Cytoprotective effect of prostacyclin on hepatic ischemia-reperfusion injury

Abstract

Hepatic ischemia-reperfusion injury is an important mechanism of liver failure that occurs in many clinical conditions, including massive hemorrhage, major hepatectomy and liver transplantation, and leads to poor outcomes. The underlying cellular and molecular reactions are extremely complex and not completely understood. Anaerobic metabolism, ATP depletion, intracellular acidosis, calcium overload, mitochondrial dysfunction, oxidative stress, activation of Kupffer cells and neutrophils, platelet aggregation, nitric oxide production, activation of the complement system and overexpression of cytokines and chemokines constitute the main pathophysiological actions and pathways for possible therapeutic strategies. Prostaglandins (PGs) are a group of biologically active lipid compounds called eicosanoids with many physiological activities. Prostacyclin (PGI₂) is a member of the PGs family with an unstable chemical structure and a very short half-life. PGI₂ has potent vasodilating activity, inhibits platelet activation and exerts anti-inflammatory effects. PGI₂ has been evaluated in chronic liver disease as a mediator of hepatic stellate cell function, an antiproliferative and antifibrotic agent and a regulator of the hepatic microcirculation. In recent decades, the cytoprotective effects of PGI₂ analogs on hepatic ischemia-reperfusion injury have been experimentally and clinically studied. Moreover, the administration of synthetic PGI₂ analogs to patients who underwent liver transplantation produced very encouraging results. The downregulation of PGE₂ production, reduction of neutrophil aggregation in liver lobules, regulation of local microcirculatory homeostasis, improvement in mitochondrial function, alleviation of hepatic oxidative stress, suppression of the c-Jun N-terminal kinase and p38 cascades and downregulation of tumor necrosis factor-alpha and interleukin-1β production constitute some of the underlying physiological mechanisms of the beneficial effects of PGI₂ on hepatic ischemia-reperfusion injury. Thus, PGI₂ analogs appear to hold great promise for the management of hepatic ischemia-reperfusion injury, but further research is needed.

Keywords: Hepatic ischemia-reperfusion injury; Oxidative stress; Prostacyclin analogs; Prostaglandins; Liver transplantation; Liver graft dysfunction

Core Tip: Hepatic ischemia-reperfusion injury is a critical event that affects the outcomes of liver surgery, transplantation and many other major clinical conditions. The reoxygenation of ischemic hepatocytes activates complex inflammatory processes, which lead to oxidative stress that has deleterious local and global consequences. Prostacyclin (PGI₂) is a well-known member of the prostaglandin family with potent vasodilative, platelet-inhibiting and anti-inflammatory effects. Several reports have detailed the cytoprotective effects of PGI₂ analogs on hepatic ischemia-reperfusion injury. In this review, we discuss the underlying mechanisms of hepatic ischemia-reperfusion injury and the potential hepatoprotective effects of PGI₂ analogs.