TCRδ(-/-) mice to dextran sodium sulphate (DSS)-induced colitis is associated with a reduced number of goblet cells. Alterations in the number of goblet cells and crypt lengths were observed in the small intestine (SI) and colon of TCRδ(-/-) mice compared to C57BL/6 wt mice. Addition of keratinocyte growth factor (KGF) to small intestinal organoid cultures from TCRδ(-/-) mice showed a marked increase in crypt growth, and both goblet cell number and redistribution along the crypts. There was no apparent difference in the thickness or organisation of the mucus layer between TCRδ(-/-) and wt mice, as measured in vivo. However, γδ T-cell deficiency led to reduced sialylated mucins in association with increased gene expression of gel-secreting Muc2 and membrane-bound mucins, including Muc13 and Muc17. Collectively, these data provide evidence that γδ T cells play an important role in maintenance of mucosal homeostasis by regulating mucin expression and promoting goblet cell function in the small intestine.

  • 9.
    Krattinger, Regina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Thasler, Wolfgang E.
    Univ Munich, Grosshadern Hosp, Dept Gen Visceral Transplantat Vasc & Thorac Surg, Munich, Germany..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    microRNA-192 suppresses the expression of the farnesoid X receptor2016In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 310, no 11, p. G1044-G1051Article in journal (Refereed)
    Abstract [en]

    Farnesoid X receptor (FXR, NR1H4) plays an important role in the regulation of bile acid homeostasis in liver and intestine and may exert protective effects against certain forms of cancer such as colon carcinoma. However, the role of FXR in cell growth regulation, apoptosis, and carcinogenesis is still controversial. Similar to FXR, microRNA-192 (miR-192) is mainly expressed in the liver and colon and plays an important role in the pathogenesis of colon carcinoma. In this study, we investigated the extent to which FXR is regulated by miR-192. Two in silico-predicted binding sites for miR-192-3p within the NR1H4-3' untranslated region (UTR) were examined in vitro by luciferase reporter assays. Wild-type and mutated forms of the NR1H4-3' UTR were subcloned into a pmirGLO vector and cotransfected into Huh-7 cells with miR-192-3p. To study the effects of miR-192 on the expression of FXR, FXR target genes and cell proliferation, Huh-7 and Caco-2 cells were transfected with miR-192-5p and -3p mimics or antagomirs. In addition, the correlation between FXR and miR-192 expression was studied by linear regression analyses in colonic adenocarcinoma tissue from 27 patients. MiR-192-3p bound specifically to the NR1H4-3' UTR and significantly decreased luciferase activity. Transfection with miR-192 led to significant decreases in NR1H4 mRNA and protein levels as well as the mRNA levels of the FXR-inducible bile acid transporters OST alpha-OST beta and OATP1B3. Significant inverse correlations were detected in colonic adenocarcinoma between NR1H4 mRNA and miR-192-3p expression. In summary, microRNA-192 suppresses the expression of FXR and FXR target genes in vitro and in vivo.

  • 10. Malmberg, Emily K.
    et al.
    Noaksson, Karin A.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johansson, Malin E. V.
    Hinojosa-Kurtzberg, Marina
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gendler, Sandra J.
    Hansson, Gunnar C.
    Increased levels of mucins in the cystic fibrosis mouse small intestine and modulator effects of the Muc1 mucin expression2006In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 291, no 2, p. G203-G210Article in journal (Refereed)
    Abstract [en]

    The mouse model (Cftr(tm1UNC)/Cftr(tm1UNC)) for cystic fibrosis (CF) shows mucus accumulation and increased Muc1 mucin mRNA levels due to altered splicing (Hinojosa-Kurtzberg AM, Johansson MEV, Madsen CS, Hansson GC, and Gendler SJ. Am J Physiol Gastrointest Liver Physiol 284: G853-G862, 2003). However, it is not known whether Muc1 is a major mucin contributing to the increased mucus and why CF/Muc1(-/-) mice show lower mucus accumulation. To address this, we have purified mucins from the small intestine of CF mice using guanidinium chloride extraction, ultracentrifugation, and gel filtration and analyzed them by slot blot, gel electrophoresis, proteomics, and immunoblotting. Normal and CF mice with wild-type (WT) Muc1 or Muc1(-/-) or that are transgenic for human MUC1 (MUC1. Tg, on a Muc1(-/-) background) were analyzed. The total amount of mucins, both soluble and insoluble in guanidinium chloride, increased up to 10-fold in the CF mice compared with non-CF animals, whereas the CF mice lacking Muc1 showed intermediate levels between the CF and non-CF mice. However, the levels of Muc3 (orthologue of human MUC17) were increased in the CF/Muc1(-/-) mice compared with the CF/MUC1. Tg animals. The amount of MUC1 mucin was increased several magnitudes in the CF mice, but MUC1 did still not appear to be a major mucin. The amount of insoluble mucus of the large intestine was also increased in the CF mice, an effect that was partially restored in the CF/Muc1(-/-) mice. The thickness of the firmly adherent mucus layer of colon in the Muc1(-/-) mice was significantly lower than that of WT mice. The results suggest that MUC1 is not a major component in the accumulated mucus of CF mice and that MUC1 can influence the amount of other mucins in a still unknown way.

  • 11.
    Marchesi, Silvia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Ortiz-Nieto, Francisco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Roneus, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Feinstein, Ricardo
    Statens Veterinärmedicinska Anstalt, Uppsala, Sweden.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Abdominal organ perfusion and inflammation in experimental sepsis: a magnetic resonance imaging study2019In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 316, no 1, p. G187-G196Article in journal (Refereed)
    Abstract [en]

    Diffusion-weighted magnetic resonance imaging (DW-MRI) uses water as contrast and enables the study of perfusion in many organs simultaneously in situ. We used DW-MRI in a sepsis model, comparing abdominal organs perfusion with global hemodynamic measurements and inflammation. Sixteen anesthetized piglets were randomized into 3 groups: HighMAP (mean arterial pressure, MAP > 65 mmHg), LowMAP (MAP between 50 and 60 mmHg) and Healthy Controls (HC). Sepsis was obtained with endotoxin and the desired MAP maintained with noradrenaline. After 6 hours DW-MRI was performed. Acute inflammation was assessed with IL-6 and TNFα in abdominal organs, ascites, and blood and by histology of intestine (duodenum). Perfusion of abdominal organs was reduced in the LowMAP group compared to the HighMAP group and HC. Liver perfusion was still reduced by 25% in the HighMAP group compared with HC. Intestinal perfusion did not differ significantly between the study groups. Cytokines concentration were generally higher in the LowMAP group but did not correlate with global hemodynamics. However, cytokines correlated with regional perfusion and, for liver and intestine, also with intra-abdominal pressure. Histopathology of intestine worsened with decreasing perfusion. In conclusion, although a low MAP (≤60 mmHg) indicated impeded abdominal perfusion in experimental sepsis, it did not predict inflammation, nor did other global measures of circulation. Decreased abdominal perfusion predicted partially inflammation but intestine, occupying most of the abdomen, and liver, were also affected by intra-abdominal pressure.

  • 12.
    Nunez, Derek J
    et al.
    GlaxoSmithKline Res & Dev Ltd, Metab Pathways & Cardiovasc Unit & Genet, Philadelphia, PA USA.
    Alexander, Myriam
    GlaxoSmithKline Res & Dev Ltd, Stockley Pk, West Drayton, Uxbridge, England.
    Yerges-Armstrong, Laura
    GlaxoSmithKline Res & Dev Ltd, Metab Pathways & Cardiovasc Unit & Genet, Philadelphia, PA USA.
    Singh, Gurparkash
    Janssen Res & Dev, Beerse, Belgium.
    Byttebier, Geert
    Janssen Res & Dev, Beerse, Belgium.
    Fabbrini, Elisa
    Janssen Res & Dev, Raritan, NJ USA.
    Waterworth, Dawn
    GlaxoSmithKline Res & Dev Ltd, Metab Pathways & Cardiovasc Unit & Genet, Philadelphia, PA USA.
    Meininger, Gary
    Janssen Res & Dev, Raritan, NJ USA.
    Galwey, Nicholas
    GlaxoSmithKline Res & Dev Ltd, Stevenage, Herts, England.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    White, Harvey D
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.
    Vannieuwenhuyse, Bart
    Janssen Res & Dev, Beerse, Belgium.
    Alazawi, William
    Queen Mary Univ London, Barts Liver Ctr, Blizard Inst, London, England.
    Kendrick, Stuart
    GlaxoSmithKline Res & Dev Ltd, Stevenage, Herts, England.
    Sattar, Naveed
    Univ Glasgow, British Heart Fdn Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland.
    Ferrannini, Ele
    CNR, Inst Clin Physiol, Pisa, Italy.
    Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials2019In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 316, no 3, p. G372-G386Article in journal (Refereed)
    Abstract [en]

    Liver enzyme concentrations are measured as safety endpoints in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT, AST) in subjects randomized to placebo who completed assessments over 36 months in a cardiovascular outcome trial (the 'STABILITY' trial; n=4264; mean age: 64.2 yr) or over 12 months in 3 trials that enrolled only subjects with type 2 diabetes (T2D) (the 'DIA' trials; n=308; mean age: 62.4 yr) to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables, and BMI, baseline T2D status, hemoglobin A1c levels and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were males, < 65 years old, obese and who had GFR > 60 mL/min/1.73m2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight, but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR and HbA1c on ALT and AST concentrations and confirm the effect of gender, age, T2D, BMI and BMI change in subjects receiving placebo in clinical trials.

  • 13.
    Petersson, Joel
    et al.
    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.
    Jansson, Emmelie A
    Patzak, Andreas
    Lundberg, Jon O
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dietary nitrate increases gastric mucosal blood flow and mucosal defense2007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 292, no 3, p. G718-G724Article in journal (Refereed)
    Abstract [en]

    Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to bioactive nitrogen oxides, including nitric oxide (NO). In this study, we investigated the gastroprotective role of nitrate intake and of luminally applied nitrite against provocation with diclofenac and taurocholate. Mucosal permeability (51Cr-EDTA clearance) and gastric mucosal blood flow (laser-Doppler flowmetry) were measured in anesthetized rats, either pretreated with nitrate in the drinking water or given acidified nitrite luminally. Diclofenac was given intravenously and taurocholate luminally to challenge the gastric mucosa. Luminal NO content and nitrite content in the gastric mucus were determined by chemiluminescence. The effect of luminal administration of acidified nitrite on the mucosal blood flow was also investigated in endothelial nitric oxide synthase-deficient mice. Rats pretreated with nitrate or given nitrite luminally had higher gastric mucosal blood flow than controls. Permeability increased more during the provocation in the controls than in the nitrate- and nitrite-treated animals. Dietary nitrate increased luminal NO levels 50 times compared with controls. Nitrate intake also resulted in nitrite accumulation in the loosely adherent mucous layer; after removal of this mucous layer, blood flow was reduced. Nitrite administrated luminally in endothelial nitric oxide synthase-deficient mice increased mucosal blood flow. We conclude that dietary nitrate and direct luminal application of acidified nitrite decrease diclofenac- and taurocholate-induced mucosal damage. The gastroprotective effect likely involves a higher mucosal blood flow caused by nonenzymatic NO production. These data suggest an important physiological role of nitrate in the diet.

  • 14.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansson, Gunnar C.
    Gendler, Sandra J.
    Velcich, Anna
    Lundberg, Jon O.
    Roos, Stefan
    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.
    Importance and regulation of the colonic mucus barrier in a mouse model of colitis2011In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 300, no 2, p. G327-G333Article in journal (Refereed)
    Abstract [en]

    The colonic mucus layer serves as an important barrier and prevents colonic bacteria from invading the mucosa and cause inflammation. The regulation of colonic mucus secretion is poorly understood. The aim of this study was to investigate the role of the mucus barrier in induction of colitis. Furthermore, regulation of mucus secretion by luminal bacterial products was studied. The colon of anesthetized Muc2−/−, Muc1−/−, wild-type (wt), and germ-free mice was exteriorized, the mucosal surface was visualized, and mucus thickness was measured with micropipettes. Colitis was induced by DSS (dextran sodium sulfate, 3%, in drinking water), and disease activity index (DAI) was assessed daily. The colonic mucosa of germ-free and conventionally housed mice was exposed to the bacterial products LPS (lipopolysaccharide) and PGN (peptidoglycan). After DSS induction of colitis, the thickness of the firmly adherent mucus layer was significantly thinner after 5 days and onward, which paralleled the increment of DAI. Muc2−/− mice, which lacked firmly adherent mucus, were predisposed to colitis, whereas Muc1−/− mice were protected with significantly lower DAI by DSS compared with wt mice. The mucus barrier increased in Muc1−/− mice in response to DSS, whereas significantly fewer T cells were recruited to the inflamed colon. Mice housed under germ-free conditions had an extremely thin adherent colonic mucus layer, but when exposed to bacterial products (PGN or LPS) the thickness of the adherent mucus layer was quickly restored to levels observed in conventionally housed mice. This study demonstrates a correlation between decreasing mucus barrier and increasing clinical symptoms during onset of colitis. Mice lacking colonic mucus (Muc2−/−) were hypersensitive to DSS-induced colitis, whereas Muc1−/− were protected, probably through the ability to increase the mucus barrier but also by decreased T cell recruitment to the afflicted site. Furthermore, the ability of bacteria to regulate the thickness of the colonic mucus was demonstrated.

  • 15.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Steege, Andreas
    Patzak, Andreas
    Hellsten, Anna
    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.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    eNOS involved in colitis-induced mucosal blood flow increase2007In: 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)
    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.

  • 16.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Atuma, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The importance of mucus layers and bicarbonate transport in preservation of gastric juxtamucosal pH2002In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 282, no 2, p. G211-G219Article in journal (Refereed)
    Abstract [en]

    Mucus thickness is suggested to be related to mucosal protection. We therefore investigated the importance of the removable mucous layer and epithelial bicarbonate transport in preservation of the gastric juxtamucosal pH (pH(jm)) during luminal acid. Anesthetized rats were prepared for intravital microscopy of the gastric mucosa, and pH(jm) was measured with pH-sensitive microelectrodes. The mucus was either left intact (IM) or removed (MR) down to the firmly attached mucous layer, and HCl (pH 1) was applied luminally. Removal of the loosely adherent mucous layer did not influence the pH(jm) during luminal acid (pentagastrin: IM/MR 7.03 +/- 0.09/6.82 +/- 0.19; pentagastrin + indomethacin: IM/MR 6.89 +/- 0.20/6.95 +/- 0.27; ranitidine: IM/MR 2.38 +/- 0.64/2.97 +/- 0.62), unless prostaglandin synthesis and acid secretion were inhibited (ranitidine + indomethacin: IM/MR 2.03 +/- 0.37/1.66 +/- 0.18). Neutral pH(jm) is maintained during endogenous acid secretion and luminal pH 1, unless DIDS was applied luminally, which resulted in a substantially decreased pH(jm) (1.37 +/- 0.21). Neutral pH(jm) is maintained by a DIDS-sensitive bicarbonate transport over the surface epithelium. The loosely adherent mucous layer only contributes to maintaining pH(jm) during luminal pH 1 if acid secretion and prostaglandin synthesis are inhibited.

  • 17.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holstad, Maria
    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.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice2003In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 285, no 1, p. G154-G162Article in journal (Refereed)
    Abstract [en]

    The role of different isoforms of nitric oxide synthase (NOS) in the gastric mucosal hyperemia, induced by 155 mM luminal hydrochloric acid (pH approximately 0.8) without a barrier breaker, was investigated. Rats were anesthetized with Inactin (120 mg/kg ip), and mice were anesthetized with Forene (2.2% in 40% oxygen gas at 150 ml/min); the gastric mucosa was exteriorized. Gastric mucosal blood flow was measured with laser-Doppler flowmetry (LDF) in rats treated with Nomega-nitro-l-arginine (l-NNA; unspecific NOS inhibitor), l-N6-(1-iminoethyl)lysine [l-NIL; inducible (i) NOS inhibitor], or S-methyl-l-thiocitrulline [SMTC; neuronal (n) NOS inhibitor], 10 mg/kg, followed by 3 mg. kg-1. h-1 iv, in iNOS-deficient (-/-) and nNOS(-/-) mice. mRNA was isolated from the gastric mucosa in iNOS(-/-) and wild-type (wt) mice, and real-time RT-PCR was performed. The effect of 155 mM acid on gastric mucosal permeability was determined by measuring the clearance of 51Cr-EDTA from blood to lumen. LDF increased by 48 +/- 13% during 155 mM HCl luminally, an increase that was abolished by l-NNA, SMTC, or l-NIL. In iNOS wt mice, LDF increased by 33 +/- 8% during luminal acid. The blood flow increase was attenuated substantially in iNOS(-/-) mice. RT-PCR revealed iNOS mRNA expression in the gastric mucosa in the iNOS wt groups. The blood flow increase in response to acid was not abolished in nNOS(-/-) mice (nNOS-sufficient mice, 39 +/- 18%; heterozygous mice, 25 +/- 19%; -/- mice, 19 +/- 7%). Mucosal permeability was transiently increased during 155 mM HCl. The results suggest that iNOS is constitutively expressed in the gastric mucosa and is involved in acid-induced hyperemia, suggesting a novel role for iNOS in gastric mucosal protection.

  • 18.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johansson, Malin E V
    Henriksnäs, Johanna
    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.
    Gendler, Sandra J
    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.
    Hansson, Gunnar C
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The gastric mucus layers: constituents and regulation of accumulation2008In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 295, no 4, p. G806-G812Article in journal (Refereed)
    Abstract [en]

    The mucus layer continuously covering the gastric mucosa consists of a loosely adherent layer that can be easily removed by suction, leaving a firmly adherent mucus layer attached to the epithelium. These two layers exhibit different gastroprotective roles; therefore, individual regulation of thickness and mucin composition were studied. Mucus thickness was measured in vivo with micropipettes in anesthetized mice [isoflurane; C57BL/6, Muc1-/-, inducible nitric oxide synthase (iNOS)-/-, and neuronal NOS (nNOS)-/-] and rats (inactin) after surgical exposure of the gastric mucosa. The two mucus layers covering the gastric mucosa were differently regulated. Luminal administration of PGE(2) increased the thickness of both layers, whereas luminal NO stimulated only firmly adherent mucus accumulation. A new gastroprotective role for iNOS was indicated since iNOS-deficient mice had thinner firmly adherent mucus layers and a lower mucus accumulation rate, whereas nNOS did not appear to be involved in mucus secretion. Downregulation of gastric mucus accumulation was observed in Muc1-/- mice. Both the firmly and loosely adherent mucus layers consisted of Muc5ac mucins. In conclusion, this study showed that, even though both the two mucus layers covering the gastric mucosa consist of Muc5ac, they are differently regulated by luminal PGE(2) and NO. A new gastroprotective role for iNOS was indicated since iNOS-/- mice had a thinner firmly adherent mucus layer. In addition, a regulatory role of Muc1 was demonstrated since downregulation of gastric mucus accumulation was observed in Muc1-/- mice.

  • 19.
    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.

  • 20.
    Shawki, Ali
    et al.
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA.;Univ Cincinnati, Coll Med, Syst Biol & Physiol Program, Cincinnati, OH USA..
    Anthony, Sarah R.
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA..
    Nose, Yasuhiro
    Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA..
    Engevik, Melinda A.
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA.;Univ Cincinnati, Coll Med, Syst Biol & Physiol Program, Cincinnati, OH USA..
    Niespodzany, Eric J.
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA..
    Barrientos, Tomasa
    Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA..
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA..
    Worrell, Roger T.
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA.;Univ Cincinnati, Coll Med, Syst Biol & Physiol Program, Cincinnati, OH USA..
    Thiele, Dennis J.
    Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA.;Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA..
    Mackenzie, Bryan
    Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45220 USA.;Univ Cincinnati, Coll Med, Syst Biol & Physiol Program, Cincinnati, OH USA..
    Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese2015In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, p. G635-G647Article in journal (Refereed)
    Abstract [en]

    Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1(int/int)). DMT1(int/int) mice exhibited a profound hypochromic-microcytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1(int/int) mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1(int/int) mice compared with DMT1(+/+) mice but no meaningful change in copper, manganese, or zinc. DMT1(int/int) mice absorbed Cu-64 and Mn-54 from an intragastric dose to the same extent as did DMT1(+/+) mice but the absorption of Fe-59 was virtually abolished in DMT1(int/int) mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc.

  • 21.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Isoflurane-induced acidosis depresses basal and PGE(2)-stimulated duodenal bicarbonate secretion in mice2007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 292, no 3, p. G899-G904Article in journal (Refereed)
    Abstract [en]

    When running in vivo experiments, it is imperative to keep arterial blood pressure and acid-base parameters within the normal physiological range. The aim of this investigation was to explore the consequences of anesthesia-induced acidosis on basal and PGE2-stimulated duodenal bicarbonate secretion. Mice (strain C57bl/6J) were kept anesthetized by a spontaneous inhalation of isoflurane. Mean arterial blood pressure (MAP), arterial acid-base balance, and duodenal mucosal bicarbonate secretion (DMBS) were studied. Two intra-arterial fluid support strategies were used: a standard Ringer solution and an isotonic Na2CO3 solution. Duodenal single perfusion was used, and DMBS was assessed by back titration of the effluent. PGE2 was used to stimulate DMBS. In Ringer solution-infused mice, isoflurane-induced acidosis became worse with time. The blood pH was 7.15–7.21 and the base excess was about –8 mM at the end of experiments. The continuous infusion of Na2CO3 solution completely compensated for the acidosis. The blood pH was 7.36–7.37 and base excess was about 1 mM at the end of the experiment. Basal and PGE2-stimulated DMBS were markedly greater in animals treated with Na2CO3 solution than in those treated with Ringer solution. MAP was slightly higher after Na2CO3 solution infusion than after Ringer solution infusion. We concluded that isoflurane-induced acidosis markedly depresses basal and PGE2-stimulated DMBS as well as the responsiveness to PGE2, effects prevented by a continuous infusion of Na2CO3. When performing in vivo experiments in isoflurane-anesthetized mice, it is recommended to supplement with a Na2CO3 infusion to maintain a normal acid-base balance.

  • 22.
    Sjöblom, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Säfsten, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Flemström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes2003In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 284, no 6, p. G1034-G1044Article in journal (Refereed)
    Abstract [en]

    The amount of melatonin present in enterochromaffin cells in the alimentary tract is much higher than that in the central nervous system, and melatonin acting at MT2 receptors mediates neural stimulation of mucosal HCO3- secretion in duodenum in vivo. We have examined effects of melatonin and receptor ligands on intracellular free calcium concentration ([Ca2+](i)) signaling in human and rat duodenal enterocytes. Clusters of interconnecting enterocytes (10-50 cells) were isolated by mild digestion ( collagenase/dispase) of human duodenal biopsies or rat duodenal mucosa loaded with fura-2 AM and attached to the bottom of a temperature-controlled perfusion chamber. Clusters provided viable preparations and respond to stimuli as a syncytium. Melatonin and melatonin receptor agonists2-iodo-N-butanoyl-5-methoxytryptamine and 2-iodomelatonin (1.0-100 nM) increased enterocyte [Ca2+](i), EC50 of melatonin being 17.0 +/- 2.6 nM. The MT2 receptor antagonists luzindole and N-pentanoyl-2-benzyltryptamine abolished the [Ca2+](i) responses. The muscarinic antagonist atropine ( 1.0 muM) was without effect on basal [Ca2+](i) and did not affect the response to melatonin. In the main type of response, [Ca2+](i) spiked rapidly and returned to basal values within 4-6 min. In another type, the initial rise in [Ca2+](i) was followed by rhythmic oscillations of high amplitude. Melatonin-induced enterocyte [Ca2+](i) signaling as well as mucosal cell-to-cell communication may be involved in stimulation of duodenal mucosal HCO3- secretion.

  • 23.
    Sommansson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Saudi, Wan Salman Wan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo2013In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 305, no 1, p. G95-G105Article in journal (Refereed)
    Abstract [en]

    Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a similar to 30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of Cr-51-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol-and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol-and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions.

  • 24.
    Spencer, Nick J.
    et al.
    Flinders Univ South Australia, Sch Med, Discipline Human Physiol, Adelaide, SA, Australia.;Flinders Univ South Australia, Sch Med, Ctr Neurosci, Adelaide, SA, Australia..
    Magnúsdóttir, Elín Ingibjörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Jakobsson, Jon E. T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kestell, Garreth
    Flinders Univ South Australia, Sch Med, Discipline Human Physiol, Adelaide, SA, Australia.;Flinders Univ South Australia, Sch Med, Ctr Neurosci, Adelaide, SA, Australia..
    Chen, Bao Nan
    Flinders Univ South Australia, Sch Med, Discipline Human Physiol, Adelaide, SA, Australia.;Flinders Univ South Australia, Sch Med, Ctr Neurosci, Adelaide, SA, Australia..
    Morris, David
    Flinders Univ South Australia, Sch Med, Discipline Human Physiol, Adelaide, SA, Australia.;Flinders Univ South Australia, Sch Med, Ctr Neurosci, Adelaide, SA, Australia..
    Brookes, Simon J.
    Flinders Univ South Australia, Sch Med, Discipline Human Physiol, Adelaide, SA, Australia.;Flinders Univ South Australia, Sch Med, Ctr Neurosci, Adelaide, SA, Australia..
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    CGRP alpha within the Trpv1-Cre population contributes to visceral nociception2018In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 314, no 2, p. G188-G200Article in journal (Refereed)
    Abstract [en]

    The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRP alpha is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRP alpha from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRP alpha-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRP alpha- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRP alpha specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRP alpha from TRPV1-expressing neurons in mice. We show that CGRP alpha from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

  • 25.
    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.

  • 26.
    Wan Saudi, Wan Salman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rudholm-Feldreich, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rosenqvist, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Näslund, Erik
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide2015In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, p. G625-G634Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

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