The effect of C1 inhibitor on intestinal ischemia and reperfusion injury

Fengxin Lu; Anil K Chauhan; Stacey M Fernandes; Meghan T Walsh; Denisa D Wagner; Alvin E Davis III

doi:10.1152/ajpgi.90460.2008

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The effect of C1 inhibitor on intestinal ischemia and reperfusion injury

Journal article

Peer reviewed

The effect of C1 inhibitor on intestinal ischemia and reperfusion injury

Fengxin Lu, Anil K Chauhan, Stacey M Fernandes, Meghan T Walsh, Denisa D Wagner and Alvin E Davis III

American journal of physiology: Gastrointestinal and liver physiology, Vol.295(5), pp.G1042-1049

11/2008

DOI: 10.1152/ajpgi.90460.2008

PMID: 18787060

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Abstract

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.

Tumor Necrosis Factor-alpha - metabolism

Receptor, Bradykinin B2 - genetics

Interleukin-3 - metabolism

Reperfusion Injury - pathology

Mice, Inbred C57BL

Tumor Necrosis Factor-alpha - blood

Gene Expression Regulation

Intestines - injuries

Reperfusion Injury - drug therapy

Reperfusion Injury - mortality

Complement C1 Inhibitor Protein - genetics

Leukocytes - physiology

Recombinant Proteins

Mesentery - cytology

Recombinant Fusion Proteins - metabolism

Mice, Knockout

Animals

L-Lactate Dehydrogenase - physiology

Mice

Complement C1 Inhibitor Protein - metabolism

Complement C3 - genetics

Granulocyte Colony-Stimulating Factor - metabolism

Intestinal Mucosa - pathology

Details

Title: Subtitle: The effect of C1 inhibitor on intestinal ischemia and reperfusion injury
Creators: Fengxin Lu - Immune Disease Inst., Harvard Medical School, Boston, Massachusetts, USA. fengxin@idi.harvard.edu
Anil K Chauhan
Stacey M Fernandes
Meghan T Walsh
Denisa D Wagner
Alvin E Davis III
Resource Type: Journal article
Publication Details: American journal of physiology: Gastrointestinal and liver physiology, Vol.295(5), pp.G1042-1049
DOI: 10.1152/ajpgi.90460.2008
PMID: 18787060
ISSN: 0193-1857
eISSN: 1522-1547
Language: English
Date published: 11/2008
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094336902771

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