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(American Journal of Pathology. 2003;162:449-455.)
© 2003 American Society for Investigative Pathology


Regular Articles

Role for the Alternative Complement Pathway in Ischemia/Reperfusion Injury

Gregory L. Stahl*, Yuanyuan Xu{dagger}, Liming Hao{ddagger}, Mendy Miller*, Jon A. Buras§, Michael Fung and Hui Zhao*

From the Department of Anesthesiology, Perioperative, and Pain Medicine,* Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; the Department of Emergency Medicine,§ Beth Israel-Deaconess Hospital, Boston, Massachusetts; the Department of Pathology,{ddagger} Yale University School of Medicine, New Haven, Connecticut; the Department of Medicine,{dagger} University of Alabama at Birmingham, Birmingham, Alabama; and the Cell Biology Department, Tanox, Incorporated, Houston, Texas

The terminal complement components play an important role in mediating tissue injury after ischemia and reperfusion (I/R) injury in rats and mice. However, the specific complement pathways involved in I/R injury are unknown. The role of the alternative pathway in I/R injury may be particularly important, as it amplifies complement activation and deposition. In this study, the role of the alternative pathway in I/R injury was evaluated using factor D-deficient (-/-) and heterozygote (+/-) mice. Gastrointestinal ischemia (GI) was induced by clamping the mesenteric artery for 20 minutes and then reperfused for 3 hours. Sham-operated control mice (+/- versus -/-) had similar baseline intestinal lactate dehydrogenase activity (P = ns). Intestinal lactate dehydrogenase activity was greater in -/- mice compared to +/- mice after GI/R (P = 0.02) thus demonstrating protection in the -/- mice. Intestinal myeloperoxidase activity in +/- mice was significantly greater than -/- mice after GI/R (P < 0.001). Pulmonary myeloperoxidase activity after GI/R was significantly higher in +/- than -/- mice (P = 0.03). Addition of human factor D to -/- animals restored GI/R injury and was prevented by a functionally inhibitory antibody against human factor D. These data suggest that the alternative complement pathway plays an important role in local and remote tissue injury after GI/R. Inhibition of factor D may represent an effective therapeutic approach for GI/R injury.



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