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

Ghazaleh Aram, James J. Potter, Xiaopu Liu, Michael S. Torbenson, Esteban Mezey

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2051-2058
Number of pages8
JournalHepatology
Volume47
Issue number6
DOIs
StatePublished - Jun 2008

ASJC Scopus subject areas

  • Hepatology

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