Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration

The role of nitric oxide (NO) in liver injury and fibrosis is unclear. The purpose of this study was to determine whether inducible NO synthase deficiency (iNOS^-/-) affects liver injury and fibrosis produced in mice by chronic carbon tetrachloride (CCl₄) administration. Wildtype (WT) or iNOS^-/- mice were subjected to biweekly CCl₄ injections over 8 weeks, whereas controls were given isovolumetric injections of olive oil. Serum aminotransferases were lower after CCl₄ in the iNOS ^-/- than in the WT mice, which correlated with decreased necrosis on liver histology. There was increased apoptosis, a lower number of stellate cells, and a lesser degree of fibrosis after CCl₄ in the iNOS ^-/- as compared with the WT mice. α₁ (I) collagen messenger RNA (mRNA) was markedly increased after CCl₄ in the WT and to a significantly lesser extent in the iNOS^-/- mice. Liver matrix metalloproteinase-9 (MMP-9) mRNA and MMP-2 mRNA were increased more in the WT than in the iNOS^-/- mice after CCl₄. Also tissue inhibitor metalloproteinase 1 (TIMP-1) mRNA was increased to a much greater extent in the WT than in the iNOS^-/- mice after CCl₄ (P < 0.05). However, MMP-9 and TIMP-1 protein, determined by western blot, were similarly increased after CCl₄ in both groups of mice. Conclusion: NO protects against CCl₄-induced apoptosis. In the absence of iNOS, there is decreased necrosis, increased apoptosis, and reduced liver fibrosis.