Chronic pulmonary infection in cystic fibrosis (CF) results in an inflammatory response with persistent neutrophil influx, which contributes to lung damage. Attenuating the response with antiinflammatory agents might delay progression of lung disease. We investigated the effects of the nonsteroidal antiinflammatory agent, ibuprofen, in a rat model of chronic Pseudomonas endobronchial infection and inflammation. The areal percentage of lung inflammation 14 days after animal inoculation with Pseudomonas-containing agarose beads was significantly less in animals treated with ibuprofen (35 mg/kg orally twice daily) (39 +/- 26% SD) compared to animals given placebo (55 +/- 25% SD) (p less than 0.05). Ibuprofen did not increase the pulmonary burden of Pseudomonas, and the ibuprofen-treated infected animals gained weight better than placebo-treated controls. The administered dose of ibuprofen provides plasma concentrations sufficient to inhibit the release of leukotriene B4 (LTB4) from rat neutrophils in vitro. Since LTB4 is a potent pro-inflammatory product that promotes neutrophil adherence, aggregation, migration, degranulation, and superoxide release, inhibition of its production by ibuprofen could inhibit inflammatory damage to the lung in this model. These data in an animal model, taken together with the success of a preliminary trial of alternate-day steroid therapy in mildly affected patients with CF, suggest that antiinflammatory therapy with ibuprofen should be considered for a new therapeutic strategy in CF.