Pathomechanisms of ischemia-reperfusion injury as the basis for novel preventive strategies: is it time for the introduction of pleiotropic compounds?

Ischemia-reperfusion-associated tissue dysfunction and organ failure still represent major complications in transplantation surgery. The pathomechanisms involve microvascular perfusion failure, ie, no-reflow and tissue hypoxia despite reperfusion and reoxygenation. However, postischemic reperfusion also provokes an inflammatory response, ie, reflow paradox, with activation of macrophages, recruitment of leukocytes, and accumulation of platelets, involving surface adhesion molecules such as P-selectin, P-selectin glycoprotein ligand (PSGL)-1, Mac-1, and intercellular adhesion molecule (ICAM)-1. These inflammatory cells produce cytokines, chemokines, lipid mediators, and oxygen radicals, which all may contribute to the manifestation of injury, including apoptosis, necrosis, and necrapoptosis. Although specific inhibition of single mediators, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and oxygen radicals, or distinct molecules, such as P-selectin and ICAM-1, has been shown to be protective in the experimental setting, these single-agent antimediator and antimolecule approaches did not find their way into clinical practice. Clinically, University of Wisconsin (UW) solution for organ preservation is still the major milestone for prevention of ischemia- and reperfusion-associated injury. Characteristically, this treatment strategy does not represent an anti-single mediator approach, but exerts protection by influencing multiple pathways involved in hypoxic and inflammatory injury, potentially restoring the overall homeostasis. This type of pleiotropic action may also be achieved by single pharmacological compounds, such as statins, erythropoietin, hemoxygenase-1, and L-glycine. In recent experimental studies, these compounds have been shown to be effective to reduce post-ischemic-reperfusion injury, and, additionally, to be associated with less side effects. Accordingly, these pleiotropic substances may represent ideal candidates for pharmacological preconditioning in patient treatment, and, thus, should be further evaluated in clinical trials.