Effect of duration of ischaemia on reduction of myocardial infarct size by inhibition of neutrophil accumulation using an anti‐CD18 monoclonal antibody

Abstract

Neutrophil accumulation is a characteristic feature of the inflammatory response in myocardial tissue which has undergone a period of ischaemia. The aim of this study was to examine whether inhibition of myocardial neutrophil infiltration, using an antibody to the CD18 leukocyte adhesion molecule, was effective in reducing infarct size in anaesthetized rabbits. Anaesthetized rabbits underwent coronary artery occlusion (CAO) for periods of 30 or 45 min followed by reperfusion for 3 h. Animals were treated intravenously 10 min prior to reperfusion with IB4, a monoclonal antibody to CD18 (1 mg kg−1) or saline (1 ml kg−1). In one group undergoing 45 min CAO, a control antibody, OKMI (1 mg kg−1) was given. Following either 30 or 45 min of CAO, administration of IB4 resulted in a <75% inhibition in neutrophil accumulation in the area at risk myocardium (AR) compared with control animals. With the 30 min occlusion period, IB4 significantly reduced myocardial infarct size, 27.2 ± 3.2% vs 67.4 ± 5.6% in the saline control group (n = 5 P < 0.01). In contrast, IB4 did not reduce infarct size following a 45 min period of ischaemia. In the same animals administration of IB4 significantly inhibited oedema formation in skin elicited by intradermal administration of the neutrophil chemoattractant f‐Met‐Leu‐Phe, but had no effect on coronary microvascular plasma protein leakage in the AR. Our results indicate that infiltrating neutrophils exacerbate tissue injury following a relatively short, 30 min period of myocardial ischaemia in the rabbit. However, protection with IB4 was no longer seen if the period of CAO was extended to 45 min. The results in this model suggest neutrophils are not a major determinant of tissue injury following more than a very short period of ischaemia.

Double-Blind, Randomized Trial of an Anti-CD18 Antibody in Conjunction With Recombinant Tissue Plasminogen Activator for Acute Myocardial Infarction

“…In rabbits with myocardial infarction, anti-CD18 therapy was effective after coronary occlusion lasting 30 but not 45 minutes. 18 By contrast, in dogs with neutrophil depletion, myocardial necrosis was reduced with ischemia of either 90 or 240 minutes. 5 Sharar et al 3 found, using a rabbit ear preparation and 6 hours of occlusion, that administration of anti-CD18 therapy immediately on reperfusion was as effective as that initiated 1 hour but not 4 hours later.…”

Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8.

“…Myeloperoxidase (MPO) activity was measured as described previously (8). The frozen NZ and AR samples were homogenized in 0.02 M NaPO4 buffer (pH 4.7) containing 0.1 M NaCl and 0.015 M Na2 EDTA, and centrifuged at 20,000 g for 15 min at 4°C.…”

“…Neutrophil accumulation is markedly accelerated during reperfusion (3,4) and early studies implicated this cell in the associated tissue damage. Thus, systemic neutrophil-depletion (5) and antibodies blocking leukocyte adhesion molecules have been shown to limit infarction (6)(7)(8). This link between neutrophils and damage is controversial, as it has been reported in some models that agents affecting neutrophils do not influence infarction (9,10).…”

A unique pathway of cardiac myocyte death caused by hypoxia–acidosis

“…Multiple additional factors contribute to cell death as the infarcted area expands and more border cells die. These include collateral damage from necrosis and infiltrating macrophages (Williams et al, 1994), additional necrotic and apoptotic death resulting from energy (glucose and ATP) depletion (Buja et al, 1993;Hochachka et al, 1996;Majno and Joris, 1995;Reimer and Ideker, 1987;Mani and Kitsis, 2003), and changes associated with hypoxia. The pathways of ischemic injury are the subjects of intensive study because descriptions of these pathways may lead to new methods of reducing tissue loss and minimizing the damage caused by infarction and heart attack.…”