Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice

Abstract

Background and Aims Alcoholic liver disease is associated with inflammation and cell death. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-apoptotic and anti-inflammatory properties. Here we tested the hypothesis that induction of HO-1 or treatment with a carbon monoxide releasing molecule (CORM) during chronic ethanol exposure protects and/or reverses ethanol-induced liver injury. Methods Female C57BL/6J mice were allowed free access to a complete liquid diet containing ethanol or pair-fed control diets for 25 days. Mice were treated with cobalt protoporphyrin (CoPP) to induce HO-1 expression during ethanol feeding or once injury had been established. Mice were also treated with CORM-A1, a CO-releasing molecule (CORM), after ethanol-induced liver injury was established. The impact of HO-1 induction on ethanol-induced cell death was investigated in primary cultures of hepatocytes. Results Induction of HO-1 during or after ethanol feeding, as well as treatment with CORM-A1, ameliorated ethanol-induced increases in AST and expression of mRNA for inflammatory cytokines. Treatment with CoPP or CORM-A1 also reduced hepatocyte cell death, indicated by decreased accumulation of CK18 cleavage products and reduced RIP3 expression in hepatocytes. Exposure of primary hepatocyte cultures to ethanol increased their sensitivity to TNFα-induced cell death; this response was attenuated by necrostatin-1, an inhibitor of necroptosis, but not by caspase inhibitors. Induction of HO-1 with CoPP or CORM-3 treatment normalized the sensitivity of hepatocytes to TNFα-induced cell death after ethanol exposure. Conclusions Therapeutic strategies to increase HO-1 and/or modulate CO availability ameliorated chronic ethanol-induced liver injury in mice, at least in part by decreasing hepatocellular death.

Induction of Haemeoxygenase-1 Directly Improves Endothelial Function in Isolated Aortas from Obese Rats through the Ampk-Pi3k/Akt-Enos Pathway

“…The haemeoxygenase-1 (HO) system is the primary pathway present in many tissues to catalyze the oxidation of heme, a potentially harmful pro-oxidant, to the biologically active molecules biliverdin, iron and carbon monoxide (CO) [1,2]. To date, two main distinct isoforms of HO have been identified: HO-1 and HO-2.…”

Anti-diabetic actions of carbon monoxide-releasing molecule (CORM)-A1: Immunomodulation and regeneration of islet beta cells

“…Indication for a potential use of CORM-A1 as pharmaceutical originates from its multiple bioactivities, such as anti-inflammatory, anti-apoptotic and antioxidant effects provided by the small amounts of CO released [11,12]. To date, CORM-A1 has been shown to be highly protective in several rodent inflammatory-related disorders, such as experimental autoimmune encephalomyelitis [13], high-fat diet induced obesity [14], and chronic ethanol-induced liver injury [15]. Our own findings demonstrated that the pharmacological application of CO by CORM-A1 protected mice from developing T1D [16].…”

Potential Molecular Mechanism of Probiotics in Alcoholic Liver Disease

“…Mice were treated with CoPP along with carbon monoxide releasing molecule-A1 (CORM-A1), a CORM to induce HO-1 expression during ethanol feeding or once injury had been established. This experimental result proved that induction of HO-1 or treatment with a CORM during chronic ethanol exposure protects and/or reverses ethanol-induced liver injury [39]. Study showed that chronic ethanol feeding increased LPS-stimulated TNF-α expression by Kupffer cells, linked with a shift to an M1 macrophage polarization.…”

“…Research showed that when mice were treated with cobalt protoporphyrin (CoPP) to induce HO-1 expression, ethanolinduced sensitivity to LPS was ameliorated [39]. Mice were treated with CoPP along with carbon monoxide releasing molecule-A1 (CORM-A1), a CORM to induce HO-1 expression during ethanol feeding or once injury had been established.…”