Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation

Abstract

Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20-250 ppm) for 1 h before and 24 h after OLT and killed 1-48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24-48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-alpha and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.

HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma

“…This suggests that there are additional mechanisms regulating c-Myc. c-Myc is also involved in some other pathway such as MAPK and ERK [Inamura et al, 2005;Kaizu et al, 2008]. Whether these pathways are redundant with down-regulation of c-Myc or cooperate in producing the down regulation in renal cell carcinoma stably expressed hepaCAM remains to be undetermined.…”

Organ Preservation: Current Concepts and New Strategies for the Next Decade

“…Moreover, CO inhalation bears the risk of adverse cardiac side-effects like dysrhythmia and decreased cardiac performance or even infarction. Using the rat liver transplantation model, it has been reported that brief recipient CO inhalation during the peritransplant period ameliorates liver graft damage and inhibits pro-inflammatory responses during transplant-induced cold hepatic IRI [139]. Inhalation of CO at a low concentration provides protection of kidney grafts against cold IRI and preserves overall improved kidney graft functioning following transplantation [140].…”

Natural heme oxygenase-1 inducers in hepatobiliary function

“…More recent data have shown that HO-1 modulates pro-inflammatory responses that are triggered via TLR4 signaling, a putative HO-1 repressor [48] . The role of CO in protecting liver grafts from cold I/R injury associated with liver transplantation has been studied by Kaizu et al [49] . Inhalation of CO reduces hepatic injury and is associated with marked downregulation of early mRNA expression for tumor necrosis factor TNF-α, interleukin IL-6, and NOS.…”