Novel Use of Fomepizole in Hepatic Ischemia Reperfusion Injury - PROJECT SUMMARY/ABSTRACT The demand for liver transplantation far exceeds the number of suitable donor organs. Despite the organ shortage, due to increased risk for ischemia reperfusion injury (IRI), many marginal donor livers with steatosis go unused. While some IRI is unavoidable in all liver operations, in the setting of liver transplantation this can lead to primary non-function or early allograft dysfunction. The increasing prevalence of obesity associated metabolic dysfunction-associated steatotic liver disease increases the demand for liver transplant while also reducing the number of suitable donor livers. To address this shortfall, we must attenuate IRI in steatotic livers. However, there are no pharmacological interventions available to achieve this goal. Development of novel therapeutics is costly and time intensive. A practical alternative is to repurpose FDA approved drugs in clinical use. Fomepizole is an appealing candidate; it is used for the treatment of ethylene glycol poisoning, and recent studies have found fomepizole to be protective against acetaminophen (APAP) hepatotoxicity. Given similarities between APAP hepatoxicity and IRI, we will test the hypothesis that fomepizole protects against IRI by modulation of lipid metabolites and determine if the same mechanisms apply in steatotic livers. While there are no pharmacological agents available to reduce IRI, the use of machine perfusion (MP) procurement (as opposed to traditional static cold storage) has gained traction in the past decade and enabled the use of marginal donor livers by reducing IRI complications. However, many donor livers still do not pass viability testing with MP and are ultimately discarded. The use of adjunctive therapies may provide additional benefits over standard MP in reducing IRI, thus further expanding the use of marginal donor livers. Hence, testing therapeutics in the setting of MP, represents a novel way to address the donor shortage. In this proposal, we will investigate if fomepizole provides additional benefit in normothermic machine perfusion using an isolated perfused rat liver model. In alignment with the R03 funding mechanism, this proposal is a logical extension of my K08 proposal and provides a clear path toward an R01. The primary goals of this proposal are to delineate the mechanisms by which fomepizole reduces liver IRI and establish collaborations and innovative platforms to test therapeutics within the evolving landscape of liver preservation. At completion, I expect to provide support for repurposing fomepizole as a primary or adjunctive therapy to salvage marginal grafts, thus enabling safe, expanded use of donor grafts to decrease waitlist mortality and improve patient outcomes.
