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Response to Acute Lung Infection with Mucoid Pseudomonas aeruginosa in Cystic Fibrosis Mice

Department of Pediatrics, Rainbow Babies and Children's Hospital, and Case Western Reserve University School of Medicine, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Anna M. van Heeckeren, D.V.M., M.S., Case Western Reserve University School of Medicine, Division of Pediatric Pulmonology, Biomedical Research Building 827, 2109 Adelbert Road, Cleveland, OH 44106-4948. E-mail: anna.vanheeckeren{at}case.edu

Rationale: Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator gene, which codes for a chloride channel, but the role of this chloride channel in inflammation induced by lung infection with Pseudomonas aeruginosa remains to be defined.

Objectives: We tested the hypothesis that loss of this chloride channel alone is sufficient to cause excessive inflammation in response to inflammatory stimuli.

Methods: We investigated the response of cystic fibrosis and wild-type mice to mucoid P. aeruginosa administered by insufflation.

Measurements: The host responses measured included survival, weight change, lung morphometry, bacterial clearance, and inflammatory mediators, and cell counts were assessed in bronchoalveolar lavage fluid.

Main Results: Depending on the dose administered and frequency of dosing, cystic fibrosis mice experienced significantly higher mortality rates, greater weight loss, higher lung pathology scores, and higher inflammatory mediator and neutrophil levels compared with wild-type mice, even after the bacteria had been cleared. Surprisingly, bacteria were cleared just as rapidly in cystic fibrosis mice as in wild-type mice, and sepsis was not observed. Chronic lung infections could not be established with mucoid P. aeruginosa in either cystic fibrosis or wild-type mice.

Conclusions: Absence of this chloride channel alone appears sufficient for exaggerated inflammation and excess mortality compared with wild-type controls in the face of mucoid P. aeruginosa lung infection. To establish chronic infection, additional factors such as bacterial trapping or poor clearance may be required.

Key Words: cystic fibrosis • cystic fibrosis transmembrane conductance regulator • inflammation • pathogenesis

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