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

• Published in: Hepatology (Baltimore, Md.) Vol. 47; no. 6; pp. 2051 - 2058
• Main Authors: Aram, Ghazaleh, Potter, James J., Liu, Xiaopu, Torbenson, Michael S., Mezey, Esteban
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2008; Wiley
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Carbon Tetrachloride - adverse effects; Collagen - genetics; Collagen - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Liver - enzymology; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - enzymology; Liver Cirrhosis - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Malondialdehyde - metabolism; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Knockout; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Other diseases. Semiology; Peroxynitrous Acid - metabolism; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transaminases - blood; Hepatic fibrosis; Enzyme; Carbon tetrachloride; Rodentia; Hepatic disease; Nitric-oxide synthase; Vertebrata; Chronic; Mammalia; Mouse; Animal; Gastroenterology; Digestive diseases; Oxidoreductases; Apoptosis
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.22278

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. Wild‐type (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. (HEPATOLOGY 2008;47:2051–2058.)