Ischemia-Reperfusion Injury of the Liver with Special Reference to Calcium-Dependent Mechanisms

Abstract

Ischemia-reperfusion (I/R) injury is a complex process involving numerous intracellular signaling pathways, mediators, cells, and pathophysiological disturbances; its prevention during liver surgery is of utmost importance. In this review, we divide hepatic I/R injury into two phases, intracellular and extracellular, for a better understanding of the processes involved. Ca2+ and Ca2+-dependent reactions play an important role as a trigger in the former phase, while the subsequent generation of bioactive substances plays a predominant role in the latter phase. These findings indicate that a combination of different therapeutic approaches against Ca2+-dependent steps may help prevent I/R injury of the liver.

Atrial Natriuretic Peptide Attenuates Elevations in Ca2+ and Protects Hepatocytes by Stimulating Net Plasma Membrane Ca2+ Efflux

“…A rise in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is a common early event in cellular injury (1)(2)(3)(4)(5)(6). Harmful increases in [Ca 2ϩ ] i can result from increased Ca 2ϩ influx, sustained Ca 2ϩ release from intracellular stores, or a reduced rate of Ca 2ϩ extrusion across the plasma membrane (1,(7)(8).…”

“…Elevated [Ca 2ϩ ] i also injures hepatocytes in several pathophysiological liver conditions, including ischemia-reperfusion injury (6,21), endotoxaemia (22), and hemorrhagic shock (23). The [Ca 2ϩ ] i rise activates Ca 2ϩ -dependent enzymes including calpain, a neutral cysteine protease (24) that plays a key role in initiation of cellular injury and subsequent necrosis or apoptosis (6,(25)(26)(27)(28)(29)(30).…”

“…In the search for cytoprotective agents and therapeutic interventions, those which suppress injurious [Ca 2ϩ ] i rises are considered highly promising (2)(3)(4)(5)(6)30). Natriuretic peptides attenuate elevations in cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) in many cell types (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50), including rat hepatocytes (51).…”

“…Atrial natriuretic peptide is a circulating hormone that has been shown to be hepatoprotective. The aim of this study was to examine the effects of atrial natriuretic peptide on potentially harmful elevations in cytosolic free Ca 2؉ (24) that plays a key role in initiation of cellular injury and subsequent necrosis or apoptosis (6,(25)(26)(27)(28)(29)(30). In hepatocytes, calpain promotes hepatocyte plasma membrane blebbing (31), induces the mitochondrial permeability transition in hepatocyte necrosis (32), and contributes to hepatocyte necrosis in anoxia (33).…”

Oxidative Stress and Liver Ischemia–Reperfusion Injury

“…The contribution of cholesterol to normothermic ischemic injury is independent of the qualitative appearance of steatosis (microsteatosis vs. macrosteatosis). Livers with microsteatosis induced by CD diet feeding are less sensitive to I/R damage than those with macrosteatosis observed in ob/ob mice [ 79 ]. However, the steatosis of CD-fed mice is relatively microvesicular compared to that of ob/ob mice, but it is more macrovesicular than that of HC-fed mice, and yet HC-fed mice are more sensitive to hepatic I/R injury than CD-fed mice.…”