title: Disruption of Type-I IFN pathway ameliorates preservation damage in mouse orthotopic liver transplantation via HO-1 dependent mechanism.
abstract: Ischemia/reperfusion injury (IRI) remains unresolved problem in clinical organ transplantation. We analyzed the role of Type-I interferon (IFN) pathway in a clinically relevant murine model of extended hepatic cold preservation followed by orthotopic liver transplantation (OLT). Livers from Type-I IFN receptor (IFNAR) knockout (KO) or wild-type (WT) mice (C57/BL6) were harvested, preserved at 4°C in UW solution for 20 h and transplanted to groups of syngeneic IFNAR KO or WT recipients. Liver graft but not recipient IFNAR deficiency was required to consistently ameliorate IRI in OLTs. Indeed, disruption of Type-I IFN signaling decreased serum alanine aminotransferase (sALT) levels (p < 0.001), diminished Suzuki's score of histological OLT damage (p < 0.01) and improved 14-day survival (from 42%[5/12] in WT to 92%[11/12] in IFNAR KO; p < 0.05). Unlike in WT group, IFNAR deficiency attenuated OLT expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL-10, ICAM-1; diminished infiltration by macrophages/PMNs; and enhanced expression of antioxidant HO-1/Nrf2. The frequency of TUNEL+ apoptotic cells and caspase-3 activity/expression selectively decreased in IFNAR KO group. Small interfering (si)RNA-directed targeting of HO-1 restored cardinal features of liver IRI in otherwise resistant IFNAR-deficient OLTs. Thus, intact Type-I IFN signaling is required for hepatic IRI, whereas HO-1 is needed for cytoprotection against innate immunity-dominated organ preservation damage in IFNAR-deficient liver transplants.
authors.affiliation: Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: X-D
authors.initials: XD
authors.lastname: Shen
authors.forename: B
authors.initials: B
authors.lastname: Ke
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: M C S
authors.initials: MC
authors.lastname: Freitas
authors.forename: W W
authors.initials: WW
authors.lastname: Chang
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007370:Interferon Type I / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007370:Interferon Type I; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase