Role of complement and perspectives for intervention in ischemia-reperfusion damage

Figures & data

Table I. Summary of selected references in preclinical and clinical trials of complement inhibition in ischemia / reperfusion injury.

Animal models
Inhibitor	Model	IR injury	References
sCR1	rat	heart	(35)
sCR1-sLe^x	mouse, baboon, rat	brain, brain, heart	(36–38)
Compstatin	pig-to-human xeno-tx	kidney	(39)
anti-C5a, minibody to C5	pig, rat allo-tx, rat	heart, heart	(40,41,82)
C5aR-antagonist, C5aR-siRNA	rat, rat, mouse syn-tx, mouse	kidney, kidney, kidney, brain, kidney	(42–46)
C3aR-antagonist	rat, mouse	intestine, brain	(47,48)
C1s-inhibitor	rabbit	heart	(50)
mimotope/anti-non-muscle myosin, anti-ribonucleoprotein	mouse, mouse	heart, intestine	(27,54)
GAGs	rabbit, rabbit	heart, heart	(56,57)
C1-INH	dog, pig, mouse, mouse, pig, pig	heart, heart, brain, brain, kidney, heart	(15,21,61–63,72)
	CD59^−/− mouse, CD55^−/− /CD59^−/mouse tx, C6^−/− mouse syn-tx, C6^−/− mouse	brain, kidney, liver, kidney	(34,64–66)
Clinical trials
Inhibitor	Setting	Clinical situation	References
Humanized anti-C5 (Eculizumab, Pexelizumab)	clinical	PNH, CABG, PTCA post MI, thrombolysis post MI, CABG, CABG/valve surgery, PTCA post MI, review	(67,75–81)
C1-INH (Cinryze), C1-INH	clinical, clinical rescue, clinical, clinical, emergency	PNH, emergency CABG post PTCA, heart, CABG post MI	(68–71)
sCR1 (TP10)	clinical	CABG, CABG/valve, lung-tx	(83–85)

sCR1 = soluble complement receptor 1; sCR1-sLe^x = sCR1 conjugated to sialyl Lewis x; C1-INH = C1-inhibitor; C5a/C3aR = C5a/ C3a receptor; siRNA = small interfering ribonucleic acid; GAGs = glycosaminoglycans; xeno-/allo-/syn-tx = xenogeneic, allogeneic, and syngeneic transplantation; PNH = paroxysmal nocturnal hemoglobinuria; CABG = coronary artery bypass surgery; PTCA = percutaneous transluminal coronary angioplasty; MI = myocardial infarction.

Figure 1. Summary of selected aspects of complement inhibition in ischemia / reperfusion injury. GAGs (glycosaminoglycans) are released from the cell surface upon reperfusion. Functional replacement of shed GAGs through DXS (low-molecular-weight dextran sulfate) that inhibits all three complement pathways. C5a/C3aR-antagonists = C5/C3a receptor antagonists. Members of the lectin pathway: MBL = mannose binding lectin; MASP = MBL-associated serine protease. Exposure of neoepitopes with subsequent binding of natural antibodies upon ischemia and reperfusion. C4b2a3b and C3bBb3b = classical- and alternative-pathway C3 convertases. TCC = terminal complement complex (C5b-9); CD55/59 = complement regulatory proteins for surface inhibition of the TCC.

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