Innate lung defenses and compromised Pseudomonas aeruginosa clearance in the malnourished mouse model of respiratory infections in cystic fibrosis

Cystic fibrosis (CF) is characterized by dysfunction of the digestive and r espiratory tracts resulting in generalized malnutrition and chronic respira tory infections. Chronic lung infections with Pseudomonas aeruginosa, inten se neutrophil-dominated airway: inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investig ated the effects of malnutrition in CF on innate lung defenses, susceptibil ity to P. aeruginosa colonization, and associated inflammation, using aeros ol models of acute and chronic infections in normal, malnourished, and tran sgenic mice. CFTRm1Unc-/- knockout mice displayed body weight variations an d showed variable pulmonary clearance of P. aeruginosa. This variability wa s not detected in bitransgenic CFTRm1Unc-/- (FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutri tion in C57BL/6J mice resulted in impaired pulmonary clearance of P. aerugi nosa. Tumor necrosis factor alpha (TNF-alpha) and nitrite levels detected u pon exposure to P. aeruginosa aerosols were lower in the lungs of the malno urished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-alpha and reactive nitrogen intermediates in P. aeruginosa cle arance was tested in TNF-alpha and inducible nitric oxide synthase (iNOS) k nockout mire. P. aeruginosa clearance was diminished in transgenic TNF-alph a- and iNOS-deficient mice. In contrast to the effects of TNF-alpha and iNO S, gamma interferon knockout mice retained a full capacity to eliminate P. aeruginosa from the lung. Malnutrition also contributed to excessive inflam mation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repe atedly infected malnourished host did not produce interleukin-10, a major a nti-inflammatory cytokine absent or diminished in the bronchoalveolar fluid s of CF patients. These results are consistent with a model in which defect ive CFTR in the intestinal tract leads to nutritional deficiency which in t urn contributes to compromised innate lung defenses, bacterial colonization , and excessive inflammation in the CF respiratory tract.