Inhibition of inducible nitric oxide synthase protects against liver injury induced by mycobacterial infection and endotoxins

Article Article scientifique Article Inhibition of inducible nitric oxide synthase protects against liver injury induced by mycobacterial infection and endotoxins eng 2004 author Guler Reto 95694 author Olleros Maria author Vesin Dominique author Parapanov Roumen author Vesin Christian 22534 author Kantengwa Salomé 21895 author Rubbia-Brandt Laura 31809 author Mensi Noury 526987 author Angelillo-Scherrer Anne author Martinez-Soria Eduardo author Tacchini-Cottier Fabienne 24343 author Garcia Irène 26048 773-781 10.1016/j.jhep.2004.07.031 15519650 0168-8278 http://www.sciencedirect.com/science/article/pii/S0168827804003551 BACKGROUND/AIMS: Bacillus Calmette Guerin (BCG) infection causes hepatic injury following granuloma formation and secretion of cytokines which render mice highly sensitive to endotoxin-mediated hepatotoxicity. This work investigates the role of inducible nitric oxide synthase (iNOS) in liver damage induced by BCG and endotoxins in BCG-infected mice. METHODS: Liver injury and cytokine activation induced by BCG and by LPS upon BCG infection (BCG/LPS) were compared in wild-type and iNOS-/- mice. RESULTS: iNOS-/- mice infected with living BCG are protected from hepatic injury when compared to wild-type mice which express iNOS protein in macrophages forming hepatic granulomas. In addition, iNOS-/- mice show a decrease in BCG-induced IFN-gamma serum levels. LPS challenge in BCG-infected mice strongly activates iNOS in the liver and spleen of wild-type mice which show important liver damage associated with a dramatic increase in TNF and IL-6 and also Th1 type cytokines. In contrast, iNOS-/- mice are protected from liver injury after BCG/LPS challenge and their TNF, IL-6 and Th1 type cytokine serum levels raise moderately. CONCLUSIONS: These results demonstrate that nitric oxide (NO) from iNOS is involved in hepatotoxicity induced by both mycobacterial infection and endotoxin effects upon BCG infection and that inhibition of NO from iNOS protects from liver injuries. Animals Interleukin-6/metabolism Lipopolysaccharides/*pharmacology Liver/enzymology Liver Diseases/immunology/*metabolism/microbiology Mice Mice, Inbred C57BL Mice, Knockout *Mycobacterium bovis Nitric Oxide/metabolism Nitric Oxide Synthase/*genetics/metabolism Nitric Oxide Synthase Type II Spleen/enzymology Th1 Cells/metabolism Tuberculosis/immunology/*metabolism Tumor Necrosis Factor-alpha/metabolism Dewey 616.07 true Journal of hepatology 41 5 1e1c9ead-e7ef-421c-8181-313cde10489e Article Restricted file1.pdf 373957 application/pdf restrictedAccess

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Inhibition of inducible nitric oxide synthase protects against liver injury induced by mycobacterial infection and endotoxins	Journal of hepatology			2004	603	0

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Kantengwa, Salomé