Nitric oxide is a highly reactive molecule that has been implicated in host defense and in tissue injury. In the present studies we analyzed the effects of brief exposure of rats to inhaled ozone on production of this mediator by lung macrophages and type II epithelial cells. We found that ozone exposure (1-2 ppm, 3 hr) induced a marked increase in spontaneous nitric oxide production by alveolar (AM) and interstitial macrophages, as well as type II cells. These effects were apparently due to increased expression of inducible nitric oxide synthase protein and mRNA, which was evident in vitro in isolated cells and in situ in histologic sections. Macrophages and epithelial cells from ozone-treated rats were also sensitized to produce increased amounts of nitric oxide in response to inflammatory cytokines such as interferon-gamma, a response that was also mediated by inducible nitric oxide synthase. Unexpectedly, we also discovered that brief inhalation of ozone caused dramatic effects on the liver, including increased production of nitric oxide by hepatocytes and enhanced protein synthesis. These data suggest that this inhaled irritant induces an acute phase response. Additional studies indicate that AM from ozone-treated rats produced significantly more tumor necrosis factor-alpha and interleukin-1 than did cells from control animals. Elevated levels of tumor necrosis factor-alpha were also noted immunohistochemically in both lung and liver tissue. These results indicate that the extrapulmonary effects of ozone may be mediated by inflammatory cytokines released by activated lung macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)