INHALED NITRIC-OXIDE PRIMES LUNG MACROPHAGES TO PRODUCE REACTIVE OXYGEN AND NITROGEN INTERMEDIATES

Inhaled nitric oxide is a selective pulmonary vasodilator used for the treatment of pulmonary hypertension. The potential adverse effects of inhaled nitric oxide are unknown and represent the focus of the prese nt studies. Whereas inhalation of nitric oxide (10 to 100 ppm, 5 h) by Balb/c mice had no effect on the number or type of cells recovered fr om the lung, a dose-related increase in bronchoalveolar lavage protein was observed, suggesting that nitric oxide induces alveolar epithelia l injury. To determine if this was associated with altered alveolar ma crophage activity, we quantified production of reactive oxygen and nit rogen intermediates by these cells. Interferon-gamma, alone or in comb ination with lipopolysaccharide (LPS), induced expression of inducible nitric oxide synthase (iNOS) protein and nitric oxide production by a lveolar macrophages. Cells from mice exposed to 20 to 100 ppm nitric o xide produced significantly more nitric oxide and expressed greater qu antities of iNOS than cells from control animals. Superoxide anion pro duction and peroxynitrite generation by alveolar macrophages were also increased after exposure of mice to nitric oxide. This was correlated with increased anti-nitrotyrosine antibody binding to macrophages in histologic sections. Taken together, these data demonstrate that inhal ed nitric oxide primes lung macrophages to release reactive oxygen and nitrogen intermediates. Increased production of these mediators by ma crophages following inhalation of nitric oxide may contribute to tissu e injury.