Inhibition of nitric oxide synthesis by L-name exacerbates acute lung injury induced by hepatic ischemia-reperfusion

Hepatic Kupffer cells and pulmonary alveolar macrophages together constitut e a macrophage-axis involved in the regulation of regional and systemic inf lammatory responses. Systemic inflammatory response syndrome induced by ove rproduced pro-inflammatory mediators is the major cause of adult respirator y distress syndrome. In the present study, we examined the anti-inflammator y role of nitric oxide (NO) in a rat model of acute lung injury induced by hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia by clamping the relevant branches of hepatic artery and portal vein, followed by a 4-h reperfusion achieved by r emoval of the vascular clamp. Four groups of animals were studied: sham con trol + saline; sham control + N-omega-nitro-L-arginine methyl ester (L-NAME , 10 mg/kg, i.v., 10 min before reperfusion); HIM + saline; HI/R + L-NAME. Results show that (1) administration of L-NAME to rats subjected to HI/R de creased plasma NO levels; however, the attenuation of NO increased plasma a lanine aminotransferase (ALT) activity and superoxide generation in the isc hemic lobes of liver, compared to HI/R alone. (2) Inhibition of NO synthesi s with L-NAME in rats subjected to HI/R also enhanced systemic inflammatory response as assessed by the increase in the number of circulating leukocyt es and levels of plasma tumor necrosis factor-alpha (TNF alpha) and interle ukin 1-beta (IL-1 beta). (3) The overwhelming systemic inflammatory respons e induced by administration of L-NAME in rats subjected to HI/R also augmen ted pulmonary vascular permeability and superoxide generation in the lung t issue. (4) Pulmonary alveolar macrophages isolated from rats subjected to H IM + L-NAME produced higher levels of TNF alpha and IL-1 beta in the supern atant of culture medium than that of rats subjected to HIM alone. (5) There were no differences between the groups of sham + saline and sharn + L-NAME in terms of plasma NO levels and ALT activity, circulating leukocytes, sup eroxide generation in the liver and lung, lavage protein levels, and TNF al pha and IL-1 beta levels in plasma and bronchoalveolar lavage fluid. Our re sults suggest that inhibition of NO synthesis by L-NAME in rats subjected t o HIM not only augments ischemic liver injury, but also enhances the system ic inflammatory response and exacerbates remote lung injury. The increase i n TNF alpha and IL-1 beta production by alveolar macrophages may, in part, account for L-NAME-induced enhancement of acute lung injury.