*Purpose: Liver ischemia-reperfusion injury (IRI), an innate-immune dominated hepatocellular damage, is a risk factor for early allograft dysfunction (EAD) and rejection crises in liver transplantation (LT). Although hypoxia-inducible factor 1-alpha (Hif-1α) is considered a key mediator of the cellular response to hypoxia, its role in clinical LT remains elusive. Here, we analyzed human LT biopsies (Bx) to investigate the impact of graft Hif-1α expression on clinical outcomes.

*Methods: Hepatic Bx were obtained after cold storage and at 2h post-reperfusion from human LT recipients (n=52) recruited under IRB protocol. Bx were retrospectively analyzed by RT-PCR (Pre-transplant Bx: Hif-1α; Post-transplant Bx: Hif-1α/CD80/CD86/ CD68/CD154/ Cathepsin G/CD4/CD28/TLR-2/TLR-4), while human LT recipients were split evenly into low-Hif-1α (n=26) vs high-Hif-1α (n=26) expression groups. In addition, 41 liver Bx samples were screened for lipid droplet cells (HE stain).

*Results: Compared with low-Hif-1α expression cohort, high-Hif-1α cases were characterized by: 1/ improved hepatocellular function, evidenced by decreased levels of sALT/sAST at POD1-7; 2/ depressed macrophage activation, i.e., suppressed mRNA levels coding for TLR2 (0.13±0.09 vs 0.28±0.18, p=0.034), TLR4 (0.12±0.09 vs 0.17±0.13, p=0.029), CD80 (0.34±0.35 vs 0.53±0.48, p=0.014), and CD68 (0.16±0.12 vs 0.30±0.24, p=0.003); 3/ depressed neutrophil activation, i.e., decreased levels of Cathepsin G (0.15±0.12 vs 0.25±0.22, p=0.036); 4/ suppressed T cell activation, i.e., CD4 (0.72±0.07 vs 1.00±0.13, p=0.008), CD28 (0.83±0.07 vs 1.00±0.09, p=0.049), and CD154 (0.17±0.16 vs 0.25±0.23, p=0.039); 4/ lower frequency of large droplet cell>10% (0% vs 26.1%, p=0.019); 5/ lower incidence of early allograft dysfunction (EAD; 11.5% vs 34.6%); as well as 6/ improved LT graft survival at 3-years (96.2% vs 69.2%, p=0.030). Classification by Hif-1α in post-transplant Bx samples also showed high- Hif-1α group was associated with the superior post-LT graft survival (100% vs 75.0%, p=0.055), suppressed innate/adaptive immune cell markers (TLR-2, TLR-4, CD80, CD68, Cathepsin G, CD4, CD28, CD154, p<0.01) and reduced fatty liver incidence (p=0.027).

*Conclusions: This study demonstrated that increased hepatic Hif-1α expression in human LT patients mitigated IR-stress and improved hepatocellular graft function. These beneficial effects were associated with suppressed innate/adaptive immune activation, lower incidence of fatty liver disease and preferable LT clinical outcomes. Hence, Hif-1α activation may not only serve as a potential biomarker of IR stress resistance but may also represent a novel therapeutic target to ameliorate IRI in LT recipients.

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