Enhanced susceptibility to pulmonary infection with Burkholderia cepacia in Cftr(-/-) mice

Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains inco mpletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia c epacia (genomovar III, ET12 strain), an opportunistic gram-negative bacteri um, from a case of CF into the lungs of Cftr mlunc(-/-) (Cftr(-/-)) and con genic Cftr(+/+) controls. Nine days after the last instillation, the CF tra nsmembrane regulator knockout mice showed persistence of viable bacteria wi th chronic severe bronchopneumonia while wild-type mice remained healthy. T he histopathological changes in the lungs of the susceptible Cftr(-/-) mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion o f neutrophils was observed in bronchoalveolar lavage fluid from the Cftr(-/ -) mice, which, despite an increased bacterial load, demonstrated minimal e vidence of activation. Alveolar macrophages from Cftr(-/-) mice also demons trated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This m urine model of chronic pneumonia thus reflects, in part, the situation in h uman patients and may help elucidate the mechanisms leading to defective ho st defense in CF.