Expression of Heme Oxygenase‐1 in Human Livers Before Transplantation Correlates with Graft Injury and Function After Transplantation

Abstract

Upregulation of heme oxygenase-1 (HO-1) has been proposed as an adaptive mechanism protecting against ischemia/reperfusion (I/R) injury. We investigated HO-1 expression in 38 human liver transplants and correlated this with I/R injury and graft function. Before transplantation, median HO-1 mRNA levels were 3.4-fold higher (range: 0.7-9.3) in donors than in normal controls. Based on the median value, livers were divided into two groups: low and high HO-1 expression. These groups had similar donor characteristics, donor serum transaminases, cold ischemia time, HSP-70 expression and the distribution of HO-1 promoter polymorphism. After reperfusion, HO-1 expression increased significantly further in the initial low HO-1 expression group, but not in the high HO-1 group. Postoperatively, serum transaminases were significantly lower and the bile salt secretion was higher in the initial low HO-1 group, compared to the high expression group. Immunofluorescence staining identified Kupffer cells as the main localization of HO-1.In conclusion, human livers with initial low HO-1 expression (<3.4 times controls) are able to induce HO-1 further during reperfusion and are associated with less injury and better function than initial high HO-1 expression (>3.4 times controls). These data suggest that an increase in HO-1 during transplantation is more protective than high HO-1 expression before transplantation.Key words: Cytoprotection, heme-oxygenase-1, ischemia/reperfusion injury, liver transplantation Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; CO, carbon monoxide; GGT, gamma glutamyltransferase; HO-1, heme oxygenase-1; HSP-70, heat shock protein-70; I/R injury, ischemia/reperfusion injury; mRNA, messenger ribonucleicacids; OLT, orthotopic liver transplantation; ROS, reactive oxygen species.

Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

“…Previous reports identified Kupffer cells as the main source of HO-1 expression in human livers [45,64] in contrast to controversial data from rat livers, where considerable expressions of HO-1 has also been found in hepatocytes [51,65] . Besides the large body of evidence demonstrating cytoprotective effects of HO-1 upregulation in transplant models in animals [37,66,67] , Geuken et al [45] suggested that high HO-1 overexpression in Kupffer cells in human liver allografts may contribute to an increased cell injury. In general, the role of Kupffer cells in fibrosis is controversial.…”

“…Moreover, increased HO-1 expression was shown in human NASH patients, reflecting the severity of the disease and the progression of liver failure [44] . Furthermore, a dual role for HO-1 expression in human liver transplants, with either cytoprotection or increased cytotoxicity, depending on the initial level of overexpression could be demonstrated [45] . These results point towards the potentially different effects of HO-1, which may be neither exclusively cytoprotective nor exclusively cytotoxic.…”

“…Recent studies indicate that the protection might be restricted to a narrow threshold of HO-1 overexpression [43][44][45][46] . High levels of HO-1 may even sensitize the cell to oxidative stress, as demonstrated in fibroblast cell cultures, where low HO-1 induction was shown to be cytoprotective, whereas excessive activation of HO-1 resulted in the accumulation of free divalent iron and increased oxidative injury [43] .…”

Natural heme oxygenase-1 inducers in hepatobiliary function

“…These results demonstrate that exogenous CO suppresses early pro-inflammatory and stress-response gene expression and efficiently improves hepatic I/R injury by downregulation of the MEK/ERK1/2 signaling pathway with CO. CO production, evaluated by CO-Hb, is associated with improved function in liver-transplanted patients [50] . Furthermore, an increase in HO-1 during transplantation is more protective than high HO-1 expression before transplantation [51] . Buis et al [52] have shown that donor HO-1 genetic polymorphism may influence the outcome of liver transplantation.…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…HO-1 is also known as a heat shock protein 32 (hsp32), which is an integral membrane protein of the smooth endoplasmic reticulum (Lin, Weis et al 2007), and is the only inducible isoform of HO. The up regulation of HO-1 provides protection against cellular stress including oxidative stress, heavy metal toxicity, UV radiation, and inflammation, thus preventing deleterious effects of Heme and mediating anti-inflammatory and antiapototic functions (Geuken, Buis et al 2005;Datta, Banerjee et al 2010). HO-1 may facilitate the repair of injured tissues through inhibition of infiltrating inflammatory cells (Datta, Dormond et al 2007).…”