Nitric oxide synthase inhibition and the induction of cytochrome P-450 affect heme oxygenase-1 messenger RNA expression after partial hepatectomy and acute inflammation in rats

Objectives: a) To evaluate in vivo, in rat liver, heme oxygenase-1 (HO-1) messenger RNA (mRNA) expression level and the regulation of 3',5'-cyclic guanosine monophosphate (cGMP) production during hepatic regeneration, localized inflammation, and systemic inflammation; and b) to investigate the effect of the induction of cytochrome P-450 and nitric oxide synthase (NOS) inhibition on HO-1 mRNA level and cGMP production in the liver. Design: Experimental, comparative study. Setting: Biochemical and molecular biology laboratory. Subjects: Six-wk-old male Sprague Dawley rats (n = 60). Interventions: We randomly divided the rats into four groups: a) saline controls; b) animals receiving lipopolysaccharide (600 mu g/kg) for systemic inflammation; c) animals receiving turpentine oil (5 mL/kg) for localized inflammation obtained by sterile abscess; and d) partially hepatectomized animals (two thirds removal of the parenchyma) for hepatic regeneration. Measurements and Main Results: Hepatic regeneration induced HO-1 mRNA expression, as shown by quantitative reverse transcription polymerase chain reaction analysis. The time course of liver HO-1 mRNA induction after partial hepatectomy and localized and systemic inflammation showed a similar and gradual increase, with a maximum at 6 hrs and a return to a minimal level 48 hrs after treatments. Liver HO-1 mRNA was overexpressed during localized vs. systemic inflammation. This overexpression was not correlated with either serum IL 6 or corticosterone concentrations, but is related to increased cGMP production. The administration of phenobarbital, a cytochrome P-450 inducer and of nitro-l arginine methyl ester, a NOS inhibitor, prevented cGMP production and abolished the overexpression of HO-1 mRNA. Conclusions: The results of this study indicate that HO-1 mRNA is induced during hepatic regeneration with a similar time course to that observed during acute inflammation. In addition, we demonstrated that: a) HO-1 mRNA is overexpressed during localized vs. systemic inflammation; b) this overexpression is not correlated with IL 6 or corticosterone concentrations but is related to intrahepatic cGMP production; c) induction of cytochromes P-450 and/or inhibition of NOS both reduce liver cGMP production and HO-1 mRNA expression. These results suggest that in rat liver, a cGMP-transducing pathway may control HO-1 mRNA expression. Thus, there may be a role for HO-1 mRNA in the modulation of the hepatic stress response.