Microbial Pathogenesis in Cystic Fibrosis: Pulmonary Clearance of Mucoid Pseudomonas aeruginosaand Inflammation in a Mouse Model of Repeated Respiratory Challenge

ABSTRACTChronic endobronchiolitis compounded by recurring Pseudomonas aeruginosainfections is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). In this study, a mouse model of repeated respiratory exposure to P. aeruginosawas established to facilitate investigations of factors contributing toP. aeruginosapersistence and associated inflammatory processes in the lung. While a single exposure to P. aeruginosaaerosols resulted in only mild histopathological changes, repeated exposure caused significant lung pathology in C57BL/6J mice. The peak of histopathological changes and inflammation in C57BL/6J mice was characterized by subacute lymphohistiocytic bronchopneumonia and persistent elevation of tumor necrosis factor alpha and macrophage inflammatory protein 2 in the lung but not in the serum. When isogenic nonmucoid (mucA+) and mucoid (mucA22) P. aeruginosastrains were compared, the mucoid cells were cleared several-fold less efficiently than the parental nonmucoid strain during the initial stages of the aerosol exposure regimen. However, the microscopic pathology findings and proinflammatory cytokine levels were similar in mice exposed to nonmucoid and mucoid P. aeruginosathroughout the infection. We also tested lung histopathology and proinflammatory cytokines in interleukin 10 (IL-10)-deficient transgenic (IL-10T) mice. Significant mortality was seen in IL-10T mice on initial challenge withP. aeruginosa, although no histopathological differences could be observed in the lungs of C57BL/6J and surviving IL-10T mice after a single exposure. However, increased pathology was detected in IL-10T mice relative to C57BL/6J after repeated challenge with P. aeruginosa. This observation supports the proposals that anti-inflammatory cytokines may play a role in suppressing P. aeruginosa-induced tissue damage during chronic infection.