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 (CCl(4)) administration. Wild-type (WT) or iNOS(-/-) mice were subjected to biweekly CCl(4) injections over 8 weeks, whereas controls were given isovolumetric injections of olive oil. Serum aminotransferases were lower after CCl(4) 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 CCl(4) in the iNOS(-/-) as compared with the WT mice. alpha(1)(I) collagen messenger RNA (mRNA) was markedly increased after CCl(4) 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 CCl(4). Also tissue inhibitor metalloproteinase 1 (TIMP-1) mRNA was increased to a much greater extent in the WT than in the iNOS(-/-) mice after CCl(4) (P < 0.05). However, MMP-9 and TIMP-1 protein, determined by western blot, were similarly increased after CCl(4) in both groups of mice.


CONCLUSIONS
NO protects against CCl(4)-induced apoptosis. In the absence of iNOS, there is decreased necrosis, increased apoptosis, and reduced liver fibrosis.
Aram
Ghazaleh
G
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2195, USA.
Potter
James J
JJ
Liu
Xiaopu
X
Torbenson
Michael S
MS
Mezey
Esteban
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D000637:Transaminases / Q000097:blood
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019715:Tissue Inhibitor of Metalloproteinase-1; D030421:Peroxynitrous Acid; D008315:Malondialdehyde; D003094:Collagen; D002251:Carbon Tetrachloride; D052247:Nitric Oxide Synthase Type II; D000637:Transaminases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9