The inflammatory response in the lungs of CF patients is excessive relative to the burden of infection and results in a progressive decline in pulmonary function and ultimately, death. In contrast to BAL fluid from healthy controls, BAL fluid from CF patients contains an abundance of proinflammatory cytokines but negligible amounts of the antiinflammatory cytokine IL-10. We propose that decreased IL-10 may be more important than the absolute quantity of proinflammatory cytokines in determining the amount of inflammation in the lungs of CF patients. To study the role of IL-10, we used the agarose bead model of chronic Pseudomonas aeruginosa (Pa) endobronchial infection in IL-10 knockout (IL-10 KO) mice and in normal mice supplemented with exogenous IL-10. Experiment 1: Bilateral infection with mucoid Pa resulted in a survival of 55% in IL-10 KO mice vs. 100% in wild-type (WT) mice after 10 days. Experiment 2: In a unilateral chronic infection model, weight loss was more severe in IL-10 KO mice than in WT mice. Inflammation as determined by quantitative histopathology was greater in IL-10 KO mice (n=6) than their WT counterparts (n=4) (26% vs. 9%, p=0.038). There was no significant difference in the recovery of Pa between the two groups, showing that this decrease in inflammation did not compromise control of the infection. Experiment 3: To determine the effect of exogenous IL-10, chronically Pa infected normal mice were treated with 1μg of recombinant human IL-10 or buffer alone TID by i.p. injection. IL-10 treated mice had a survival of 44% as compared to 22% in controls (p=0.02). In animals sacrificed 10 days after infection, IL-10 treated mice had only 3% PMNs and a mean total cell count of 1.3 ×105/mL of BAL fluid while untreated mice had 23% PMNs and a mean total cell count of 2.4 ×106/mL. Taken together, these data suggest that IL-10 plays an important role in regulating the inflammatory response to Pa in the lung, and that therapy with IL-10 may have beneficial effects.