The effect of C1 inhibitor on intestinal ischemia and reperfusion injury.
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.
Lu
Fengxin
F
Immune Disease Inst., Harvard Medical School, Boston, Massachusetts, USA. fengxin@idi.harvard.edu
Chauhan
Anil K
AK
Fernandes
Stacey M
SM
Walsh
Meghan T
MT
Wagner
Denisa D
DD
Davis
Alvin E
AE
D000818:Animals; D050718:Complement C1 Inhibitor Protein / Q000235:genetics* / Q000378:metabolism*; D003176:Complement C3 / Q000235:genetics; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D007422:Intestines / Q000293:injuries*; D007770:L-Lactate Dehydrogenase / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D008643:Mesentery / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
D050718:Complement C1 Inhibitor Protein; D003176:Complement C3; D007377:Interleukin-3; D043782:Receptor, Bradykinin B2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C487284:Serping1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; D007770:L-Lactate Dehydrogenase