Early and Late Preconditioning Prevent Ischemia / Reperfusion Injury: Signalling Pathways Mediating the Adaptive Metamorphosis to a Protective Phenotype in Preconditioned Tissues

Preconditioning refers to a phenomenon whereby tissues are rendered resistant to the deleterious effects of prolonged ischemia and reperfusion (I/R) by prior exposure to oxidants, brief periods of vascular occlusion, endotoxin derivatives, heat shock, a variety of pharmacologic agents (chemical or pharmacologic preconditioning) or chronic ethanol consumption (6, 11, 16, 26, 29, 35, 40, 42, 48, 55, 71). Of these perturbations, our best understanding of the mechanisms involved in conferring protection is related to ischemic preconditioning (IPC). The beneficial effects of IPC are not related to improved collateral flow but instead represent an enhanced intrinsic ability of tissues to tolerate ischemia. However, recent work indicates that in addition to its anti-ischemic effects, IPC also completely prevents the reperfusion component of tissue injury by abrogating the inflammatory changes that are initiated in the microcirculation upon restitution of blood flow (1, 7, 14, 29, 36, 40, 41, 75). Additional support for this concept is provided by the demonstration that endothelium-dependent vasoregulatory mechanisms remain intact in preconditioned tissues (42, 71). Taken together, these observations indicate that adaptive changes in the microvasculature play a key role in the development of the preconditioned state. Thus, understanding the mechanisms whereby both arterial and venular endothelium enter a protective or defensive phenotype as a result of preconditioning may lead to the development of novel therapeutic strategies to manage I/R injury.