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

Abstract

† These authors contributed equally to this work.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.

The impact of cortisol in steatotic and non‐steatotic liver surgery

“…Indeed, the role of ACh does differ in various pathologic states, proving advantageous in haemorrhagic shock, myocardial ischaemia and pancreatitis , but promoting inflammation and damage in chronic obstructive pulmonary disease . Our results for PH under I/R are nonetheless unlike than those detailed in previous reports of liver transplants from brain‐dead donors, whereby steatotic grafts were protected by ACh during prolonged (6‐hrs) cold ischaemia . This is expected because the systemic alterations induced by brain death (absent during PH under I/R), the extent and type of ischaemia ( i.e .…”

Use of Steatotic Grafts in Liver Transplantation: Current Status

“…This is particularly problematic in LT from cadaveric donors because of the very short period of time available in which to pretreat them in this emergency procedure. Many of the previously mentioned studies (13 of 23) were performed in rat models with moderate steatotic livers . Of these studies,11 used fatty livers from Zucker rats; 5 used a methionine‐choline deficient diet and 5 a HFD, both models of steatohepatitis.…”

“…Given this, it would be extremely useful to make a clear distinction between the different types of steatosis (obesity/nutritionally induced versus alcoholic) for each surgical situation in order to design therapies that demonstrate its effectiveness under experimental conditions similar to those in the clinical setting. Moreover, few studies have closely mimicked the clinical practice of steatotic LT . In contrast, most studies reported I/R under normothermic conditions with or without hepatic resection .…”

“…(57) The injurious effects of BD are mainly mediated through KC activation, leading to tumor necrosis factor α (TNF-α) amplification. BD induction resulted in a reduction in adrenocorticotropic Review ARticle | 777 hormone (ACTH), cortisol, high-mobility group box 1 (HMGB1), and TLR4 in steatotic LT compared with nonsteatotic LT. (53,57,65,66) All of these mechanisms increased the vulnerability of steatotic livers to IRI.…”

“…In this sense, just 1 study (81) compared whether the effect of the drug used is dependent on the type of steatosis, although it was performed in a normothermic condition rather than LT. Furthermore, the majority of drugs/treatments were administered in donors before IRI (57,(63)(64)(65)(66)76,(78)(79)(80)(81)83,84,87,88) ; it would be interesting to evaluate whether these drugs are equally effective when applied to recipients which would make their clinical use easier. In addition, in order to ensure effective strategies, the drug pretreatment times tend to be long in donors.…”