Characterization of inflammation during chronic bronchopulmonary Pseudomonas aeruginosa infection in resistant and susceptible inbred mouse strains

Studies in cystic fibrosis patients have suggested that the balance between pro- and anti-inflammatory cytokines may be important in controlling infection and tissue destruction during bronchopulmonary Pseudomonas aeruginosa (PA) infection. Here, the inflammatory response was characterized in a murine model of bronchopulmonary PA infection in resistant BALB/c and susceptible C57BL/6 mice following intratracheal inoculation with 10 5 CFU of mucoid PA entrapped in agar beads. On day 7 post infection, BALB/c mice had significantly less bacteria and significantly more IL-10 in the lungs as compared to C57BL/6 mice while the levels of TNF-alpha and IFN-gamma levels were comparable. Bronchoalveolar lavage revealed that the significantly lower lung inflammatory response in BALB/c mice was composed of 45% PMN, 30% lymphocytes and 25% macrophages while that of C57BL/6 mice was composed of 62% PMN, 8% lymphocytes, and 30% macrophages. Alveolar macrophages from C57BL/6 mice spontaneously produced significantly higher NO levels while cells from BALB/c mice produced significantly more TNF-alpha, either spontaneously or following stimulation with LPS or heat-killed PA. There was no difference in IL-10 production. Lung PMN from either strain produced undetectable levels of NO and high levels of TNF-alpha. PMN from BALB/c mice, however, produced significantly higher levels of IL-10. The severity of infection in both strains of mice was exacerbated by administration of the anti-IL-10 mAb JES5-2A5. IL-10 neutralization resulted in an increased inflammatory response, increased bacterial counts, and increased TNF-alpha levels in both mouse strains. The increased inflammatory response in resistant BALB/c mice was due to a significant influx of macrophages whereas in susceptible C57BL/6 mice a significant influx of PMN and decreased numbers of macrophages were observed. Taken together, these results suggest that an intricate network of cells and cytokines regulates the pulmonary infl