Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Abstract

The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, Po0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both Po0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (Po0.05) and EP only in 4 days (Po0.05). Mucosal endothelial injury led to hypoxia (Po0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1a and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC. KEYWORDS: endothelial damage; epithelial permeability; hypoxia; inflammatory bowel disease; ulcerative colitis; vascular permeability Ulcerative colitis (UC) is characterized by chronic, recurrent ulcers and inflammation of the colonic mucosa. It has been postulated that impaired epithelial barrier function, resulting in penetration of bacteria and other antigens into the mucosa, is one of the major factors of UC pathogenesis.

Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium‐induced murine colitis

“…() reported that pharmacological inhibition of TRPV4 prevents LPS‐induced endothelial dysfunction and increase in mesenteric artery permeability in mouse mesenteric arteries. Endothelial damage increases colonic vascular permeability, contributing to the pathogenesis of experimental colitis in rats and mice (Tolstanova et al, ). In this study, we found that the TRPV4 channel was up‐regulated in mouse endothelial cells during inflammatory conditions and a TRPV4 agonist increased vascular permeability in the colon of mice with DSS‐induced colitis, which was abolished by i.v.…”

The Gastrointestinal Circulation: Physiology and Pathophysiology

“…An increased vascular permeability has been described in the inflamed colon of different mouse and rat models of experimental colitis (20,236,338,340,346,352,491). The increased vascular permeability appears to precede the mucosal barrier failure that accompanies this condition (490). Since increased vascular permeability is a critical component of the angiogenic response, an effort has been made to link the two events in experimental colitis.…”

Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis

“…32,33 In this report, we evaluated the impact of Mk2 homozygous deletion (Mk2 À / À ) and WIN55, an agonist of CB receptors, on the local and systemic inflammatory response in mice with DSS-induced colitis taking advantage of the availability of Mk2 À / À mice and the mouse colitis model. Our results confirm that uptake of 4% DSS in drinking water for 7 consecutive days causes colitis with Figure 3 Inflammatory cell counting in colonic specimens of mice with dextran sodium sulfate (DSS)-induced colitis.…”