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  • 1.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liu, Haoyu
    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.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Microbiol, Uppsala, Sweden..
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 217, no 4, p. 300-310Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to investigate whether two Lactobacillus reuteri strains (rat-derived R2LC and human-derived ATCC PTA 4659 (4659)) could protect mice against colitis, as well as delineate the mechanisms behind this protection.

    Methods: Mice were given L.reuteri R2LC or 4659 by gavage once daily for 14days, and colitis was induced by addition of 3% DSS (dextran sulphate sodium) to drinking water for the last 7days of this period. The severity of disease was assessed through clinical observations, histological evaluation and ELISA measurements of myeloperoxidase (MPO) and pro-inflammatory cytokines from colonic samples. Mucus thickness was measured invivo with micropipettes, and tight junction protein expression was assessed using immunohistochemistry.

    Results: Colitis severity was significantly reduced by L.reuteri R2LC or 4659 when evaluated both clinically and histologically. The inflammation markers MPO, IL-1, IL-6 and mKC (mouse keratinocyte chemoattractant) were increased by DSS and significantly reduced by the L.reuteri strains. The firmly adherent mucus thickness was reduced by DSS, but significantly increased by L.reuteri in both control and DSS-treated mice. Expression of the tight junction proteins occludin and ZO-1 was significantly increased in the bottom of the colonic crypts by L.reuteri R2LC.

    Conclusion: These results demonstrate that each of the two different L. reuteri strains, one human-derived and one-rat-derived, protects against colitis in mice. Mechanisms behind this protection could at least partly be explained by the increased mucus thickness as well as a tightened epithelium in the stem cell area of the crypts.

  • 2.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Roos, Stefan
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    CX3CR1 deficiency alters response to L-reuteri treatment of DSS-induced colitis in mice2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 902.10Article in journal (Other academic)
  • 3.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, no 12, p. 1183-1189Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that water extracts from Helicobacter pylori reduce gastric mucosal blood flow by approximately 15%. It has also been suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis. Our aim was to examine whether the reduction in blood flow induced by H. pylori is the direct consequence of an NO synthase inhibition and the possible involvement of mast cell degranulation.

    METHODS: A water extract was produced from wildtype strain 88-23. The extract was applied on the exteriorized gastric corporal mucosa in inactin-anesthetized rats, after removing as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured with laser-Doppler flowmetry.

    RESULTS: In rats pretreated with the NO synthase inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40 min after application of the extract, and a 27% +/- 9% reduction after another 20 min with saline. The reduction was abolished by concomitant pretreatment with the mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor antagonist WEB2086.

    CONCLUSION: The reduction in mucosal blood flow induced by the extract was probably mediated through an acute inflammatory response involving mast cell degranulation with consequent PAF secretion. The effect on blood flow was not the result of a decrease in vascular tone due to an inhibition of endogenous NO biosynthesis.

  • 4.
    Atuma, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Extracts of Helicobacter pylori reduce gastric mucosal blood flow through a VacA- and CagA-independent pathway in rats1998In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 33, no 12, p. 1256-1261Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Helicobacter pylori may interfere with gastroduodenal protective mechanisms. Such effects could be due to a direct interaction with gastric epithelial cells but also to the action of a wide range of secreted and membrane-bound virulence factors. Our aim was to study the acute effects of water extracts produced from H. pylori on gastric mucosal blood flow and acid secretion and to relate them to VacA and CagA activity.

    METHOD: Extracts were produced from strains 88-23 and A5, both wild type; A5VacA, an isogenic mutant lacking expression of the vacuolating cytotoxin (VacA) and the immunodominant antigen (CagA); and Escherichia coli strain ATCC-25922. Bacterial extracts were applied on the exteriorized gastric corporal mucosa in inactin-anaesthetized rats after removal of as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured by means of laser-Doppler flowmetry.

    RESULTS: All H. pylori extracts, including the extract from 88-23 heated to 100 degrees C for 30 min, significantly reduced blood flow by 15%-19%, whereas E. coli had no significant effect on blood flow.

    CONCLUSION: A factor or a combination of factors, other than VacA and CagA released from H. pylori, might compromise the natural defence of the gastric corporal mucosa by reducing mucosal blood flow. The factor is heat-stable and lacking or less potent in E. coli.

  • 5. Björne, Håkan
    et al.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Weitzberg, Eddie
    Holm, Lena
    Lundberg, Jon
    Nitrite in saliva increases gastric mucosal blood flow and mucus thickness2004In: The Journal of Clinical Investigation, Vol. 113, no 1, p. 106-114Article in journal (Refereed)
  • 6. Dicksved, Johan
    et al.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Willing, Ben
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Rang, Sara
    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.
    Roos, Stefan
    Lactobacillus reuteri Maintains a Functional Mucosal Barrier during DSS Treatment Despite Mucus Layer Dysfunction2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e46399-Article in journal (Refereed)
    Abstract [en]

    Treatment with the probiotic bacterium Lactobacillus reuteri has been shown to prevent dextran sodium sulfate (DSS)-induced colitis in rats. This is partly due to reduced P-selectin-dependent leukocyte-and platelet-endothelial cell interactions, however, the mechanism behind this protective effect is still unknown. In the present study a combination of culture dependent and molecular based T-RFLP profiling was used to investigate the influence of L. reuteri on the colonic mucosal barrier of DSS treated rats. It was first demonstrated that the two colonic mucus layers of control animals had different bacterial community composition and that fewer bacteria resided in the firmly adherent layer. During DSS induced colitis, the number of bacteria in the inner firmly adherent mucus layer increased and bacterial composition of the two layers no longer differed. In addition, induction of colitis dramatically altered the microbial composition in both firmly and loosely adherent mucus layers. Despite protecting against colitis, treatment with L. reuteri did not improve the integrity of the mucus layer or prevent distortion of the mucus microbiota caused by DSS. However, L. reuteri decreased the bacterial translocation from the intestine to mesenteric lymph nodes during DSS treatment, which might be an important part of the mechanisms by which L. reuteri ameliorates DSS induced colitis.

  • 7. Granger, D. Neil
    et al.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kvietys, Peter
    The Gastrointestinal Circulation: Physiology and Pathophysiology2015In: COMPREHENSIVE PHYSIOLOGY, ISSN 2040-4603, Vol. 5, no 3, p. 1541-1583Article in journal (Refereed)
    Abstract [en]

    The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response. (C) 2015 American Physiological Society.

  • 8. Granstam, S O
    et al.
    Jönson, C
    Fändriks, L
    Holm, Lena
    Flemström, G
    Effects of cigarette smoke and nicotine on duodenal bicarbonate secretion in the rabbit and the rat.1990In: Journal of Clinical Gastroenterology, ISSN 0192-0790, E-ISSN 1539-2031, Vol. 12 Suppl 1, p. S19-24Article in journal (Refereed)
    Abstract [en]

    The effects of short-time exposure to cigarette smoke on duodenal mucosal bicarbonate secretion were studied in anesthetized rabbits and rats. The bicarbonate secretion was measured by continuous titration of recirculating luminal perfusate. In artificially ventilated rabbits, intermittent exposure to cigarette smoke during two 10-min periods caused a marked (approximately 40%) decrease (p less than 0.01) in duodenal bicarbonate secretion. After the exposures, secretion gradually recovered and had returned to the pre-exposure rate after 50 min. The decrease in secretion was associated with decreases in heart rate (approximately 15%) and blood pressure (approximately 30%) that, however, were of shorter duration. Neither reduced amounts of smoke (1/6 or 1/3) nor nicotine (25-1,000 micrograms/kg, intravenously) had any major effect on the bicarbonate secretion. In the spontaneously breathing rat, smoke was administered for 1-2 breaths every 30 s during a 5-min period. This exposure resulted in a significant (p less than 0.05) decrease in bicarbonate secretion and some increase in the blood pressure. Exposure to smoke had no effect on the secretion in rats with both splanchnic nerves cut, suggesting neural sympathetic mediation of the smoke-induced inhibition.

  • 9.
    Halldin, Krister
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Ridderstråle, Yvonne
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Reproductive impairment in Japanese quail (Coturnix japonica) after in ovo exposure to o,p'-DDT.2003In: Arch Toxicol, ISSN 0340-5761, Vol. 77, no 2, p. 116-22Article in journal (Refereed)
  • 10.
    Henriksnäs, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Atuma, Christer
    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.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engstrand, Lars
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute effects of Helicobacter pylori extracts on gastric mucosal blood flow in the mouse2009In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 15, no 2, p. 219-225Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE).

    METHODS: The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser-Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/- mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed.

    RESULTS: In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wild-type mice exposed to HPE.

    CONCLUSION: A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways.

  • 11.
    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.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engstrand, L
    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.
    An in vivo model for gastric physiological and pathophysiological studies in the mouse2005In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 184, no 2, p. 151-159Article in journal (Refereed)
    Abstract [en]

    Aim:  In vivo models for studying gastrointestinal physiology and pathophysiology are well established in rats. Since a number of genetically modified mice are available there is a need for reliable mouse models. The aim of this project was to develop an in vivo mouse model for gastrointestinal studies.

    Methods: C57bl/6, NMRI and transgenic FVB/N (expressing human α-1,3/4-fucosyltransferase) mice were anaesthetized with isoflurane and the gastric mucosa exteriorized for intravital microscopy. Acid–base status and acid secretion were measured and blood pressure was continuously monitored. Gastric mucosal blood flow was recorded by laser-Doppler flowmetry. Mucus thickness and accumulation rate were measured with micropipettes.

    Results: We have developed an in vivo mouse model for studies of the gastric mucosa. With isoflurane anaesthesia the preparation can be studied for up to 5 h with stable blood pressure and mucosal blood flow. Acid–base status agrees with results from other laboratories. Blood flow increased in both C57bl/6 and α1.3/4-FT mice in response to luminal HCl, and the mucus gel could be divided into a firmly and a loosely adherent layer, all comparable with results in the rat. However, the firmly adherent mucus layer was thinner (45 ± 2 μm), and the mucus accumulation rate lower, than in the rat. Furthermore, both basal and stimulated acid secretion showed lower outputs than in the rat.

    Conclusions: This model has great potential for investigations of gastrointestinal physiology and pathophysiology and can be applied for Helicobacter pylori infection studies.

  • 12.
    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.

  • 13. Holm, Lena
    et al.
    Agren, J
    Persson, A E
    Stimulation of acid secretion increases the gastric gland luminal pressure in the rat.1992In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 103, no 6, p. 1797-803Article in journal (Refereed)
    Abstract [en]

    The gastric mucosal gland luminal pressure was measured in vivo with a pressure-sensitive microelectrode technique (servo-null) in anesthetized rats. A microelectrode was inserted into a gland lumen by means of a micromanipulator at an angle of 30 degrees to the mucosal surface. Acid secretion was estimated by measuring the pH in the solution covering the mucosa. During control conditions, when the mucosa was secreting acid spontaneously, gland luminal pressure was 12.3 +/- 1.2 mm Hg. At about 9 minutes after starting pentagastrin administration, the luminal pressure stabilized at 17.2 +/- 1.7 mm Hg. In the rats given impromidine (500 micrograms.kg-1.h-1) luminal pressure gradually increased (during 9-10 minutes) from a control level of 9.0 +/- 1.9 to 17.3 +/- 2.6 mm Hg. During the majority of experiments, the luminal pressure oscillated at 3-7 cycles per minute. The results show that intraluminal pressure increases during stimulated acid secretion, indicating that a resistance to the volume secretion exists in the upper part of the gastric crypts. This hydrostatic pressure may well be the driving force for creating channels for acid and pepsin to cross the mucus layer covering the mucosal surface.

  • 14. Holm, Lena
    et al.
    Flemström, G
    Microscopy of acid transport at the gastric surface in vivo.1990In: Journal of internal medicine. Supplement, ISSN 0955-7873, Vol. 732, p. 91-5Article in journal (Refereed)
    Abstract [en]

    In vivo microscopy of the gastric surface, and pH-sensitive dyes, were used to study the movement of acid formed in the gastric crypts across the mucus layer adherent to the gastric surface and into the lumen. Rats were anaesthetized and the stomach gently exteriorized. When the pH-sensitive dye Congo red was applied luminally to stain the gel, predominantly red spots (pH greater than 5) and occasional blue spots (pH less than 3), located above the outlets of the crypts, were observed in spontaneously-secreting mucosae. Maximal stimulation of acid secretion (pentagastrin, 40 micrograms kg-1 h-1) resulted in the appearance only of blue spots, but the pH in the mucus gel between the crypts remained more alkaline, as indicated by pink staining. The fluorescence dye acridine orange was injected intravenously to an estimated blood concentration of 10(-5)M in another type of experiment. This dye is concentrated and secreted by the parietal cells. Pronounced fluorescence was observed within spots of the gastric surface corresponding to the outlets of the gastric crypts, but no fluorescence was detected outside these areas. The results obtained with both dyes strongly suggest that acid (and pepsin) is transported across the mucus gel only at restricted sites.

  • 15. Holm, Lena
    et al.
    Flemström, G
    Nylander, O
    Duodenal alkaline secretion in rabbits: influence of artificial ventilation.1990In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 138, no 4, p. 471-8Article in journal (Refereed)
    Abstract [en]

    The effect of artificial ventilation on duodenal alkaline secretion and blood flow was studied in sodium pentobarbital-anaesthetized rabbits. A duodenal segment (approximately 3 cm) was cannulated in situ and continuously perfused with isotonic saline, and the bicarbonate secretion was titrated by pH-stat. Compared with the spontaneous breathing state, artificial ventilation improved the respiratory status of the animal, increasing Po2 and decreasing both Pco2 and plasma bicarbonate. Duodenal blood flow as measured with laser-Doppler flowmetry was not altered but the alkaline secretion was reduced. Pretreatment with the alpha 2-adrenoceptor antagonist yohimbine (0.5 mg kg-1 i.v., followed by 0.5 mg kg-1 h-1 i.v.) or the ganglionic blocker hexamethonium (10 mg kg-1 i.v.) did not affect the decline in duodenal alkaline secretion in response to artificial ventilation. Nor did these pretreatments affect the changes in plasma bicarbonate and Pco2 or significantly alter the blood flow. Increasing Pco2 in the respirator air increased the plasma Pco2 and bicarbonate concentration as well as the duodenal bicarbonate secretion. Pretreatment with the carbonic anhydrase inhibitor acetazolamide (80 mg kg-1 i.v.) reduced the bicarbonate secretion, and artificial ventilation induced a further reduction. Increasing Pco2 in the respirator in the animals pretreated with acetazolamide did not affect the bicarbonate secretion. Duodenal alkaline secretion was thus always reduced on artificial ventilation. The mechanism for this reduction does not seem to involve the sympathetic nervous system or the blood flow, but appears to be the consequence of alterations in the plasma concentration of bicarbonate and the plasma Pco2.

  • 16. Holm, Lena
    et al.
    Jägare, A
    Histamine is not involved in pentagastrin-induced gastric mucosal vasodilation in the rat.1994In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 266, no 1 Pt 1, p. G55-61Article in journal (Refereed)
    Abstract [en]

    The effects of histamine and its role in the gastric mucosal vascular response to pentagastrin were studied in anesthetized rats. Blood flow was measured with laser-Doppler flowmetry (LDF) and with red blood cell velocity measurements in the superficial mucosal microcirculation. Acid secretion was determined by titration of the saline covering 0.8 cm2 of the fundic mucosa. Pentagastrin (40 micrograms.kg-1 x h-1 i.v. induced a blood flow increase (+40%), which was not significantly altered by ranitidine (H2-receptor antagonist, 2 mg/kg iv bolus), whereas the stimulated acid output was abolished. In experiments in which the H1-receptor antagonist pyrilamine (2.5 mg/kg i.v. bolus) was administered before pentagastrin stimulation, pentagastrin still increased blood flow by approximately 60%. Intravenous histamine (4 mg.kg-1 x h-1) induced a blood flow reduction in parallel with the reduction in blood pressure (vascular resistance unchanged). Even during intra-arterial (thoracic aorta) infusion of histamine (1 or 4 mg.kg-1 x h-1), gastric vascular resistance was unchanged. In animals pretreated with pyrilamine, histamine (4 mg.kg-1 x h-1 i.v.) left the gastric blood flow and blood pressure unchanged. These results indicate that the pentagastrin-induced increase in the rat gastric blood flow is not dependent on histamine.

  • 17. Holm, Lena
    et al.
    Jägare, A
    Influence of tactile stimulation of the rat gastric mucosa on blood flow and acid output.1993In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 265, no 2 Pt 1, p. G303-9Article in journal (Refereed)
    Abstract [en]

    The influence of tactile stimulation of the gastric mucosa (mimics the mechanical influence of the food bolus) on the gastric mucosal blood flow and acid output was studied in rats anesthetized with Inactin. Blood flow was measured with laser-Doppler flowmetry (LDF) with the probe positioned above the gastric mucosa, and acid secretion was measured at regular intervals by titration of the saline covering 0.8 cm2 of the mucosa. After gentle tactile stimulation (wiping with cotton tips) of the mucosa for 20 s, blood flow increased to approximately 250% of the control value and then returned to the control level 15 min later, whereas acid output was transiently reduced immediately after tactile stimulation. Pretreatment with lidocaine, methysergide, or hexamethonium did not change the results of tactile stimulation on the blood flow. After indomethacin (3 mg/kg i.v.) LDF was significantly reduced by 33% and the hyperemic response to tactile stimulation was almost abolished. This suggests that endogenously released prostaglandins, not evoked through activation of intramural reflexes that can be blocked by lidocaine, methysergide or hexamethonium, are responsible for the hyperemia seen after tactile stimulation of the gastric mucosa.

  • 18. Holm, Lena
    et al.
    Jägare, A
    Role of prostaglandins in regulation of gastric mucosal blood flow and acid secretion.1992In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 263, no 4 Pt 1, p. G446-51Article in journal (Refereed)
    Abstract [en]

    The role of prostaglandins in the rat gastric mucosal vascular response to acid stimulation was studied. Blood flow was measured with laser-Doppler flowmetry (LDF) and with red blood cell velocity measurements in the superficial mucosa; acid secretion was determined by titration. Baseline acid output was calculated to be 0.026 +/- 0.011 mueq/min. Pentagastrin (20 and 40 micrograms.kg-1.h-1 iv) significantly increased acid output to 0.387 +/- 0.104 and 0.546 +/- 0.220 mueq/min and LDF to 119 +/- 10 and 132 +/- 13% of control, respectively. LDF was significantly reduced by 15% after indomethacin (3 mg/kg iv) and was not changed by pentagastrin, whereas acid secretion increased to similar levels as without indomethacin pretreatment. The H2-agonist impromidine (100 and 500 micrograms.kg-1.h-1 iv) induced a dose-dependent increase in acid secretion (0.178 +/- 0.068 and 0.330 +/- 0.072 mueq/min, respectively) while blood flow was unchanged. Despite a substantial blood flow reduction (-38%) by indomethacin, impromidine did not alter blood flow, and acid secretion was dose dependently increased to similar values as without indomethacin pretreatment. These results provide further evidence that there is not necessarily any correlation between blood flow and acid secretion and that the pentagastrin-induced blood flow increase depends on prostaglandin release.

  • 19. Holm, Lena
    et al.
    Morsing, P
    Casellas, D
    Persson, A E
    Resetting of the pressure range for blood flow autoregulation in the rat kidney.1990In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 138, no 3, p. 395-401Article in journal (Refereed)
    Abstract [en]

    Both a myogenic response and the tubuloglomerular feedback control mechanism seem to be involved in autoregulation of glomerular filtration rate (GFR) and renal blood flow (RBF). Earlier experiments have shown that clamping of renal arterial perfusion pressure, below the autoregulatory range, reduces single-nephron GFR, and that this low value is maintained during the first 10-15 min after release of the clamp. It was also found that the tubuloglomerular feedback mechanism in the early declamp phase was strongly activated to reduce GFR. These findings can not be easily understood with the current knowledge of autoregulation, but would suggest a resetting of RBF and GFR autoregulation to a new level. To test this, left renal arterial perfusion pressure was reduced from 100 to 60 mmHg during 20 min with and without angiotensin converting enzyme inhibition (0.5 mg i.v. enalapril). Renal blood flow was measured with laser-Doppler flowmetry. When arterial perfusion pressure was reduced from 100 to 60 mmHg for 20 min, RBF was reduced to 77% of control and remained at this low level during the first minutes of declamp. In this situation there was an autoregulation to a new level. Renal blood flow was then slowly normalized (16.1 min). In the enalapril-treated animals RBF was only reduced to 85% during the 20 min of clamping and returned immediately to the control level at declamp. Thus, these experiments demonstrate that if renal blood flow is decreased by reducing the perfusion pressure below the normal autoregulatory range the pressure range for blood flow autoregulation resets to a lower level and that this change is mediated via the renin-angiotensin system.

  • 20.
    Holm, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Perry, Michael
    Expression of ICAM-1 and P-selectin in the surface microcirculation of the rat gastrointestinal mucosa1999Chapter in book (Other academic)
  • 21.
    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.
    Assessment of mucus thickness and production in situ2012In: Methods in molecular biology, ISSN 1064-3745, Vol. 842, p. 217-227Article in journal (Refereed)
    Abstract [en]

    The nature of the mucus gel layer covering the gastrointestinal tract makes it difficult to study outside its natural site attached to the mucosa. Here, we describe a technique for intravital microscopy studies of the mucus gel layer from the stomach down to the colon in anesthetized rats and mice. Mucus thickness and accumulation rate in each segment of the gastrointestinal tract is measured with a micropipette technique under observation through a stereomicroscope. In this way, the nature of the mucus gel in vivo is readily studied, and effects of interventions or disease on the mucus can be determined in longitudinal studies or by comparing animals. Using this technique, we have been able to demonstrate that there are two forms of mucus gel adherent to the stomach and colon mucosa: one layer which is removable by suction and an underlying firm adherent gel layer, while in the small intestine, all mucus adhering to the mucosa can easily be removed.

  • 22.
    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.

  • 23.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Effects of omeprazole on gastric mucosal microcirculation and acid secretion in the rat1987In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 92, no 3, p. 716-723Article in journal (Refereed)
    Abstract [en]

    Omeprazole, a potent long-acting inhibitor of gastric acid secretion that exerts its inhibitory action by direct blocking of the H+, K+-adenosine triphosphatase in the parietal cells, was either applied topically to the solution bathing the exposed mucosa of the test rats or administered intravenously as a bolus injection. The superficial mucosal vessels were monitored on a television screen through a microscope and videorecorded for off-line analysis of red cell velocities and vessel diameters, from which blood flow was calculated. Intravenous omeprazole (5 or 10 mumol/kg) totally abolished the basal secretion 15-25 min after injection, with a parallel decrease in blood flow of approximately 25% for both doses. Omeprazole, 5 mumol/kg, given intravenously to rats stimulated with pentagastrin (20 micrograms/kg X h) significantly inhibited the stimulated acid output, but the blood flow was not significantly decreased. Topical application of omeprazole (2.5 mM in 6 ml) significantly increased blood flow (approximately 15%) while in contact with the mucosa both in the resting and in the pentagastrin (20 micrograms/kg X h)-stimulated situations. However, 10-20 min after the application period, blood flow was restored to the values before application of omeprazole and the acid output was significantly decreased. The results indicate that omeprazole exerts only minor influences on the gastric mucosal microcirculation in spite of its potent acid-inhibitory effect.

  • 24.
    Holm-Rutili, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Effects of prostaglandin E1, E2 and 16,16-dimethyl-E2 on gastric mucosal microcirculation and basal acid output in the rat1986In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 127, no 3, p. 313-321Article in journal (Refereed)
    Abstract [en]

    The effects of prostaglandins E1 (PGE1), E2 (PGE2) and 16,16-dimethyl-E2 (16,16-dm-PGE2) on the gastric mucosal microcirculation and (spontaneous) acid output were studied in anaesthetized rats. The superficial mucosal vessels were monitored on a TV screen using a microscope, TV camera and videorecorder for off-line analysis of red cell velocities (VRBC) and vessel diameters, from which the blood flow (QRBC) was calculated. The prostaglandins were either applied topically to the solution bathing the exposed mucosa or administered intravenously as a continuous infusion. Topical application of PGE1 (0.5 or 5 micrograms ml-1), PGE2 (5 or 50 micrograms ml-1) or 16,16-dm-PGE2 (0.005, 0.05 or 0.5 microgram ml-1) increased VRBC dose-dependently without altering acid output, except for the highest dose of PGE2 (50 micrograms ml-1) which inhibited acid output. The latter occurred in spite of a seven- to eight-fold increase in VRBC. Mucus secretion (evidenced by an impaired resolution of the TV image) also increased during topical application of the prostaglandins especially at higher doses. Intravenous PGE1, PGE2 (2.0 micrograms kg-1 min-1) or 16,16-dm-PGE2 (0.02 microgram kg-1 min-1) caused an initial and transient (5-10 min) fall in systemic arterial blood pressure and a decrease in VRBC and acid output. Intravenous 16,16-dm-PGE2 in a dose which did not affect secretion or systemic arterial blood pressure (0.002 microgram kg-1 min-1) still significantly reduced VRBC. Thus, topically applied PGE1, PGE2 or 16,16-dm-PGE2 dose-dependently increase VRBC while intravenous administration of the same prostaglandins reduce VRBC.

  • 25.
    Holm-Rutili, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Berglindh, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Pentagastrin and gastric mucosal blood flow1986In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 250, no 5 Pt 1, p. G575-G580Article in journal (Refereed)
    Abstract [en]

    The effect of pentagastrin on mucosal microcirculation was studied in rats by use of intravital microscopy. The superficial mucosal vessels were videorecorded for off-line analysis of red cell velocities (VRBC) and vessel diameters, from which blood flow (QRBC) was calculated. Resting mucosal blood flow calculated from single microvascular flow data, and vessel distribution was 40 ml X min-1 X 100 g-1. Pentagastrin infused intravenously in a dose of 20 micrograms X kg-1 X h-1 resulted in submaximal acid secretion (approximately 60%) and a significant increase in QRBC by 47 +/- 14%. When given in a dose of 96 micrograms X kg-1 X h-1 iv, it resulted in maximal acid secretion and an increase in QRBC by 36 +/- 14%. In another series of experiments the results of QRBC measurements during infusion of pentagastrin (20 micrograms X kg-1 X h-1 iv) were compared with those of aminopyrine (AP) clearance or laser-Doppler flowmetry (LDF) in the same animals. Gastric mucosal blood flow determined by [14C]AP clearance increased by 309 +/- 115%, whereas QRBC increased by 34 +/- 11%. When determined by LDF, blood flow increased by 41 +/- 22%, a value similar to the increase in QRBC (50 +/- 19%). Thus, the percent increase in blood flow during pentagastrin infusion estimated by AP clearance was considerably higher than that observed by either direct microvascular measurements or by LDF.

  • 26.
    Holm-Rutili, Lena
    et al.
    Department of Physiology, College of Medicine, University of South Alabama, Mobile, Alabama 36688.
    Perry, M A
    Granger, D N
    Autoregulation of gastric blood flow and oxygen uptake1981In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 241, no 2, p. G143-G149Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to determine whether the ability of the stomach to autoregulate blood flow and oxygen uptake is altered by sympathetic denervation. Blood flow, oxygen extraction, local arterial pressure, and venous pressure were continuously monitored in sympathetically innervated and denervated autoperfused dog stomach preparations. As perfusion pressure was reduced in increments from 120 to 20 mmHg in innervated preparations, blood flow and oxygen uptake decreased while oxygen extraction and vascular resistance increased. Reductions in perfusion pressure in denervated preparations resulted in a decrease in blood flow, oxygen uptake, and vascular resistance, whereas oxygen extraction increased. The ability of the stomach to regulate blood flow and oxygen uptake was significantly improved after denervation, i.e., vascular resistance decreased and oxygen uptake remained relatively constant when arterial pressure was reduced. Oxygen uptake in denervated stomachs was generally higher than that in innervated stomachs. Autoregulation of gastric blood flow therefore appears to be improved by denervation. The better autoregulation observed after denervation may result either from a reduction in sympathetic tone and/or the increase in gastric oxygen demand.

  • 27.
    Holm-Rutili, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Öbrink, Karl Johan
    Rat gastric mucosal microcirculation in vivo1985In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 248, no 6 Pt 1, p. G741-G746Article in journal (Refereed)
    Abstract [en]

    The superficial gastric mucosal microcirculation was observed microscopically by transillumination in the anesthetized rat. The vessels surrounding the gastric crypts were monitored on a television screen through a microscope and the pictures stored on a videotape for off-line analysis of red cell velocity (VRBC) and vessel diameter. From these measurements microvascular volume flows were calculated. VRBC reached steady values after 1-4 h (mean 2 h) and showed a regular pulsatile flow (4-7 cycles/min) in most experiments. Acid output was measured at regular intervals; 50% of the rats showed no spontaneous acid output, but the others secreted up to 100 mu eq/h. The microvessels in the superficial mucosa were classified into three orders according to their branching hierarchy and relative dimensions, and their distribution per unit mass was estimated. VRBC and volume flow were shown to decrease in the successive orders of the microvessels. Calculation of organ blood flow from microvascular flow data and vessel distribution gave values (21 ml.min-1.100 g tissue-1) that agree with earlier reported values. A higher flow velocity was detected in rats with spontaneous acid output than in those without, but there was a poor correlation between the magnitude of the acid output and VRBC. Pentagastrin (96 micrograms.kg-1.h-1) induced a significant increase in both blood flow and acid secretion. Results from this study indicate that this experimental model is potentially useful for studies of the correlation between acid secretion and mucosal blood flow.

  • 28. Jakobsdottir, Greta
    et al.
    Jadert, Cecilia
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nyman, Margareta E.
    Propionic and butyric acids, formed in the caecum of rats fed highly fermentable dietary fibre, are reflected in portal and aortic serum2013In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 110, no 9, p. 1565-1572Article in journal (Refereed)
    Abstract [en]

    SCFA are important end products formed during colonic fermentation of dietary fibre (DF). It has been suggested that propionic and butyric acids affect metabolic parameters, low-grade systemic inflammation, insulin resistance and obesity. The aim of the present study was to investigate whether the various SCFA profiles observed after fermentation in the caecum of rats fed pectin, guar gum and fructo-oligosaccharides (FOS) were also represented in hepatic portal and aortic serum. The SCFA in serum were extracted using hollow fibre-supported liquid membrane extraction before GLC analysis. The concentrations of acetic, propionic and butyric acids in caecal content correlated well with those in portal serum (P<0.001) for all the three diets. A weaker correlation was found for propionic and butyric acids between the caecal content and aortic serum (P<0.05). Butyric acid concentration in caecal content was also reflected in the aortic serum (P=0.019) of rats fed FOS. FOS gave rather low amounts of the SCFA, especially butyric acid, but caecal tissue weight was higher with FOS than with the other two diets. This may be explained by rapid fermentation and quick utilisation/absorption of the SCFA. The present study also showed that propionic acid was metabolised/utilised to a higher extent than butyric acid by colonocytes before reaching the liver. We conclude that the formation of propionic and butyric acids in the caecum is reflected by increased concentrations in the aortic blood. This approach may therefore simplify the evaluation and study of SCFA from DF in human subjects.

  • 29. Jansson, Emmelie A
    et al.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Reinders, Claudia
    Sobko, Tanja
    Björne, Håkan
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weitzberg, Eddie
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon O
    Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate2007In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 42, no 4, p. 510-518Article in journal (Refereed)
    Abstract [en]

    Nitrate is abundant in our diet with particularly high levels in many vegetables. Ingested nitrate is concentrated in saliva and reduced to nitrite by bacteria in the oral cavity. We recently reported that application of nitrite-containing saliva to the gastric mucosa increases superficial blood flow and mucus generation via acid-catalyzed formation of bioactive nitrogen oxides including nitric oxide. Here we studied if dietary supplementation with nitrate would protect against gastric damage caused by a nonsteroidal anti-inflammatory drug. Rats received sodium nitrate in the drinking water for 1 week in daily doses of 0.1 or 1 mmol kg− 1. Control rats received 1 mmol kg− 1 sodium chloride. Diclofenac (30 mg kg− 1) was then given orally and the animals were examined 4 h later. In separate experiments we studied the effects of dietary nitrate on intragastric NO levels and mucus formation. Luminal levels of NO gas were greatly increased in nitrate-fed animals. The thickness of the mucus layer increased after nitrate supplementation and gene expression of MUC6 was upregulated in the gastric mucosa. Nitrate pretreatment dose dependently and potently reduced diclofenac-induced gastric lesions. Inflammatory activity was reduced in the rats receiving nitrate as indicated by lower mucosal myeloperoxidase activity and expression of inducible NO synthase. We conclude that dietary nitrate protects against diclofenac-induced gastric ulcers likely via enhanced nitrite-dependent intragastric NO formation and concomitant stimulation of mucus formation. Future studies will reveal if a diet rich in nitrate can offer an additional nutritional approach to preventing and treating peptic ulcer disease.

  • 30. Jansson, Emmelie Å
    et al.
    Huang, Liyue
    Malkey, Ronny
    Govoni, Mirco
    Nihlén, Carina
    Olsson, Annika
    Stensdotter, Margareta
    Petersson, Joel
    Holm, Lena
    Department of Physiology and Pharmacology, Division of Anesthesiology and Intensive Care, Karolinska Institutet.
    Weitzberg, Eddie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon O
    A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis2008In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 4, no 7, p. 411-417Article in journal (Refereed)
    Abstract [en]

    Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.

  • 31. Johansson, Malin E. V.
    et al.
    Gustafsson, Jenny K.
    Sjöberg, Karolina E.
    Petersson, Joel
    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.
    Sjövall, Henrik
    Hansson, Gunnar C.
    Bacteria Penetrate the Inner Mucus Layer before Inflammation in the Dextran Sulfate Colitis Model2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 8, p. e12238-Article in journal (Refereed)
    Abstract [en]

    Background: Protection of the large intestine with its enormous amount of commensal bacteria is a challenge that became easier to understand when we recently could describe that colon has an inner attached mucus layer devoid of bacteria (Johansson et al. (2008) Proc. Natl. Acad. Sci. USA 105, 15064-15069). The bacteria are thus kept at a distance from the epithelial cells and lack of this layer, as in Muc2-null mice, allow bacteria to contact the epithelium. This causes colitis and later on colon cancer, similar to the human disease Ulcerative Colitis, a disease that still lacks a pathogenetic explanation. Dextran Sulfate (DSS) in the drinking water is the most widely used animal model for experimental colitis. In this model, the inflammation is observed after 3-5 days, but early events explaining why DSS causes this has not been described. Principal Findings: When mucus formed on top of colon explant cultures were exposed to 3% DSS, the thickness of the inner mucus layer decreased and became permeable to 2 mm fluorescent beads after 15 min. Both DSS and Dextran readily penetrated the mucus, but Dextran had no effect on thickness or permeability. When DSS was given in the drinking water to mice and the colon was stained for bacteria and the Muc2 mucin, bacteria were shown to penetrate the inner mucus layer and reach the epithelial cells already within 12 hours, long before any infiltration of inflammatory cells. Conclusion: DSS thus causes quick alterations in the inner colon mucus layer that makes it permeable to bacteria. The bacteria that reach the epithelial cells probably trigger an inflammatory reaction. These observations suggest that altered properties or lack of the inner colon mucus layer may be an initial event in the development of colitis.

  • 32. Johansson, Malin E V
    et al.
    Phillipson, Mia
    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.
    Velcich, Anna
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansson, Gunnar C
    The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 39, p. 15064-15069Article in journal (Refereed)
    Abstract [en]

    We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.

  • 33. Johansson, Mia
    et al.
    Synnerstad, Ingrid
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acid transport through channels in the mucous layer of rat stomach2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 119, no 5, p. 1297-1304Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: We have reported previously that secreted acid moves through the mucous layer in restricted areas above the gastric crypts. The aim of this study was to visualize and study the dynamics of this event.

    METHODS: Anesthetized rats prepared for intravital microscopy of the gastric mucosa were divided in the following groups with respect to acid secretion: spontaneous; stimulated (pentagastrin, 40 microg. kg(-1). h(-1)); transiently inhibited (omeprazole, 400 micromol. kg(-1) for 7 days); and totally inhibited (omeprazole, 3 x 200 micromol. kg(-1) for 7 days). The mucus was stained with Congo red (blue, pH < 3; red, pH > 5.2), and photographs were taken through a stereomicroscope.

    RESULTS: During acid secretion, blue-colored crypt openings with attached thread-like (5-7 microm wide) structures (designated channels) were seen passing from the crypt openings through the mucus to the lumen. Red-colored channels and crypt openings were observed when acid secretion was transiently inhibited. Red-colored crypt openings but no channels were found after total inhibition of acid secretion for a week.

    CONCLUSIONS: The results suggest that secreted acid is transported through channels within the mucus. These channels are probably created by the high intraglandular pressure pushing acid and glandular mucus into the gel.

  • 34. Jädert, Cecilia
    et al.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lundberg, Jon O.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury2012In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 52, no 3, p. 683-692Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in INF-alpha-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues.

  • 35. Jädert, Cecilia
    et al.
    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.
    Lundberg, Jon O
    Borniquel, Sara
    Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease2014In: Redox biology, ISSN 2213-2317, Vol. 2, p. 73-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Inorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis.

    METHODS: Colitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1 mM) or nitrate (10 mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS-induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells.

    RESULTS: Concurrent administration of DSS and nitrite (1 mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10 mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration.

    CONCLUSION: Nitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution.

  • 36. Jönson, C
    et al.
    Holm, Lena
    Jansson, T
    Fändriks, L
    Effects of hypovolemia on blood flow, arterial [HCO3-], and HCO3- output in the rat duodenum.1990In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 259, no 2 Pt 1, p. G179-83Article in journal (Refereed)
    Abstract [en]

    The effects of bleeding-induced hypovolemia on duodenal blood flow (microsphere technique), arterial [HCO3-], and duodenal HCO3- secretion (in situ titration) were investigated in chloralose-anesthetized rats. A 10% decrease in blood volume reduced duodenal HCO3- secretion by 44%, duodenal blood flow by 31%, and arterial [HCO3-] by 11%. In a group with cervically cut vagal nerves, basal duodenal HCO3- secretion was greater than 50% lower compared with controls. Basal blood flow and arterial [HCO3-] were on similar levels as in nonvagotomized animals. Furthermore, bleeding failed to lower duodenal alkaline output in rats with cut vagal nerves, although blood flow and arterial [HCO3-] were reduced to a similar extent as in the vagally intact controls. In a yohimbine-treated group, a 10% bleeding reduced duodenal blood flow by 28% and arterial [HCO3-] by 7% without influencing duodenal HCO3- secretion. We suggest that the hypovolemia-induced inhibition of duodenal alkaline secretion is not caused by a decrease in blood and/or arterial [HCO3-]. Instead, other factors may be of importance, for example, neural effects on enteric secretomotor neurons or directly on the secreting epithelium.

  • 37.
    Karimi, Shokoufeh
    et al.
    Swedish Univ Agr Sci, Dept Microbiol, Uppsala BioCtr, Uppsala, Sweden..
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vagesjö, Evelina
    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.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jonsson, Hans
    Swedish Univ Agr Sci, Dept Microbiol, Uppsala BioCtr, Uppsala, Sweden..
    Roos, Stefan
    Swedish Univ Agr Sci, Dept Microbiol, Uppsala BioCtr, Uppsala, Sweden..
    In Vivo and In Vitro Detection of Luminescent and Fluorescent Lactobacillus reuteri and Application of Red Fluorescent mCherry for Assessing Plasmid Persistence2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151969Article in journal (Refereed)
    Abstract [en]

    Lactobacillus reuteri is a symbiont that inhabits the gastrointestinal (GI) tract of mammals, and several strains are used as probiotics. After introduction of probiotic strains in a complex ecosystem like the GI tract, keeping track of them is a challenge. The main objectives of this study were to introduce reporter proteins that would enable in vivo and in vitro detection of L. reuteri and increase knowledge about its interactions with the host. We describe for the first time cloning of codon-optimized reporter genes encoding click beetle red luciferase (CBRluc) and red fluorescent protein mCherry in L. reuteri strains ATCC PTA 6475 and R2LC. The plasmid persistence of mCherry-expressing lactobacilli was evaluated by both flow cytometry (FCM) and conventional plate count (PC), and the plasmid loss rates measured by FCM were lower overall than those determined by PC. Neutralization of pH and longer induction duration significantly improved the mCherry signal. The persistency, dose-dependent signal intensity and localization of the recombinant bacteria in the GI tract of mice were studied with an in vivo imaging system (IVIS), which allowed us to detect fluorescence from 6475-CBRluc-mCherry given at a dose of 1x10(10) CFU and luminescence signals at doses ranging from 1x10(5) to 1x10(10) CFU. Both 6475-CBRluc-mCherry and R2LC-CBRluc were localized in the colon 1 and 2 h after ingestion, but the majority of the latter were still found in the stomach, possibly reflecting niche specificity for R2LC. Finally, an in vitro experiment showed that mCherry-producing R2LC adhered efficiently to the intra cellular junctions of cultured IPEC-J2 cells. In conclusion, the two reporter genes CBRluc and mCherry were shown to be suitable markers for biophotonic imaging (BPI) of L. reuteri and may provide useful tools for future studies of in vivo and in vitro interactions between the bacteria and the host.

  • 38. 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.

  • 39.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Basal and induced NO formation in the pharyngo-oral tract influences estimates of alveolar NO levels2009In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 106, no 2, p. 513-519Article in journal (Refereed)
    Abstract [en]

    The present study analyzed how models currently used to distinguish alveolar from bronchial contribution to exhaled nitric oxide (NO) are affected by manipulation of NO formation in the pharyngo-oral tract. Exhaled NO was measured at multiple flow rates in 15 healthy subjects in two experiments: 1) measurements at baseline and 5 min after chlorhexidine (CHX) mouthwash and 2) measurements at baseline, 60 min after ingestion of 10 mg NaNO3/kg body wt, and 5 min after CHX mouthwash. Alveolar NO concentration (CalvNO) and bronchial flux (J′awNO) were calculated by using the slope-intercept model with or without adjustment for trumpet shape of airways and axial diffusion (TMAD). Salivary nitrate and nitrite were measured in the second experiment. CalvNO [median (range)] was reduced from 1.16 ppb (0.77, 1.96) at baseline to 0.84 ppb (0.57, 1.48) 5 min after CHX mouthwash (P < 0.001). The TMAD-adjusted CalvNO value after CHX mouthwash was 0.50 ppb (0, 0.85). The nitrate load increased J′awNO from 32.2 nl/min (12.2, 60.3) to 57.1 nl/min (22.0, 119) in all subjects and CalvNO from 1.47 ppb (0.73, 1.95) to 1.87 ppb (10.85, 7.20) in subjects with high nitrate turnover (>10-fold increase of salivary nitrite after nitrate load). CHX mouthwash reduced CalvNO levels to 1.15 ppb (0.72, 2.07) in these subjects with high nitrate turnover. All these results remained consistent after TMAD adjustment. We conclude that estimated alveolar NO concentration is affected by pharyngo-oral tract production of NO in healthy subjects, with a decrease after CHX mouthwash. Moreover, unknown ingestion of dietary nitrate could significantly increase estimated alveolar NO in subjects with high nitrate turnover, and this might be falsely interpreted as a sign of peripheral inflammation. These findings were robust for TMAD.

  • 40. 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.

  • 41. Morsing, P
    et al.
    Stenberg, A
    Casellas, D
    Mimran, A
    Müller-Suur, C
    Thorup, C
    Holm, Lena
    Persson, A E
    Renal interstitial pressure and tubuloglomerular feedback control in rats during infusion of atrial natriuretic peptide (ANP).1992In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 146, no 3, p. 393-8Article in journal (Refereed)
    Abstract [en]

    Atrial natriuretic peptide (ANP), injected at physiological concentrations, is known to induce both natriuresis and diuresis. It has been suggested by some investigators that these changes result from an increasing glomerular filtration rate (GFR), but others have been unable to demonstrate an increased GFR. The tubuloglomerular feedback (TGF) mechanism is an important regulator of GFR, and the sensitivity of TGF is decreased during ANP administration. Furthermore, resetting of TGF is, in most instances, related to changes in renal interstitial hydrostatic and oncotic pressures. It is also known that ANP may increase capillary permeability which may change renal interstitial pressure. The present study was performed to examine renal interstitial pressures and the TGF mechanism during ANP infusion. In accordance with previous studies, TGF sensitivity was found to be decreased. The tubular flow rate which elicited half the maximal drop in stop-flow pressure (Psf) was increased from 18.5 to 25.7 nl min-1. In contrast, ANP infusion resulted in a decreased interstitial hydrostatic pressure and an increased interstitial oncotic pressure. From previous experiments, such changes in interstitial pressures would be expected to increase TGF sensitivity. The changes in interstitial pressure cannot, therefore, directly explain the resetting of the feedback mechanism. In conclusion, the present paper shows a decreased renal net interstitial pressure after intravenous administration of ANP.

  • 42. Nylander, O
    et al.
    Holm, Lena
    Wilander, E
    Hällgren, A
    Exposure of the duodenum to high concentrations of hydrochloric acid. Effects on mucosal permeability, alkaline secretion, and blood flow.1994In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 29, no 5, p. 437-44Article in journal (Refereed)
    Abstract [en]

    Proximal duodenum was perfused with HCl for 5 min and the effects on blood-to-lumen clearance of 51Cr-EDTA (ED-Cl), morphology, luminal alkalinization, and blood flow determined in anesthetized rats. The rate of alkalinization was determined by back titration and blood flow assessed by laser Doppler flowmetry or by ultrasonic transit time flowmetry. Perfusion of duodenum with 30, 50 or 100 mM HCl for 5 min increased ED-Cl in a concentration-dependent manner and induced a small increase in alkalinization but had no effect on blood flow. At 55 min after cessation of perfusion with 100 mM HCl ED-Cl was 2.2-fold higher than control whereas the ED-Cl values in animals perfused with 30 or 50 mM HCl were not different from pre-acid control values. 100 mM HCl also induced an increase in 14C-mannitol and 14C-polyethylene glycol 4000 clearance, suggesting that HCl does indeed increase mucosal permeability. The 100 mM HCl-induced rise in mucosal permeability most probably reflects disturbance of mucosal integrity because three of five animals exhibited villous tip damage. The increases in ED-Cl in response to 100 mM HCl were the same in control rats as in rats with the renal pedicles ligated, indicating that the acid susceptibility is not affected by acute functional nephrectomy.

  • 43. Nylander, O
    et al.
    Hällgren, A
    Holm, Lena
    Duodenal mucosal alkaline secretion, permeability, and blood flow.1993In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 265, no 6 Pt 1, p. G1029-38Article in journal (Refereed)
    Abstract [en]

    The relationship between duodenal mucosal alkaline secretion, permeability, and blood flow was examined in anesthetized rats. Duodenum was perfused with saline, and rate of luminal alkalinization (LA), mucosal permeability (clearance of 51Cr-EDTA from blood to lumen), effluent volume, mean arterial blood pressure (MABP), and blood flow (laser-Doppler flowmetry) were determined. Infusion of vasoactive intestinal polypeptide (VIP, 13.5 micrograms.kg-1 x h-1 i.v.) increased LA and fluid secretion but decreased MABP and mucosal permeability. The concentration of base in the secreted fluid was 45 mM. Systemic infusion of VIP (2.5 micrograms.kg-1 x h-1) increased LA and fluid secretion; the HCO3- concentration in secreted fluid was 86 mM. The lower VIP dose affected neither blood flow nor mucosal permeability. Both intravenous (10 mg/kg + 3 mg.kg-1 x h-1) and intraluminal (3 x 10(-3) M) N omega-nitro-L-arginine (L-NNA) increased LA and effluent volume; the HCO3- concentration in the secreted fluid was 38 and 44 mM, respectively. Intravenous, but not intraluminal, L-NNA increased mucosal permeability and decreased blood flow. Reduction of arterial blood pressure by blood withdrawal or by injection of prazosin (50 micrograms/kg i.v.) or hexamethonium (20 mg/kg i.v.) decreased LA and mucosal permeability. Prazosin decreased blood flow, whereas hexamethonium slightly increased blood flow. We conclude that NO may be an inhibitory regulator of LA and that both L-NNA and VIP increase LA via stimulation of active HCO3- transport. VIP probably increases HCO3- and fluid secretion by two separate ion transport mechanisms. No causal relationship exists between LA and blood flow, between LA and mucosal permeability, or between mucosal permeability and blood flow. A positive linear correlation exists between MABP and mucosal permeability, suggesting that marked changes of MABP may influence permeation of small water-soluble solutes across duodenal mucosa.

  • 44. Nylander, O
    et al.
    Wilander, E
    Larson, G M
    Holm, Lena
    Vasoactive intestinal polypeptide reduces hydrochloric acid-induced duodenal mucosal permeability.1993In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 264, no 2 Pt 1, p. G272-9Article in journal (Refereed)
    Abstract [en]

    The duodenum in anesthetized rats was perfused with HCl, and mucosal integrity was assessed by measuring the clearance of 51Cr-labeled EDTA from blood to lumen and/or by morphological examination (lesion score). Duodenal blood flow was determined by laser Doppler flowmetry and luminal alkalinization as well as H+ disappearance by backtitration. Intravenous infusion of vasoactive intestinal polypeptide (VIP; 13.5 micrograms.kg-1.h-1) increased luminal alkalinization threefold and decreased clearance of 51Cr-EDTA by 50%. VIP also decreased arterial blood pressure and induced a small and irregular decrease in duodenal blood flow. Perfusion with 10 mM HCl increased clearance of 51Cr-EDTA 2.1-fold, but the lesion score was not different from that in saline-perfused animals. Perfusion with 20 mM HCl increased clearance of 51Cr-EDTA four-fold and induced a greater lesion score than did 10 mM. Perfusion with either 10 or 20 mM HCl did not affect the duodenal blood flow. VIP reduced the rise in clearance of 51Cr-EDTA in response to 10 mM but not that to 20 mM HCl. Intravenous injection of prazosin (50 micrograms/kg) decreased luminal alkalinization, clearance of 51Cr-EDTA, blood pressure, and duodenal blood flow. In prazosin-pretreated rats, perfusion with 10 mM HCl increased clearance of 51Cr-EDTA 2.6-fold, and the lesion score was greater in this group than in animals infused with VIP. A positive linear correlation was obtained between HCO3- secretion and the mean rate of H+ disappearance.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 45. Perry, M A
    et al.
    Phillipson, Mia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Holm, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Transmural gradient of leukocyte-endothelial interaction in the rat gastrointestinal tract.2005In: Am J Physiol Gastrointest Liver Physiol, ISSN 0193-1857, Vol. 289, no 5, p. G852-9Article in journal (Refereed)
  • 46.
    Petersson, Joel
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Björne, Håkan
    Phillipson, Mia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Weitzberg, Eddie
    Holm, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon O.
    Nitrite in salvia increases gastric mucosal blood flow and mucus thickness2004In: J. Clin. Invest., Vol. 113, p. 106-114Article in journal (Refereed)
  • 47.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlström, Mattias
    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.
    Phillipson, Mia
    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.
    Jägare, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Roos, Stefan
    Jansson, Emmelie Å.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lundberg, Jon O.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash2009In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 46, no 8, p. 1068-1075Article in journal (Refereed)
    Abstract [en]

    Recently, it has been suggested that the supposedly inert nitrite anion is reduced in vivo to form bioactive nitric oxide with physiological and therapeutic implications in the gastrointestinal and cardiovascular systems. Intake of nitrate-rich food such as vegetables results in increased levels of circulating nitrite in a process suggested to involve nitrate-reducing bacteria in the oral cavity. Here we investigated the importance of the oral microflora and dietary nitrate in regulation of gastric mucosal defense and blood pressure. Rats were treated twice daily with a commercial antiseptic mouthwash while they were given nitrate-supplemented drinking water. The mouthwash greatly reduced the number of nitrate-reducing oral bacteria and as a consequence, nitrate-induced increases in gastric NO and circulating nitrite levels were markedly reduced. With the mouthwash the observed nitrate-induced increase in gastric mucus thickness was attenuated and the gastroprotective effect against an ulcerogenic compound was lost. Furthermore, the decrease in systemic blood pressure seen during nitrate supplementation was now absent. These results suggest that oral symbiotic bacteria modulate gastrointestinal and cardiovascular function via bioactivation of salivary nitrate. Excessive use of antiseptic mouthwashes may attenuate the bioactivity of dietary nitrate.

  • 48.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jadert, Cecilia
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Borniquel, Sara
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Physiological recycling of endogenous nitrate by oral bacteria regulates gastric mucus thickness2015In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 89, p. 241-247Article in journal (Refereed)
    Abstract [en]

    Background: Inorganic nitrate from exogenous and endogenous sources is accumulated in saliva, reduced to nitrite by oral bacteria and further converted to nitric oxide (NO) and other bioactive nitrogen oxides in the acidic gastric lumen. To further explore the role of oral microbiota in this process we examined the gastric mucus layer in germ free (GF) and conventional mice given different doses of nitrate and nitrite. Methods: Mice were given either nitrate (100 mg/kg/d) or nitrite (0.55-11 mg/kg/d) in the drinking water for 7 days, with the lowest nitrite dose resembling the levels provided by swallowing of fasting saliva. The gastric mucus layer was measured in vivo. Results: GF animals were almost devoid of the firmly adherent mucus layer compared to conventional mice. Dietary nitrate increased the mucus thickness in conventional animals but had no effect in GF mice. In contrast, nitrite at all doses, restored the mucus thickness in GF mice to the same levels as in conventional animals. The nitrite-mediated increase in gastric mucus thickness was not inhibited by the soluble guanylyl cyclase inhibitor ODQ. Mice treated with antibiotics had significantly thinner mucus than controls. Additional studies on mucin gene expression demonstrated down regulation of Muc5ac and Much in germ free mice after nitrite treatment. Conclusion: Oral bacteria remotely modulate gastric mucus generation via bioactivation of salivary nitrate. In the absence of a dietary nitrate intake, salivary nitrate originates mainly from NO synthase. Thus, oxidized NO from the endothelium and elsewhere is recycled to regulate gastric mucus homeostasis.

  • 49.
    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.

  • 50.
    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.

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