Nitric oxide synthase expression is induced in hepatocytes in vivo during hepatic inflammation

Nitric oxide (NO.) is a short-lived biologic mediator produced by the enzyme NO. synthase (NOS) which exists in constitutive and inducible isoforms. Previously, we have shown that hepatocytes express an inducible NOS in vitro following exposure to the combination of lipopolysaccharide and inflammatory cytokines. The purpose of the present study is to characterize the induction of NOS in vivo in rat hepatocytes during chronic hepatic inflammation triggered by Corynebacterium parvum injection and to correlate NO. synthesis with the timing of liver injury. Using Northern blot hybridization, hepatocyte-inducible NOS mRNA was detected 3 days after C. parvum administration and was not found in normal hepatocytes. Hepatocyte NOS activity was significantly increased 3 to 7 days after C. parvum. Plasma concentrations of nitrite and nitrate (NO2- + NO3-), the stable end products of NO. oxidation, increased from a basal concentration of 21.0 +/- 2.5 to 2439.6 +/- 364.2 microM 3 days after injection. Urinary excretion of NO2- + NO3- also increased in a parallel manner. Plasma liver injury enzymes were elevated three to sixfold in vivo at 3 to 5 days following C. parvum and coincided with the period of maximal NO production. The results show that NO. is produced directly by hepatocytes in vivo during hepatic inflammation and suggest a role for NO. in mediating the hepatic response to inflammatory stimuli.