NO-IL-6/10-IL-1ß axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats.

Introduction: Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). Material and methods: Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. Results: BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1ß, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1ß only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1ß inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1ß only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1ß effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1ß action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1ß regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1ß seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1ß, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1ß levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. Conclusion: Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1ß in non-steatotic livers and NO-IL-10-IL-1ß in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.

A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation.

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.

Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.