As we gain more understanding of the problem of ischemia-reperfusion injury, the emphasis has shifted from free radicals to complement as the main culprit. The role of the complement system will continue to be a vigorously investigated field for the foreseeable future. It is most likely that there is interaction among all three known pathways of the complement system. However, depending upon the particular organ involved and whether ischemia and reperfusion are synchronous, such as in hemorrhage, one complement pathway might dominate. The potential benefits are enormous if current animal studies examining the role of complement in diverse conditions as limb ischemia, wound healing and hemorrhagic hypotension could be translated into positive clinical trials. It would certainly change the way we look at many disease processes in the body, and would clearly change therapy.
Complement: A group of serum and cell surface proteins that generate effectors of innate and adaptive immune responses through interactions with one another or with the rest of the immune response system. The term was first coined following its discovery by Jules Bordet, a Belgian Nobel laureate, in the late 19th century.
Ischemia antigen: The antigen thought to be formed following ischemia that binds to naturally occurring IgM, forming an immune complex that then activates C1 binding, complement activation, and formation of C3a and C3b. C3b then activates the rest of the complement cascade, resulting in the formation of the membrane attack complex that causes cell injury.
Membrane attack complex: Terminal C5b-9 common end product of the complement cascade which is inserted into cell membranes. It has both cytolytic and noncytolytic effects, with the latter thought to be more important by causing irreversible cell injury by attracting activated neutrophils.
sCR1: Naturally occurring soluble form of the C3b-C4b cell surface receptor, CR1. Now bioengineered and in Phase II clinical trials.
Supported by U.S. Public Health Service Grant P50 GM52585.
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In: Shock and Related Capillary Phenomena, V. H. Moon, ed., pp. 236-251. Philadelphia: Oxford Medical Publications. In the late 1800s, Walter Bradford Cannon, the Harvard physiologist, proposed the humoral theory of disease, arguing that all bodily functions are controlled by circulating factors. He and colleagues fueled much of the early research on ischemia-reperfusion injury.
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8. Kyriakides, C., Austen, W., Jr., Wang, Y., Favuzza, J., Kobzik, L., Moore, F. D., Jr., and Hechtman, H. B. (1999). Skeletal muscle reperfusion injury is mediated by neutrophils and the complement attack complex. Am. J. Physiol. 277(6 part 1), C1263-C1268.
9. Stahl, G. L., Xu, Y., Hao, L., Miller, M., Buras, J. A., Fung, M., and Zhao, H. (2003). Role for the alternative complement pathway in ischemia reperfusion injury. Am. J. Pathol. 162(2), 449-455.
10. Riedemann, N. C., and Ward, P. A. (2003). Complement in ischemia reperfusion injury. Am. J. Pathol. 162(2), 363-367.
11. Chan, R. K., Ding, G., Verna, N., Ibrahim, S. I., Oakes, S., Hechtman, H. B., Moore, F. D., Jr. (2004) IgM binding to injured tissue precedes complement activaion during skeletal muscle ischemia-reperfusion Journal of Surgical Research 122(1), 29-35.
Dr Shahrul Ibrahim is a graduate of The Royal College of Surgeons in Ireland and a Member of The Royal College of Surgeons of Edinburgh. He did his surgical training in Cumbria and East Yorkshire, UK, and is currently a surgical research fellow at the Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Dr Rodney Chan is a graduate of MIT and qualified from Harvard Medical School. He is on the Brigham and Women's Surgical Residency Program and currently a surgical research fellow at the Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Dr Herbert Hechtman is a graduate of Harvard Medical School and is Professor of Surgery at the Brigham and Women's Hospital and Harvard Medical School, Boston, MA. He has authored several books and published extensively on the subject of ischemia-reperfusion injury.
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