Donor Hepatic Steatosis Induce Exacerbated Ischemia-Reperfusion Injury Through Activation of Innate Immune Response Molecular Pathways

BACKGROUND: Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation after LT. METHODS: Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines evaluation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray average algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. RESULTS: Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circulating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. CONCLUSIONS: Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Preemptive strategies should consider it for safety usage of steatotic livers.