Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury.
Complement depletion with cobra venom factor (CVF) before coronary artery ligation has been previously shown to reduce subsequent ischemic myocardial tissue injury in the baboon; however, whether complement depletion after the initiation of acute myocardial ischemia affords similar myocardial preservation is not known. Both complement depletion with CVF or the administration of certain nonsteroidal anti-inflammatory drugs, including ibuprofen, are thought to decrease myocardial infarct size by reducing polymorphonuclear leukocytic (PMN) infiltration; nevertheless, complement activation also could alter tissue injury by PMN-independent actions. Thus, the relative effects of CVF administered after coronary artery ligation on the subsequent development of myocardial tissue injury were assessed in a baboon myocardial infarction model. The animals were randomized into three treatment groups (n = 6): either CVF (125 units/kg) or saline was given 30 minutes after coronary artery ligation, and ibuprofen (12.5 mg/kg) was administered 30 minutes and 4 hours after ligation. The extent of ischemic myocardial injury was assessed 24 hours later. Relative to saline-treated baboons, both CVF and ibuprofen reduced PMN infiltration (36 +/- 4 vs. 24 +/- 4 and 24 +/- 4 PMN/mm2, respectively; mean +/- SEM) and histological evidence of transmural myocardial infarction (100% vs. 47% and 53%, respectively) in electrocardiographically designated, expected infarct sites. In both saline- and ibuprofen-treated animals, there was extensive localization of C4, C3, and C5 in all infarct sites; in contrast, there was only C4 localization in the CVF-treated baboons. When expected infarct sites were assessed for creatine kinase content as an indicator of tissue injury, there was significantly less epicardial and endocardial creatine kinase depletion in the CVF-treated animals (31.7 +/- 5.6% and 39.3 +/- 4.8%) than in the saline-treated animals (54.1 +/- 5.4% and 59.0 +/- 4.7%; p = 0.012 and 0.011, respectively). The percent creatine kinase depletion in the ibuprofen-treated animals was intermediate between the two other groups. These results suggest that depletion of complement after coronary ligation has beneficial effects in reducing tissue injury that cannot be explained solely on the basis of reducing PMN infiltration into the ischemic myocardium.
Crawford
M H
MH
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7872.
Grover
F L
FL
Kolb
W P
WP
McMahan
C A
CA
O'Rourke
R A
RA
McManus
L M
LM
Pinckard
R N
RN
D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D003165:Complement System Proteins / Q000032:analysis; D003327:Coronary Disease / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D003402:Creatine Kinase / Q000378:metabolism; D004546:Elapid Venoms / Q000494:pharmacology / Q000627:therapeutic use; D006439:Hemodynamics; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010215:Papio
D004546:Elapid Venoms; C016310:cobra venom factor; D003165:Complement System Proteins; D003402:Creatine Kinase; D007052:Ibuprofen