Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

Abstract

Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of bile flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2+, involved in IR injury and ischemic preconditioning. It is concluded that bile flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2+ in hepatocytes plays a key role in the normal regulation of bile flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.

Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease

“…Increased cytosolic Ca 2+ is a key event in the pathological process of I/R injury because Ca 2+ can induce the opening of mitochondrial permeability transition pore and lead to mitochondrial swelling and the release of cyt c from mitochondria, initiating cell apoptosis and necrosis (31,32). A rapid increase in hepatocyte Ca 2+ was detected after the onset of reperfusion, but not during the ischemic phase (33). In the present study, we show that mitochondrial CBS accumulation during liver ischemia is associated with increased production of H 2 S in mitochondria, and H 2 S inhibits Ca 2+ -induced cyt c release and mitochondrial swelling in vitro.…”

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“…5,6 During ischemiareperfusion injury, NO has a protective effects by scavenging free radicals, relaxing vascular smooth muscle, and affecting antiapoptosis. 6,7 Inhalation of NO gas after liver transplant lowers hepatocyte apoptosis. 8 During acute rejection, vascular endothelial cell damage occurs, and the eNOS pathway may be involved.…”

Hepatic artery bridging lessens temporary ischemic injury to bile canaliculi

“…Microvilli in bile canaliculus epithelial cells consist of Factin microfilaments, which are very important for bile excretion [7] . The continuous assembly and disassembly of Factin microfilaments promote bile duct contraction and bile excretion; therefore, the loss of Factin microfilaments leads to bile secretion disorder [9,10] . Some researchers have confirmed that cofilin and heat shock protein 27 (HSP27) are very important in the assembly and disassembly of F-actin microfilaments [11,12] .…”