Molecular responses to ischemia and reperfusion in the liver

Abstract

Ischemia/reperfusion (IR) injury occurs when oxygen is rapidly reintroduced into ischemic tissue, resulting in cell death and necrotic tissue damage. This is a major concern during liver transplantation procedures since there is an inevitable interruption and subsequent restoration of circulation. IR injury in liver tissue is initiated through reactive oxygen species (ROS), which are generated by hepatocytes during IR insult. Although these ROS are thought to play a protective roll since they are known to activate several pathways involved in the hypoxic response, they also trigger a localized sterile immune response that results in the recruitment of Kupffer cells and neutrophils to the site of IR insult. These immune cells generate larger quantities of ROS that trigger apoptosis and oncotic necrosis in liver tissue. In this review, we will summarize what is currently known about the response of liver tissue to IR insult at the molecular level.

Ischemia/Reperfusion

“…Ligation of C3a and C5a receptors on Kupffer cells stimulates phospholipase C to produce diacylglycerol (DAG) and inositol 3-phosphate (IP 3 ). DAG stimulates protein kinase C (PKC)-dependent ROS production by NADPH oxidase (648a). ROS production is further reinforced by the effect of IP 3 to stimulate Ca 2+ mobilization from internal stores and uptake from the extracellular compartment.…”

“…Once activated by the aforementioned mechanisms in I/R, overexuberant production of oxidants, cytokines, PAF, and other proinflammatory mediators by Kupffer cells contribute to postischemic liver injury and remodeling (58, 108, 351, 374, 375, 378, 648a). MMP-9 released from Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells also contributes to the pathogenesis of hepatic I/R in the first 24 h of reperfusion but then switch roles at later times to facilitate liver recovery (235, 519).…”

Understanding the Origins of Ischemia and Reperfusion

“…It took many years to characterize this lesion that appears simple but has been problematic to recognize what causes damage after its inception. Subsequent to the initial immune damage other elements get activated like platelets, complement, regulatory T-cells, dendritic cells, and other elements of the inflammatory machinery (12,13). Previous work by our group has presented various solutions to the definition and improvement of this lesion (12)(13)(14)(15).…”

The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury

“…The only curative treatment for liver cirrhosis remains transplantation. As part of liver transplantation, the hepatic blood flow is temporarily interrupted to aid surgery, but this leads to the development of ischemia/reperfusion injury (IRI) once blood flow to the liver is restored . Moreover, 20% of the complications following liver transplantation, including graft dysfunction and/or primary graft nonfunction, are directly attributable to IRI …”

“…However, the mechanisms that regulate injury to LEC during IRI remain to be fully determined. It is known that reactive oxygen species (ROS) are key regulators of liver IRI . ROS can be generated by both parenchymal and nonparenchymal cells (eg, Kupffer cells) within the liver during IRI .…”