Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis

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ABSTRACT: Alcoholic hepatitis (AH) is a major liver disease, and has an inpatient mortality of between 25-40%. Liver inflammation is a key feature of AH, yet the factors which drive this inflammatory response are not known. We have identified novel key drivers of liver inflammation which are the subject of this application. We have also identified novel proteomic and molecular markers in AH which will be used to predict prognosis. We have shown that activation of the nuclear (hypoxia inhibitory factor 1-α: HIF-1α) pathway was required for the development of sustained sterile inflammation, which suggested that inhibition of HIF-1α may be therapeutic in AH[1]. In a high throughput screen cardiac glycoside were identified to have significant ability to inhibit HIF-1α[2]. The preliminary data demonstrates i) Up-regulation of HIF-1α dependent genes in liver tissues from early AH, as compared to severe AH, from the InTeam consortium ii) Ability of digoxin to reduce tissue damage in a model of alcohol, and others forms of liver injury. iii) Digoxin binds to the enzyme pyruvate kinase M2 (PKM2), iv) Digoxin reduces PKM2 binding to the HIF-1α promoter and limits up-regulation of HIF-1α, and HIF-1α response genes. v) An aptamer based proteomic analysis of serum shows that in patients with the AH and the systemic inflammatory response (SIRS) there is an increase in tumor necrosis factor related proteins, low affinity immunoglobulin gamma Fc region receptor II, complement components, kallikrein and fibroblast growth factors. vi) Serum DNA is known to be a pro-inflammatory ligand and serum DNA levels correlated with peripheral blood white cell count in AH. Aim 1. Obtain clinical data supporting the therapeutic use of digoxin in alcoholic hepatitis. Aim 2. Identify dominant and novel targets that are regulated by PKM2 in alcoholic hepatitis. Aim 3. Obtain plasma proteomic and molecular data to allow for early identification of patients with SIRS. Collectively this will allow us to obtain the necessary data towards clinically testing low dose digoxin in AH. In addition, it will allow us to identify novel protein markers and pro-inflammatory signals in the serum of patients with AH. Finally, we will be able to identify if any of the novel protein markers are associated with the novel PKM2 pathway we have identified.