Ischemia/Reperfusion Injury: Pathophysiology, Current Clinical Management, and Potential Preventive Approaches

Abstract

Myocardial ischemia reperfusion syndrome is a complex entity where many inflammatory mediators play different roles, both to enhance myocardial infarction-derived damage and to heal injury. In such a setting, the establishment of an effective therapy to treat this condition has been elusive, perhaps because the experimental treatments have been conceived to block just one of the many pathogenic pathways of the disease, or because they thwart the tissue-repairing phase of the syndrome. Either way, we think that a discussion about the pathophysiology of the disease and the mechanisms of action of some drugs may shed some clarity on the topic.

Figure 1

Inflammation during the Th1 tissue-damaging immune response of MIRS. Blood clots generate ischemia, which causes necrosis. Released DAMPs induce neutrophil and monocyte activation trough TLR and inflammasome activation, which in turn potentiate Th1 polarization. Inflammatory monocytes mature and become M1 macrophages. Tissue damage amplification comes in the form of NETs, granule components, and ROS produced by innate cells and direct complement attack.

Figure 2

The Th2-mediated reparative phase of MIRS. N2 neutrophils and M2 macrophages both produce high levels of IL-10 to dampen N1, Ly6C^hi, and M1-mediated degradation of tissue integrity. Also, M2 macrophages induce Th2 and Treg differentiation, while both suppress Th1 development, and Tregs thwart Th2 cells. M2 differentiation is possible by phagocytosis of the neutrophil apoptotic bodies. M2 and Treg cells mediate tissue repair.

Figure 3

Immune-regulatory drugs could thwart destructive inflammation and promote tissue repair. Corticosteroids could enhance M2 differentiation while blocking NET, ROS, and granule-component deposition, thus blocking inflammatory damage. Also, azithromycin and rosuvastatin may induce cardioprotective leukocytes.