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iNOS-dependent increase in colonic mucus thickness in DSS-colitic rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. (Lena Holm)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. (Lena Holm)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. (Lena Holm)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Stellan Sandler)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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

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

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

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

 

 

Keyword [en]
Experimental colitis, DSS, mucus thickness, MUC2, iNOS, prostaglandins
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-112500OAI: oai:DiVA.org:uu-112500DiVA: diva2:287680
Available from: 2010-01-19 Created: 2010-01-14 Last updated: 2010-01-20
In thesis
1. Microcirculation, Mucus and Microbiota in Inflammatory Bowel Disease
Open this publication in new window or tab >>Microcirculation, Mucus and Microbiota in Inflammatory Bowel Disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 516
Keyword
inflammatory bowel diseases, experimental colitis, DSS, TNBS, colonic mucosal blood flow, laser-doppler flowmetry, colonic mucus thickness, MUC2, colonic mucosal barrier function, iNOS, eNOS, probiotics, Lactobacilli, Lactobacillus reuteri, colonic microbiota, T-RFLP, bacterial translocation, intravital microscopy, P-selectin, leukocyte recruitment, platelet recruitment
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-112718 (URN)978-91-554-7710-3 (ISBN)
Public defence
2010-03-06, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2010-02-12 Created: 2010-01-19 Last updated: 2010-02-12Bibliographically approved

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Schreiber, OlofPetersson, JoelJägare, AnnikaPhillipson, MiaHolm, Lena

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