Protective effect of ischemic preconditioning against hepatic ischemia-reperfusion injury and associated remote organ damage

Abstract

Hepatic ischemia-reperfusion injury is a significant complication of liver surgery, including major hepatectomy, trauma surgery and liver transplantation. It is a key factor in postoperative organ failure, which negatively affects prognosis and overall patient survival. Beyond its localized hepatic effects, ischemia-reperfusion injury is increasingly recognized as a potent trigger of the systemic inflammatory response and remote organ damage. The cellular and molecular mechanisms involved are highly complicated and have yet to be entirely elucidated. The core pathophysiological mechanisms of hepatic ischemia-reperfusion injury include a transition to anaerobic metabolism and adenosine triphosphate depletion; the development of intracellular acidosis and calcium overload; the impairment of mitochondrial function; oxidative stress; the activation and accumulation of distinct cell populations, notably Kupffer cells, neutrophils and platelets; the upregulation and downregulation of microRNAs; increased nitric oxide production; and the triggering of an immune system response with the activation of the complement system and excessive cytokine release. Ischemic preconditioning (IP) is a surgical technique in which brief cycles of controlled ischemia followed by reperfusion are applied directly to an organ, aiming to enhance its tolerance to subsequent prolonged ischemia. Hepatic IP has been demonstrated to reduce ischemia-reperfusion injury by decreasing the release of proinflammatory cytokines and damage-associated molecular patterns; suppressing reactive oxygen species production; activating the antioxidant enzyme heme-oxygenase 1, caspase, heat shock proteins and protein kinase cascades; modulating energy supplies and electrolyte homeostasis; and intervening in cell death pathways. In addition to its local effects on the liver, growing evidence indicates that IP also provides systemic advantages by reducing the inflammatory response and limiting injury to distant organs following major hepatic injury. This review integrates current data on IP, highlighting its role in hepatic protection and prevention of remote organ damage, while exploring the underlying mechanisms and translational potential of this approach in hepatic surgery and transplantation.

Keywords: Hepatic ischemia-reperfusion injury; Remote organ damage; Systemic inflammatory response; Ischemic preconditioning; Liver transplantation; Protective method; Pathophysiological mechanisms

Core Tip: Hepatic ischemia-reperfusion injury remains a critical challenge in liver surgery and transplantation and results in increased postoperative morbidity and mortality. The complexity of the underlying pathophysiological mechanisms makes liver damage difficult to manage. Ischemic preconditioning is a promising protective strategy that limits hepatic injury while providing systemic benefits through the regulation of oxidative stress, the inflammatory response, and programmed cell death pathways. By offering protection to remote organs, ischemic preconditioning has the potential to enhance the outcomes of transplantation and other high-risk procedures, although further studies are needed to establish optimal clinical protocols.