Proteinase-Activated Receptor-1 Linked to Inflammatory Bowel Disease

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Proteinase-Activated Receptor-1 Linked to Inflammatory Bowel Disease

NEW YORK (Reuters Health) Nov 22 - Proteinase-activated receptor-1 (PAR1) may play an important role in the pathogenesis of inflammatory bowel disease (IBD), according to a report in the November issue of The Journal of Clinical Investigation.

"Considering the proinflammatory effects observed upon PAR1 activation in different tissues or cells, the abundant expression of PAR1 in the gastrointestinal tract, and the fact that proteinases that activate PAR1...are found in increased concentrations in the intestine of IBD patients, we hypothesized that PAR1 activation in the intestine may be involved in the pathogenesis of IBD," write Dr. Nathalie Vergnolle from University of Calgary, Alberta, Canada and colleagues.

The authors investigated PAR1 expression in the colon of IBD patients and mice with experimental colitis.

PAR1 expression was increased 7-fold in colon tissue from Crohn's disease patients and 3.5-fold in colon tissue from ulcerative colitis patients, compared with normal colon, the authors report.

Administration of PAR1 agonist directly into mouse colon caused mucosal erosions and submucosal edema similar to that seen in mouse models of colitis, the report indicates, whereas administration of a PAR1 antagonist reduced inflammation in two mouse models of IBD.

Mouse bred to lack PAR1 showed significantly less severe colitis after intracolonic administration of TNBS or DSS, the agents used to induce colitis in the two models of IBD, the researchers note.

"These results support our hypothesis that PAR1 activation plays a proinflammatory role in IBD," the authors conclude. "This role involves, secondarily, an increase in intestinal permeability and, primarily, the activation of monocytic cells from the lamina propria, leading to cytokine release."

"Proteases have to be considered as active signaling molecules of chronic inflammatory diseases and potential targets for IBD treatments," Dr. Vergnolle explained. "Bleeding and thrombin release in IBD also have to be considered as potential aggravating factors for inflammation."

"We are now looking at the role of PAR1 in other animal models of colitis, particularly Th2-type inflammation," Dr. Vergnolle said. "We are investigating how PAR1 activation could modulate the cytokine profiles of colonic tissues."

J Clin Invest 2004;114:1446-1456.