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.
1 Transplant Division, Department of Surgery, University of Virginia, Charlottesville, VA. 2 Department of Pathology, Virginia Commonwealth University, Richmond, VA. 3 Department of Pathology, University of Virginia, Charlottesville, VA.
Ricardo C
RC
Gehrau
Valeria R
VR
Mas
Catherine I
CI
Dumur
Jihee L
JL
Suh
Ashish K
AK
Sharma
Helen P
HP
Cathro
Daniel G
DG
Maluf
D015415:Biomarkers / Q000378:metabolism*; D001706:Biopsy; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005234:Fatty Liver / Q000150:complications / Q000473:pathology / Q000601:surgery*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008099:Liver / Q000473:pathology*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D014019:Tissue Donors
D015415:Biomarkers; D016207:Cytokines; D012313:RNA