Recombinant soluble CR1 suppressed complement activation, inflammation, and necrosis associated with reperfusion of ischemic myocardium.
In summary, conversion of wild-type CR1 to a soluble form (sCR1) creates a potent inhibitor of complement activation by both the classical and alternative pathways by inhibiting the C3/C5 convertases. In the rat reperfusion infarct model, sCR1 significantly suppresses complement activation at the endothelial surface of capillaries and venules. This suppression of complement activation is accompanied by reduced accumulation of leukocytes within the infarct zone, perhaps because of reduction of the generation of C5a, which promotes expression of leukocyte adhesion receptors and leukocyte chemotaxis. In addition, formation of the C5b-9 attack complex, which may contribute to direct endothelial injury, was suppressed by sCR1. The inhibition of complement activation and leukocyte infiltration by sCR1 explains the observed significant reduction in myocardial necrosis after ischemia and reperfusion. These studies have identified sCR1 as a potential agent for therapeutic intervention in diseases associated with complement-dependent tissue injury.
Weisman
H F
HF
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Bartow
T
T
Leppo
M K
MK
Boyle
M P
MP
Marsh
H C
HC
Carson
G R
GR
Roux
K H
KH
Weisfeldt
M L
ML
Fearon
D T
DT
D000595:Amino Acid Sequence; D000818:Animals; D003167:Complement Activation; D003169:Complement Inactivator Proteins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000517:prevention & control; D008969:Molecular Sequence Data; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D011951:Receptors, Complement / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000502:physiology; D012995:Solubility
D003169:Complement Inactivator Proteins; D011951:Receptors, Complement; D011994:Recombinant Proteins