Hepatic Ischemia/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration

Abstract

Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.

Figure 1

Events contributing to inflammatory liver injury after ischemia/reperfusion (I/R). Oxidant stress induced by I/R results in the release of complement, high-mobility group box 1 (HMGB1), and IL-23, which activate Kupffer cells and induce their production of TNF-α. TNF-α propagates the inflammatory response by upregulating adhesion molecules on endothelial cells and inducing expression of CXC chemokines by hepatocytes. At the same time, CD4 T cells are transiently recruited to the liver and, along with the increased expression of CXC chemokines and adhesion molecules, facilitates neutrophil recruitment into the liver parenchyma. Neutrophils then directly injure hepatocytes via oxidants and proteases, leading to necrotic cell death.

Figure 2

Cell-specific roles of nuclear factor κB (NF-κB) in liver injury and recovery and regeneration. NF-κB is a driver of the inflammatory response: I/R induces the generation of reactive oxygen species (ROS) in Kupffer cells, which activates NF-κB resulting in the production and release of proinflammatory cytokines, such as TNF-α, by Kupffer cells. These proinflammatory cytokines activate other cell types to produce inflammatory mediators, such as adhesion molecules and chemokines, which facilitate the recruitment of neutrophils. NF-κB is a key modulator of hepatocyte survival: ROS generated by Kupffer cells also impacts hepatocytes and contributes to mitochondrial dysfunction. NF-κB activation in hepatocytes leads to the production of several cytoprotective proteins that mitigate mitochondrial dysfunction and contribute to hepatocyte survival and proliferation.

Figure 3

Remodeling of liver tissue after I/R injury. During liver repair and regeneration after I/R injury, a frontal boundary (arrows) of phagocytes, stellate cells, and others clears and remodels necrotic tissue (above boundary) such that regenerating hepatocytes can restore functional mass and normal architecture (below boundary).