Current knowledge on oxidative stress in hepatic ischemia/reperfusion.

Ischemia/reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, despite several attempts to solve the problem. The redox balance, which is pivotal for normal function and integrity of tissues, is dysregulated during I/R, leading to an accumulation of reactive oxygen species (ROS). Formation of ROS and oxidant stress are the disease mechanisms most commonly invoked in hepatic I/R injury. The present review examines published results regarding possible sources of ROS and their effects in the context of I/R injury. We also review the effect of oxidative stress on marginal livers, which are more vulnerable to I/R-induced oxidative stress. Strategies to improve the viability of marginal livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. The review also considers the therapeutic strategies developed in recent years to reduce the oxidative stress induced by hepatic I/R, and we seek to explain why some of them have not been applied clinically. New antioxidant strategies that have yielded promising results for hepatic I/R injury are discussed.

Tauroursodeoxycholic acid affects PPARγ and TLR4 in Steatotic liver transplantation.

Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-γ (PPARγ) and damage. When PPARγ was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARγ, and the PPARγ antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNß (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARγ antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARγ and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.

The Current Knowledge of the Role of PPAR in Hepatic Ischemia-Reperfusion Injury.

Strategies to improve the viability of steatotic livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid metabolism and inflammation. In this paper, we review the PPAR signaling pathways and present some of their lesser-known functions in liver regeneration. Potential therapies based on PPAR regulation will be discussed. The data suggest that further investigations are required to elucidate whether PPAR could be a potential therapeutic target in liver surgery and to determine the most effective therapies that selectively regulate PPAR with minor side effects.

The current state of knowledge of hepatic ischemia-reperfusion injury based on its study in experimental models.

The present review focuses on the numerous experimental models used to study the complexity of hepatic ischemia/reperfusion (I/R) injury. Although experimental models of hepatic I/R injury represent a compromise between the clinical reality and experimental simplification, the clinical transfer of experimental results is problematic because of anatomical and physiological differences and the inevitable simplification of experimental work. In this review, the strengths and limitations of the various models of hepatic I/R are discussed. Several strategies to protect the liver from I/R injury have been developed in animal models and, some of these, might find their way into clinical practice. We also attempt to highlight the fact that the mechanisms responsible for hepatic I/R injury depend on the experimental model used, and therefore the therapeutic strategies also differ according to the model used. Thus, the choice of model must therefore be adapted to the clinical question being answered.