Heme breakdown and ischemia/reperfusion injury in grafted liver during living donor liver transplantation

Living donor liver transplantation (LDLT) requires ischemia/reperfusion(I/R), which can cause early graft injury. However, the detailed mechanism ofI/R injury remains unknown. Heme oxygenase-1 (HO-1) is a rate-limiting enzymein heme catabolism and results in the production of iron, carbon monoxide (CO),and biliverdin IXα. Furthermore, in animals, HO-1 has a protective effect againstoxidative stress associated with I/R injury. However, in humans, the molecularmechanism and clinical significance of HO-1 remain unclear. We previously demonstratedthat exhaled CO levels increase during LDLT, and postulated that this may indicateI/R injury. In this study, we elucidate the origin of increased exhaled CO levelsand the role of HO-1 in I/R injury during LDLT. We studied 29 LDLT donors andrecipients each. For investigation of HO-1 gene expression by polymerase chainreaction and HO-1 localization by immunohistological staining, liver biopsiesfrom the grafted liver were conducted twice, once before and once after I/R. ExhaledCO levels and HO-1 gene expression levels significantly increased after I/R. Inaddition, HO-1 levels significantly increased after I/R in Kupffer cells. Furthermore,we found a significant positive correlation between exhaled CO levels and HO-1gene expression levels. These results indicated that increased heme breakdownin the grafted liver is the source of increased exhaled CO levels. We also founda significant relationship between HO-1 gene expression levels and alanine aminotransferase(ALT) levels; i.e., the higher the HO-1 gene expression levels, the higher theALT levels. These results suggest that HO-1-mediated heme breakdown is causedby I/R during LDLT, since it is associated with increased exhaled CO levels andliver damage.