Abstract 1922
Poster Session I, Saturday, 5/1 (poster 95)
Because of its activity as a potent local vasodilator, inhaled nitric oxide is increasingly used in the treatment of persistent pulmonary hypertension of the newborn. However, little is known about the toxicity of this free radical gas. Using Balb/c mice, we found that inhaled nitric oxide (20-100 ppm, 5 h) increased bronchoalveolar lavage (BAL) fluid protein, suggesting that nitric oxide induces injury to the alveolar epithelium. Alveolar macrophages isolated from animals treated with inhaled nitric oxide were found to be primed to produce increased amounts of nitric oxide, peroxynitrite, and superoxide anion, each of which has been implicated in tissue injury. In mice genetically engineered to be deficient in inducible nitric oxide synthase, we found no alterations in BAL protein in response to inhaled nitric oxide. Moreover, alveolar macrophages isolated from these animals did not produce nitric oxide or peroxynitrite. Interestingly, we also observed reduced toxicity of inhaled nitric oxide in mice overexpressing superoxide dismutase. This enzyme catalyzes the removal of superoxide anion, preempting the generation of peroxynitrite, which is a long-lived and toxic oxidant. Furthermore, mice lacking p55 tumor necrosis factor-α receptor were protected from pulmonary injury induced by inhaled nitric oxide. Taken together, these data indicate that endogenously produced reactive oxygen and nitrogen intermediates contribute to the toxicity of inhaled nitric oxide. Alveolar macrophages are primed for increased production of these intermediates following inhalation of nitric oxide by mechanisms which are related to tumor necrosis factor-α.
