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Recipient HO‐1 inducibility is essential for posttransplant hepatic HO‐1 expression and graft protection: From bench‐to‐bedside
Author(s) -
Kageyama Shoichi,
Hirao Hirofumi,
Nakamura Kojiro,
Ke Bibo,
Zhang Min,
Ito Takahiro,
Aziz Antony,
Oncel Damla,
Kaldas Fady M.,
Busuttil Ronald W.,
Sosa Rebecca A.,
Reed Elaine F.,
Araujo Jesus A.,
KupiecWeglinski Jerzy W.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15043
Subject(s) - medicine , cxcl2 , cxcl1 , chemokine , transplantation , heme oxygenase , ex vivo , cxcl10 , cytoprotection , myeloid , immunology , andrology , inflammation , in vivo , heme , chemokine receptor , oxidative stress , biology , biochemistry , microbiology and biotechnology , enzyme
By documenting potent antioxidative and anti‐inflammatory functions, preclinical studies encourage heme oxygenase‐1 (HO‐1)‐inducing regimens in clinical orthotopic liver transplantation (OLT). We aimed to determine the importance of recipient‐derived HO‐1 in murine and human OLTs. Hepatic biopsies from 51 OLT patients were screened for HO‐1 expression (Western blots) prior to put‐in (basal) and post reperfusion (stressed) and correlated with the hepatocellular function. In parallel, livers from HO‐1 proficient mice (WT; C57/BL6), subjected to ex vivo cold storage (18 hour), were transplanted to syngeneic myeloid HO‐1 deficient (mHO‐1 KO) or FLOX (control) hosts, and sampled postreperfusion (6 hour). In human OLT, posttransplant but not pretransplant HO‐1 expression correlated negatively with ALT levels ( P = .0178). High posttransplant but not pretransplant HO‐1 expression trended with improved OLT survival. Compared with controls, livers transplanted into mHO‐1 KO recipient mice had decreased HO‐1 levels, exacerbated hepatic damage/frequency of TUNEL+ cells, increased mRNA levels coding for TNF α /CXCL1/CXCL2/CXCL10, higher frequency of Ly6G+/4HN+ neutrophils; and enhanced MPO activity. Peritoneal neutrophils from mHO‐1 KO mice exhibited higher CellRox+ ratio and increased TNF α /CXCL1/CXCL2/CXCL10 expression. By demonstrating the importance of posttransplant recipient HO‐1 phenotype in hepatic macrophage/neutrophil regulation and function, this translational study identifies recipient HO‐1 inducibility as a novel biomarker of ischemic stress resistance in OLT.