Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene

22 pages, 7 figures, 1 table.The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.This work was supported by grants 98/0120, 2FD97-1432, and 08.3/0030/98 from Dirección General de Investigación Científica y Técnica, CICYT, and Comunidad de Madrid, respectively, and from Fundación Ramón Areces (X Concurso Nacional 1997).Peer reviewe