The effect of cortisol in rat steatotic and non-steatotic liver transplantation from brain-dead donors

Abstract

In the present study, we examined the effects of cortisol on steatotic and non-steatotic liver grafts from brain-dead donors and characterized the underlying mechanisms involved. Non-steatotic liver grafts showed reduced cortisol and increased cortisone levels in association with up-regulation of enzymes that inactivate cortisol. Conversely, steatotic liver grafts exhibited increased cortisol and reduced cortisone levels. The enzymes involved in cortisol generation were overexpressed, and those involved in cortisol inactivation or clearance were down-regulated in steatotic liver grafts. Exogenous administration of cortisol negatively affected hepatic damage and survival rate in non-steatotic liver transplantation (LT); however, cortisol treatment up-regulated the phosphoinositide 3-kinase (PI3K)-protein kinase C (PKC) pathway, resulting in protection against the deleterious effects of brain-dead donors on damage and inflammatory response in steatotic LT as well as in increased survival of recipients. The present study highlights the differences in the role of cortisol and hepatic mechanisms that regulate cortisol levels based on the type of liver. Our findings suggest that cortisol treatment is a feasible and highly protective strategy to reduce the adverse effects of brain-dead donor livers in order to ultimately improve liver graft quality in the presence of steatosis, whereas cortisol treatment would not be recommended for non-steatotic liver grafts.

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.…”

“…(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.…”

“…Many of the previously mentioned studies (13 of 23) were performed in rat models with moderate steatotic livers. (53,57,62,63,65,66,76,(78)(79)(80)84,86,87) Of these studies,11 used fatty livers from Zucker rats (53,57,62,63,65,66,68,77,78,(87)(88)(89) ; 5 used a methionine-choline deficient diet (53,68,82,83,89) and 5 a HFD, (64,(79)(80)(81)85,88) both models of steatohepatitis. Finally, in 2 studies steatohepatitis was induced by alcohol.…”

“…(64,76) Only 3 experimental studies used steatotic grafts from previously induced BD donors. (57,65,66) Considering the complexity of the mechanisms involved in hepatic IRI, the experimental conditions used will have a great impact, eg, type of research (in vitro, ex vivo, or in vivo), type of ischemia applied (warm or cold), period of ischemia (ranging from minutes to days), extent of hepatic ischemia (partial or total), or the subclinical situation of the graft (healthy, steatotic, aged, and so on). The effectiveness of a certain strategy could differ depending on the surgical conditions evaluated.…”