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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/G1042    most recent 90460.2008v2 90460.2008v1 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 PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lu, F. Articles by Davis, A. E. PubMed PubMed Citation Articles by Lu, F. Articles by Davis, A. E., III

INFLAMMATION/IMMUNITY/MEDIATORS

The effect of C1 inhibitor on intestinal ischemia and reperfusion injury

¹Immune Disease Institute, ²Department of Pathology, Harvard Medical School, Boston, Massachusetts

Submitted 29 July 2008 ; accepted in final form 8 September 2008

Complement activation and neutrophil stimulation are two major components in events leading to ischemia and reperfusion (IR) injury. C1 inhibitor (C1INH) inhibits activation of each of the three pathways of complement activation and of the contact system. It is also endowed with anti-inflammatory properties that are independent of protease inhibition. The goal of these studies was to investigate the role and mechanism of C1INH in alleviating IR-induced intestinal injury. C57BL/6, C1INH-deficient (C1INH^–/–), bradykinin type 2 receptor-deficient (Bk2R^–/–), and C3-deficient mice (C3^–/–) were randomized into three groups: sham operated control, IR, and IR + C1INH-treated groups. Ischemia was generated by occlusion of the superior mesenteric artery followed by reperfusion. C1INH or reactive center-cleaved inactive C1INH (iC1INH) was injected intravenously before reperfusion. IR resulted in intestinal injury in C57BL/6, C1INH^–/–, Bk2R^–/–, and C3^–/– mice with significantly increased neutrophil infiltration into intestinal tissue. In each mouse strain, C1INH treatment reduced intestinal tissue injury and attenuated leukocyte infiltration compared with the untreated IR group. C1INH inhibited leukocyte rolling in the mesenteric veins of both C57BL/6 and C3-deficient mice subjected to IR. C1INH treatment also improved the survival rate of C57BL/6 and C1INH^–/– mice following IR. Similar findings were observed in the IR animals treated with iC1INH. These studies emphasize the therapeutic benefit of C1INH in preventing intestinal injury caused by IR. In addition to the protective activities mediated via inhibition of the complement system, these studies indicate that C1INH also plays a direct role in suppression of leukocyte transmigration into reperfused tissue.

complement inhibition; leukocyte transmigration