Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs.
The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.
Division of Cardiovascular Medicine, University of California, Davis 95616.
E A
EA
Amsterdam
G L
GL
Stahl
H L
HL
Pan
S V
SV
Rendig
M P
MP
Fletcher
J C
JC
Longhurst
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001794:Blood Pressure; D002449:Cell Aggregation; D002634:Chemotaxis, Leukocyte; D015936:Complement C5a / Q000276:immunology* / Q000502:physiology; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000502:physiology / Q000503:physiopathology; D003971:Diastole; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice / Q000276:immunology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D012039:Regional Blood Flow; D013481:Superoxides / Q000097:blood; D013552:Swine; D016277:Ventricular Function, Left
D000911:Antibodies, Monoclonal; D013481:Superoxides; D015936:Complement C5a; D009195:Peroxidase