Infiltration of polymorphonuclear cells into the post-ischaemic myocardium is dependent on β2 and α4 integrins

Much of the evidence to date suggests that a key component of cardiac remodelling after myocardial infarction (MI) is an inflammatory response which can modulate left ventricular tissue repair (Entman et al. 1991; Pfeffer et al. 1991; Frangogiannis et al. 2002). As part of this inflammatory response, leucocytes have been shown to accumulate within the myocardium following MI (Leff & Repine 1990; Lucchesi 1990). In fact polymorphonuclear cells (PMN) have been suggested to be important effector cells not only responsible for tissue repair (healing) but also responsible for some of the observed myocardial cell damage (Duilio et al. 2001). The PMN’s migrate to sites of inflammation in response to chemotactic signals and utilizing specific cell adhesion molecule mediated adherence, activation and transmigration through the vascular endothelium (Frenette & Wagner 1996a,b). CD18 integrins are cell adhesion molecules expressed by circulating neutrophils which can bind to ICAM-1 and ICAM-2 expressed on endothelial cells facilitating firm adhesion to the endothelium prior to extravasation (Kukielka et al. 1993). Expression of both of these cell adhesion molecules has been shown to increase in response to ischaemia. Supporting a key role for CD18/ICAM-1 (-2) interactions in neutrophil infiltration has been the demonstration of the cardioprotective effects of monoclonal antibody (mAb) blockade of CD18, and blockade of ICAM-1 in models of myocardial ischaemic reperfusion injury (Simpson et al. 1988; Ma et al. 1991, 1992; Lefer et al. 1993, 1996; Yamazaki et al. 1993; Aversano et al. 1995; Hartman et al. 1995; Arai et al. 1996). More recently data from knockout mice deficient in either CD18 or ICAM-1 have shown modest reduction in PMN infiltration ranging from 32% to 54% following myocardial ischaemia (Palazzo et al. 1998; Briaud et al. 2001). However, the degree of myocardial protection from PMN infiltration using these approaches has been variable depending on the model and experimental protocol utilized suggesting increased complexity and likely yet to be identified mechanisms controlling trafficking (Ma et al. 1991, 1992; Lefer et al. 1993, 1996; Aversano et al. 1995; Hartman et al. 1995; Arai et al. 1996). In addition, most experimental models and evidence to date have looked at PMN infiltration in the setting of ischaemia reperfusion rather than infarction where the blood supply is not restored. Finally, the clinical application of strategies aimed at limiting PMN infiltration targeting CD18/ICAM-1have largely failed (Baran et al. 2001; Rusnak et al. 2001). Taken together there remains significant controversy as to the kinetics and adhesion pathways controlling PMN infiltration into post-ischaemic myocardium and its role in myocardial injury.