Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury

Abstract

Expression of endothelial and leukocyte cell adhesion molecules is a principal determinant of polymorphonuclear neutrophil (PMN) recruitment during inflammation. It has been demonstrated that pharmacological inhibition of these molecules can attenuate PMN influx and subsequent tissue injury. We determined the temporal expression of alpha-granule membrane protein-40 (P-selectin), endothelial leukocyte adhesion molecule 1 (E-selectin), and intercellular cell adhesion molecule 1 (ICAM-1) after coronary artery occlusion and up to 3 days of reperfusion. The expression of all of these cell adhesion molecules peaked around 24 h of reperfusion. We determined the extent to which these molecules contribute to PMN infiltration by utilizing mice deficient (-/-) in P-selectin, E-selectin, ICAM-1, and CD18. Each group underwent 30 min of in vivo, regional, left anterior descending (LAD) coronary artery ischemia and 24 h of reperfusion. PMN accumulation in the ischemic-reperfused (I/R) zone was assessed using histological techniques. Deficiencies of P-selectin, E-selectin, ICAM-1, or CD18 resulted in significant (P < 0.05) attenuation of PMN infiltration into the I/R myocardium (MI/R). In addition, P-selectin, E-selectin, ICAM-1, and CD18 -/- mice exhibited significantly (P < 0.05) smaller areas of necrosis after MI/R compared with wild-type mice. These data demonstrate that MI/R induces coronary vascular expression of P-selectin, E-selectin, and ICAM-1 in mice. Furthermore, genetic deficiency of P-selectin, E-selectin, ICAM-1, or CD18 attenuates PMN sequestration and myocardial injury after in vivo MI/R. We conclude that P-selectin, E-selectin, ICAM-1, and CD18 are involved in the pathogenesis of MI/R injury in mice.

Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

“…Mice deficient in P-selectin and E-selectin, for instance, manifest with about 40% reduction of tissue damage in the model of myocardial IRI [28]. Similar reduction of myocardial IRI was observed after genetic targeting of endothelial Ig-family member ICAM-1 [28]. Indirect ALI is another example of a condition in which the tissue damage is caused by excessive leukocyte recruitment.…”

“…Inhibition of leukocyte-endothelial interaction by blocking the classical adhesion molecules has shown to reduce tissue damage in IRI in numerous studies using gene-targeted animals [27]. Mice deficient in P-selectin and E-selectin, for instance, manifest with about 40% reduction of tissue damage in the model of myocardial IRI [28]. Similar reduction of myocardial IRI was observed after genetic targeting of endothelial Ig-family member ICAM-1 [28].…”

Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function

“…Inhibition of leukocyte transmigration is one possible mechanism by which H 2 S restrains the extent of inflammation and thereby limits the extent of myocardial infarction. A number of studies (16) have cited the influence of IL-1␤ on the development of ischemic injury in the heart and the pathogenic role of inflammatory cytokines in the recruitment and subsequent migration of inflammatory cells into the heart (17).…”

Inhibition of Polymorphonuclear Leukocyte–Mediated Graft Damage Synergizes With Short-Term Costimulatory Blockade to Prevent Cardiac Allograft Rejection

“…The histological hallmark of this early innate immune response is a PMNdominant infiltrate that contributes to parenchymal tissue damage, stimulates the upregulation of adhesion and MHC molecules on the vascular endothelium, and induces production of cytokines and chemokines that promote leukocyte trafficking to the allograft. 28,29 In addition, this intragraft proinflammatory milieu stimulates the maturation and emigration of donor-derived antigen-presenting cells from the graft to draining lymphoid tissue, where they prime naïve recipient alloreactive T cells.…”