The Effect of High-Mobility Group Box 1 in Rat Steatotic and Nonsteatotic Liver Transplantation From Donors After Brain Death.

High-mobility group box 1 (HMGB1) has been described in different inflammatory disorders, and the deleterious effects of brain death (BD) may counteract the protection conferred by ischemic preconditioning (IP), the only surgical strategy that is being applied in clinical liver transplantation. Our study examined how HMGB1 may affect preconditioned and unpreconditioned steatotic and nonsteatotic liver grafts from donors after BD (DBDs) for transplantation. HMGB1 was pharmacologically modulated in liver grafts from DBDs, and HMGB1-underlying mechanisms were characterized. We found that BD decreased HMGB1 in preconditioned and unpreconditioned livers and was associated with inflammation and damage. Exogenous HMGB1 in DBDs activates phosphoinositide-3-kinase and Akt and reduces hepatic inflammation and damage, increasing the survival of recipients. Combination of IP and exogenous HMGB1 shows additional benefits compared with HMGB1 alone. This study provides new mechanistic insights into the pathophysiology of BD-derived liver graft damage and contributes to the development of novel and efficient strategies to ultimately improve liver graft quality.

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.

Therapeutic targets in liver transplantation: angiotensin II in nonsteatotic grafts and angiotensin-(1-7) in steatotic grafts.

Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1-7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1-7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1-7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1-7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1-7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1-7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1-7), which is specific for steatotic liver grafts.

[Ischemia-reperfusion syndrome associated with liver transplantation: an update]. / Síndrome de isquemia-reperfusión asociado al trasplante hepático: una visión actualizada.

Ischemia-reperfusion (I/R) injury is the main cause of both initial graft dysfunction and primary failure in liver transplantation. The search for therapeutic strategies to prevent I/R injury has led to research into promising drugs, although most have not been used clinically. Gene therapy requires better transfection techniques, avoiding vector toxicity, and ethical debate before being used clinically. Ischemic preconditioning is the first therapeutic strategy used in clinical practice to reduce I/R injury in hepatectomies for tumors. Future research will provide data on the effectiveness of ischemic preconditioning in reducing I/R injury associated with liver transplantation, and in reducing the vulnerability of steatotic grafts to I/R syndrome so that they can be used in transplantation, thus relieving the organ shortage.

Síndrome de isquemia-reperfusión asociado al trasplante hepático: una visión actualizada / Ischemia-reperfusion syndrome associated with liver transplantation: an update

La lesión por isquemia reperfusión (I/R) es la causa principal tanto del mal funcionamiento inicial del injerto como del fallo primario en el trasplante hepático. La búsqueda de estrategias terapéuticas para prevenir la lesión por I/R ha conducido a la utilización de fármacos esperanzadores, aunque la gran mayoría de ellos no ha alcanzado una aplicación clínica. La terapia génica requiere mejorar las técnicas de transfección, evitar la toxicidad de vectores y una discusión ética antes de alcanzar el nivel clínico. El precondicionamiento isquémico (PC) es la primera estrategia terapéutica utilizada en la clínica para reducir la lesión por I/R en hepatectomías de tumores. Futuras investigaciones aportarán datos acerca de la efectividad del PC para reducir la lesión por I/R asociada al trasplante hepático, y aumentar la poca tolerancia de los injertos esteatósicos al síndrome de I/R para su utilización en el trasplante y aliviar, así, la carencia de órganos

Ischemia-reperfusion (I/R) injury is the main cause of both initial graft dysfunction and primary failure in liver transplantation. The search for therapeutic strategies to prevent I/R injury has led to research into promising drugs, although most have not been used clinically. Gene therapy requires better transfection techniques, avoiding vector toxicity, and ethical debate before being used clinically. Ischemic preconditioning is the first therapeutic strategy used in clinical practice to reduce I/R injury in hepatectomies for tumors. Future research will provide data on the effectiveness of ischemic preconditioning in reducing I/R injury associated with liver transplantation, and in reducing the vulnerability of steatotic grafts to I/R syndrome so that they can be used in transplantation, thus relieving the organ shortage

How ischaemic preconditioning protects small liver grafts.

Interleukin-1 (IL-1) and transforming growth factor-beta (TGFbeta) are key inhibitors of hepatocyte proliferation after hepatectomy. IL-1 inhibition by heat shock proteins (HSPs) has been reported in inflammatory processes. A recent study indicated the benefits of ischaemic preconditioning in reduced-size orthotopic liver transplantation (ROLT). The present study examined: (a) the effect of ischaemic preconditioning on IL-1 and TGFbeta in ROLT; (b) whether preconditioning protects small liver grafts through HSP induction; and (c) whether the potential benefits of preconditioning on HSP is related to IL-1 inhibition. Our results, obtained with an IL-1 receptor antagonist, indicated the injurious effects of IL-1 in ischaemia-reperfusion (I/R) injury and established a relationship between IL-1 and growth factors. Thus, IL-1 reduced hepatocyte growth factor (HGF) and promoted TGFbeta release, thus contributing to the impaired liver regeneration associated with ROLT. Preconditioning inhibited IL-1 through nitric oxide (NO), thereby protecting against the injurious effects of IL-1. In addition, by another pathway independent of NO, preconditioning induced HSP70 and haem-oxygenase-1 (HO-1). HO-1 protected against I/R injury and liver regeneration, whereas the benefits resulting from HSP70 were mainly related to hepatocyte proliferation. These results suggest a mechanism that explains the effectiveness of preconditioning in ROLT. They suggest, too, that other strategies, in addition to preconditioning, that modulate IL-1 and/or HSPs could be considered in clinical situations requiring liver regeneration such as small liver grafts.