Innate Lung Defenses and CompromisedPseudomonas aeruginosaClearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis

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Abstract
Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections. Chronic lung infections withPseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility toP. aeruginosacolonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished, and transgenic mice.CFTRm1Unc−/−knockout mice displayed body weight variations and showed variable pulmonary clearance ofP. aeruginosa. This variability was not detected in bitransgenicCFTRm1Unc−/−(FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J mice resulted in impaired pulmonary clearance ofP. aeruginosa. Tumor necrosis factor alpha (TNF-α) and nitrite levels detected upon exposure toP. aeruginosaaerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-α and reactive nitrogen intermediates inP. aeruginosaclearance was tested in TNF-α and inducible nitric oxide synthase (iNOS) knockout mice.P. aeruginosaclearance was diminished in transgenic TNF-α- and iNOS-deficient mice. In contrast to the effects of TNF-α and iNOS, gamma interferon knockout mice retained a full capacity to eliminateP. aeruginosafrom the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge withP. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defectiveCFTRin the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial colonization, and excessive inflammation in the CF respiratory tract.