Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1.
OBJECTIVE
A blocking monoclonal antibody to intercellular adhesion molecule-1 (ICAM-1), CL18/6, previously has been demonstrated to inhibit neutrophil attachment to isolated vascular endothelium and cardiomyocytes. Due to the well known participation of ICAM-1 in the inflammatory responses associated with myocardial ischemia/reperfusion injury, we investigated if CL18/6 could attenuate myocardial ischemia/reperfusion injury in vivo.


METHODS
Saline (3-5 ml, i.v., n = 6), non-blocking control MAb CL18/1D8 or CL18/6 (both 0.5 mg kg-1, i.v., n = 4) were administered prior to coronary occlusion (1 h) and subsequent reperfusion (5 h) produced by inflation of a coronary balloon angioplasty catheter in isoflurane-anesthetized, closed-chest dogs. Heart rate and arterial pressure were measured, and regional myocardial blood flow (rMBF), and myeloperoxidase activity (MPO) to index local neutrophil sequestration, were determined. Myocardial infarct size (IS) was evaluated using the tetrazolium staining technique and expressed as a percent of area at risk (AR).


RESULTS
Changes in heart rate and arterial pressure were insignificant throughout the experiment. rMBF (mean +/- s.e.m.) in the ischemic subendocardium for each treatment group was: Saline (0.07 +/- 0.02 ml min-1 g-1); CL18/1D8 (0.04 +/- 0.02); CL18/6 (0.06 +/- 0.02). IS/AR% was: saline (37 +/- 3%); CL18/1D8 (39 +/- 9%); CL18/6 (15 +/- 4%*); * = significantly different from CL18/1D8 and saline, P < 0.05. MPO assayed from AR immediately adjacent to the infarct was significantly reduced below infarct MPO only in the CL18/6 treated group-36%).


CONCLUSIONS
The results indicate that CL18/6 antagonism of ICAM-1 provided cardioprotection associated with reduced neutrophil activity in vulnerable myocardium, and suggest that ICAM-1 mediated neutrophil sequestration in endangered cardiac tissue is an important mechanism of myocardial ischemia/reperfusion injury.
Hartman
J C
JC
Upjohn Company, Kalamazoo, MI 49001, USA.
Anderson
D C
DC
Wiltse
A L
AL
Lane
C L
CL
Rosenbloom
C L
CL
Manning
A M
AM
Humphrey
W R
WR
Wall
T M
TM
Shebuski
R J
RJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000032:analysis
D000911:Antibodies, Monoclonal; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase