NITRIC-OXIDE INHIBITS INFLAMMATORY CYTOKINE PRODUCTION BY HUMAN ALVEOLAR MACROPHAGES

High levels of nitric oxide (NO) have been reported in exhaled air of asthmatic individuals. Because alveolar macrophages (AM) are major pro ducers of cytokines, and bronchoalveolar lavage fluid (BALF) from asth matic individuals contains increased levels of inflammatory cytokines, this study was undertaken to determine whether NO modified the produc tion of inflammatory cytokines by human AM. AM were obtained from norm al volunteers by fiberoptic bronchoscopy. Tumor necrosis factor-alpha (TNF-alpha) production stimulated by lipopolysaccharide (LPS; 0.5 mu g /ml) was measured with an enzyme-linked immunosorbent assay (ELISA). N O generated from 2,2-(hydroxynitrosohydrazono)-bis-ethanamine (DETA NO NOate) (0.1 to 1.0 mM) inhibited TNF-alpha secretion in a dose-depende nt manner. At 1 mM DETA NONOate, mean inhibition (+/- SEM) of TNF-alph a secretion was 56 +/- 4% (P = 0.002). To determine whether this effec t was cytokine specific, interleukin-1 beta (IL-1 beta) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) were evaluated, and DETA N ONOate was also found to inhibit both of these cytokines. Basal cytoki ne levels from unstimulated AM were unaffected by NO. These findings i ndicate that NO is a patent inhibitor of cytokine production by stimul ated human AM.