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This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/G678    most recent 00361.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Tsuboi, H. Articles by Yoshikawa, T. Search for Related Content PubMed PubMed Citation Articles by Tsuboi, H. Articles by Yoshikawa, T.

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Role of the thrombin/protease-activated receptor 1 pathway in intestinal ischemia-reperfusion injury in rats

Departments of ¹Inflammation and Immunology, ²Medical Proteomics ³Biomedical Safety Science, and ⁴Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto; and ⁵Hirakata Research Laboratory, Research and Development Division, Benesis Corporation, Osaka, Japan

Submitted 4 August 2006 ; accepted in final form 2 October 2006

ABSTRACT

CXC chemokines, including human interleukin-8 and rat cytokine-induced neutrophil chemoattractant-1, play a crucial role in the pathogenesis of intestinal inflammation induced by ischemia-reperfusion (I-R). Thrombin and its specific receptor, protease-activated receptor 1 (PAR1), act as important players in inflammation. However, the association between thrombin activation and chemokine production during I-R has not been well studied. We investigated whether thrombin and PAR1 might be involved in the pathophysiology of intestinal I-R, using an in vivo model. Intestinal damage was induced by clamping the superior mesenteric artery for 30 min followed by reperfusion in male Wistar rats. Thrombin-antithrombin complex was measured as an indicator of thrombin activation. PAR1 expression in the intestine was evaluated by real-time PCR. The severity of the intestinal mucosal injury was evaluated on the distal segment of the ileum by several biochemical markers and histological findings. Reperfusion significantly increased the serum levels of thrombin-antithrombin complex and enhanced PAR1 expression in the intestinal mucosa. The levels of both intraluminal hemoglobin and protein were significantly increased in the I-R group. The mucosal myeloperoxidase activity and expressions and/or productions of cytokine-induced neutrophil chemoattractant-1 and TNF- were significantly increased after I-R. These increases were inhibited by the treatment of rat with antithrombin intravenously before I-R at a dose of 30 U/kg. These results suggest that the thrombin/PAR1 pathway plays an important role in the production of these cytokines during I-R and that antithrombin exerts potent anti-inflammatory effects on this injury via inhibition of proinflammatory cytokines.

thrombin-antithrombin complex; proinflammatory cytokine; anti-inflammatory effect