Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies.
Ischemia-reperfusion (I/R) injury provides a substantial limitation to further improvements in the development of therapeutic strategies for ischemia-related diseases. Studies in animal I/R models, including intestinal, hindlimb, kidney, and myocardial I/R models, have established a key role of the complement system in mediation of I/R injury using complement inhibitors and knock-out animal models. As complement activation has been shown to be an early event in I/R injury, inhibiting its activation or its components may offer tissue protection after reperfusion. However, clinical study results using complement inhibitors have largely been disappointing. Therefore, identification of a more specific pathogenic target for therapeutic intervention seems to be warranted. For this purpose more detailed knowledge of the responsible pathway of complement activation in I/R injury is required. Recent evidence from in vitro and in vivo models suggests involvement of both the classic and the lectin pathways in I/R injury via exposition of neo-epitopes in ischemic membranes. However, most of these findings have been obtained in knock-out murine models and have for a large part remained unconfirmed in the human setting. The observation that the relative role of each pathway seems to differ among organs complicates matters further. Whether a defective complement system protects from I/R injury in humans remains largely unknown. Most importantly, involvement of mannose-binding lectin as the main initiator of the lectin pathway has not been demonstrated at tissue level in human I/R injury to date. Thus, conclusions drawn from animal I/R studies should be extrapolated to the human setting with caution.
Diepenhorst
Gwendolyn M P
GM
Department of Surgery, Surgical Laboratory, Academic Medical Center, Amsterdam, the Netherlands.
van Gulik
Thomas M
TM
Hack
C Erik
CE
D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D003165:Complement System Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D051381:Rats; D015427:Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology* / Q000517:prevention & control
D003165:Complement System Proteins