TY - JOUR
T1 - Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection
T2 - From bench-to-bedside
AU - Kageyama, Shoichi
AU - Hirao, Hirofumi
AU - Nakamura, Kojiro
AU - Ke, Bibo
AU - Zhang, Min
AU - Ito, Takahiro
AU - Aziz, Antony
AU - Oncel, Damla
AU - Kaldas, Fady M.
AU - Busuttil, Ronald W.
AU - Sosa, Rebecca A.
AU - Reed, Elaine F.
AU - Araujo, Jesus A.
AU - Kupiec-Weglinski, Jerzy W.
N1 - Funding Information:
This work was supported by NIH Grants PO1 AI120944; RO1 DK062357, DK107533, DK102110 (to JWKW); NIH RO1 ES016959, R56 ES016959-06 (to JAA); and the Dumont-UCLA Research Foundation. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility. We thank Ko Takanashi (UCLA-TPCL) for immunohistochemical assistance.
Publisher Copyright:
© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - basic (laboratory) research/science
KW - immunobiology
KW - ischemia reperfusion injury (IRI)
KW - liver disease: immune/inflammatory
KW - liver transplantation/hepatology
KW - organ perfusion and preservation
KW - protocol biopsy
KW - tissue injury and repair
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85052380063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052380063&partnerID=8YFLogxK
U2 - 10.1111/ajt.15043
DO - 10.1111/ajt.15043
M3 - Article
C2 - 30059195
AN - SCOPUS:85052380063
VL - 19
SP - 356
EP - 367
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 2
ER -