Many preclinical studies on protective functions of heme oxygenase-1 (HO-1; hsp32) in orthotopic liver transplantation (OLT) have encouraged application of HO-1 inducing regimens in clinical OLT as well as increase the necessity of criteria to quest for putative clinical responders. Human HO-1 gene expression is modulated by polymorphism genotype, while previous clinical studies showed donor HO-1 genotype to correlate with clinical outcomes. However, the significance of recipient HO-1 inducibility remains unknown. We aimed to determine whether recipient HO-1 status may affect graft HO-1 levels and outcomes. Fifty-one liver transplant patients were recruited under IRB protocol. Liver biopsies sampled pre-transplant (prior to put-in) and 2h post-reperfusion (prior to abdominal closure) were analyzed by Western blots. Post-transplant (r=-0.3306, p=0.0178) but not pre-transplant (r=-0.2138, p=0.1320) HO-1 expression correlated negatively with sALT at POD1. High post-transplant but not high pre-transplant HO-1 correlated with superior post-OLT survival (2-year, pre-high/low=81.1/92.4% [n=25/26]; post-high/low=92.6/80.7%[n=25/26]), indicating post-transplant HO-1 is crucial for hepatoprotection. Post-transplant HO-1 not only correlated with pre-transplant HO-1 (r=0.5564, p<0.0001) but also with post-/pre-transplant HO-1 ratio (r=0.3696, p=0.0076). WT mouse liver grafts with extended (18h) cold storage were orthotopically transplanted into myeloid-specific HO-1 knockout (mHO-1 KO) or FLOX control (Con) mice. mHO-1 KO recipients had decreased HO-1 levels by nearly half, as compared to Con at 6h post-reperfusion, and exacerbated liver damage, evidenced by sALT/AST, Suzuki's histological grading and frequency of TUNEL+ cells (n=4-5, p<0.05). mHO-1 KO recipients showed increased mRNA levels coding for TNFα/CXCL1/CXCL2/CXCL10, increased number of Ly6G/CD11b/4hydroxynonenal+ cells, and enhanced MPO activity (p<0.05). Peritoneal neutrophils from mHO-1 KO mice exhibited higher CellRox+ ratio, increased mRNA levels of TNFα/CXCL1/CXCL2/CXCL10 (p<0.05). In conclusion, this translational study is the first to identify the significance of recipient HO-1 inducibility upon graft protection. Recipient genotype assessment warrants further evaluation for confirmation and future personalized molecular therapy in organ transplantation.

CITATION INFORMATION: Kageyama S., Nakamura K., Ito T., Aziz A., Ke B., Sossa R., Reed E., Kaldas F., Busuttil R., Kupiec-Weglinski J. Recipient HO-1 Deficiency Decreases Post-Transplant Graft HO-1 Expression and Exacerbates Liver Transplant Damage Am J Transplant. 2017;17 (suppl 3).

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