Preconditioning for Protection from Ischemic Injury: Discriminating Cause From Effect From Epiphenomenon

Abstract

The quest for protection from ischemic (actually ischemia/reperfusion) injury is not new, but in the past several years, this concept has been approached somewhat more rigorously by investigators addressing important clinical problems, particularly heart attack, cardiopulmonary bypass, stroke, peripheral vascular embolism, and the preservation of organs for transplantation. Much of the recent work has focused on the rather remarkable observation that relatively short periods of ischemia sustained just prior to a more prolonged (i.e., clinically relevant) episode appear to have improved the tolerance to the latter in a number of organs, including the heart, brain, 1 spinal cord, 2 skeletal muscle, 3 retina, kidney, intestine, 4 -6 and liver.

Tumor necrosis factor suppression and microcirculatory disturbance amelioration in ischemia/reperfusion injury of rat liver after ischemic preconditioning†

“…There may be various linear sequences of pathways, and each of these sequences interacts with and branches into others. Furthermore, those pathways may be additive, antagonistic, or synergistic each other 31 . In the present study, the differences of TNF‐α in serum and tissue between the control and IPC groups were statistically significant but not substantial compared with other parameters such as hepatic enzymes and morphological findings, suggesting that TNF‐α may be one of the potential mediators associated with the IPC mechanism as well as the other mediators previously reported.…”

“…It is reasonable to note that TNF‐α may not be the only key mediator in the mechanism of IPC. Upon reviewing the literature concerning the preconditioning effect in the organs, various mediators or pathways were suggested to contribute to the mechanism 31 . As for hepatic preconditioning, adenosine A2 receptor activation, in particular, has been suggested to be involved in the mechanism of preconditioning 6,7 .…”

Comparison of Ischemic Preconditioning and Intermittent and Continuous Inflow Occlusion in the Murine Liver

“…20,21 We recently demonstrated in a mouse model that ischemic preconditioning protects against lethal ischemic stress through downregulation of the apoptotic pathway. 22 Various mediators have been implicated in the protective mechanisms of ischemic preconditioning (e.g., nitric oxide, 20 adenosine, 23 and others 24 ). We recently provided evidence that a preconditioning period of 10 minutes followed by 10 minutes of reperfusion confers protection against prolonged ischemic insults in patients undergoing liver resections.…”

“…Taken together, downregulation of apoptotic cell death appears to be a central mechanism of protection, rather than only an epiphenomenon. 24 Staining with hematoxylin and eosin was used to evaluate morphologic changes in the postischemic liver tissue. In tissue subjected to continuous inflow occlusion (with either 75 or 120 minutes of ischemia) and in the preconditioning group with 120 minutes of ischemia, we observed a pattern of tissue destruction that could also be a result of necrotic changes.…”

Hypoxia-reoxygenation-induced chemokine transcription is not prevented by preconditioning or intermittent hypoxia, in mice hepatocytes

“…It consists of a short period of ischemia followed by a short period of reperfusion before the beginning of prolonged ischemia. This process protects against lethal ischemic stress [24,26–28]. We have shown recently [29] that intermittent ischemia in an in vivo I/R model or intermittent hypoxia, in cultured hepatocytes, significantly reduced apoptosis through reduction of JNK 1 /SAPK 1 activation and downregulation of caspase 3 activity.…”