Ischemia Reperfusion Injury and Immune Modulation: New Insights into Pathogenesis and Therapy

Abstract

Ischemia-reperfusion injury (IR) is a counterintuitive condition in which the reintegration of blood supply to an ischemic tissue results in an increase in cellular damage as well as an exaggeration of a harmful inflammatory response. It is an acute pathophysiological mechanism underlying morbidity and mortality of a broad range of clinical syndromes, such as myocardial infarction, stroke, organ transplantation and shock. The mechanism of IR is another complex process wherein metabolic perturbation, oxidative stress, intracellular calcium overload, and an extensive activation of innate and adaptive immune systems are intertwined. The review gives an excellent summary of the existing knowledge regarding the molecular and cellular pathways involved in the development of IR, especially the critical role of immune modulation. We explore organ-relevant phenotypes, interrogate major signal transduction mechanisms (NF-kB, NLRP3 inflammasome, and HIF), and assess the interactions among cell death pathways (apoptosis and necroptosis). Moreover, we evaluate critically the terrain of therapeutic approaches, including conventional and emerging frontiers of pharmacotherapy, cellular/gene therapy, and nanomedicine. Finally, we address more sophisticated immune-modulating approaches like monoclonal antibodies, RNA-based therapeutics, and present the guidelines in which biomarkers, personalized medicine, and merging multi-omics and artificial intelligence bridge the knowledge-to-clinical practice gap.