Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside

Shoichi Kageyama, Hirofumi Hirao, Kojiro Nakamura, Bibo Ke, Min Zhang, Takahiro Ito, Antony Aziz, Damla Oncel, Fady M. Kaldas, Ronald W. Busuttil, Rebecca A. Sosa, Elaine F. Reed, Jesus A. Araujo, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 TNFα/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 TNFα/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.

Original languageEnglish (US)
Pages (from-to)356-367
Number of pages12
JournalAmerican Journal of Transplantation
Issue number2
StatePublished - Feb 2019


  • basic (laboratory) research/science
  • immunobiology
  • ischemia reperfusion injury (IRI)
  • liver disease: immune/inflammatory
  • liver transplantation/hepatology
  • organ perfusion and preservation
  • protocol biopsy
  • tissue injury and repair
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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