Key result
Anti-TNF-alpha inhibits LPS-induced hepatic lesions and iNOS expression, suggesting nitric oxide mediates liver injury.
Nitric oxide from iNOS may play a role in LPS-induced hepatic injury in D-GalN-sensitized mice, an experimental model of endotoxic shock.
Implicates iNOS-derived NO in experimental endotoxic liver injury; hypothesis-generating for human sepsis therapies, should not change practice.
The role of nitric oxide (NO) in lipopolysaccharide (LPS)-induced hepatic injury was studied in D-galactosamine (D-GalN)-sensitized mice. The inducible isoform of NO synthase (iNOS) was immunohistochemically detected on hepatocytes around blood vessels in livers of mice injected with D-GalN and LPS not on hepatocytes in mice injected with D-GalN or LPS alone, although mRNA for iNOS was found in those mice. Nitrotyrosine (NT) was also found in livers of mice injected with D-GalN and LPS. The localization of NT was consistent with that of iNOS, and the time courses of NT and iNOS expression were almost the same. Expression of iNOS and NT was detected exclusively in the hepatic lesions of mice injected with D-GalN and LPS. Anti-tumor necrosis factor alpha neutralizing antibody inhibited iNOS and NT expression and hepatic injury. The results suggested that NO from iNOS may play a role in LPS-induced hepatic injury on D-GalN-sensitized mice as an experimental endotoxic shock model.
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Morikawa et al. (1999) studied LPS-induced hepatic injury (endotoxic shock model). D-Galactosamine and Lipopolysaccharide vs. PBS, D-GalN alone, or LPS alone was evaluated on Expression of iNOS and Nitrotyrosine (NT) and hepatic injury. Administration of D-galactosamine and LPS induced iNOS and nitrotyrosine expression exclusively in hepatic lesions, which was inhibited by anti-TNF-alpha antibody, suggesting NO mediates hepatic injury.
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