Innate Lung Defenses and Compromised Pseudomonas aeruginosa Clearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis

doi:10.1128/IAI.68.4.2142-2147.2000

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Infection and Immunity, April 2000, p. 2142-2147, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Innate Lung Defenses and Compromised Pseudomonas aeruginosa Clearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis

H. Yu,¹ S. Z. Nasr,² and V. Deretic¹^,^*

Departments of Microbiology and Immunology¹ and Pediatrics,² University of Michigan Medical School, Ann Arbor, Michigan

Received 28 September 1999/Returned for modification 22 November 1999/Accepted 3 January 2000

Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutritionand chronic respiratory infections. Chronic lung infections withPseudomonas aeruginosa, intense neutrophil-dominated airway inflammation,and progressive lung disease are the major cause of high morbidityand mortality in CF. Here we investigated the effects of malnutritionin CF on innate lung defenses, susceptibility to P. aeruginosacolonization, and associated inflammation, using aerosol modelsof acute and chronic infections in normal, malnourished, and transgenicmice. CFTR^m1Unc/ knockout mice displayed body weight variations and showed variablepulmonary clearance of P. aeruginosa. This variability was notdetected in bitransgenic CFTR^m1Unc/(FABP-hCFTR) mice in which the intestinal defect had been corrected.Diet-induced protein calorie malnutrition in C57BL/6J mice resultedin impaired pulmonary clearance of P. aeruginosa. Tumor necrosisfactor alpha (TNF- $alpha$ ) and nitrite levels detected upon exposureto P. aeruginosa aerosols were lower in the lungs of the malnourishedC57BL/6J mice relative than in lungs of mice fed a normal diet.The role of TNF- $alpha$ and reactive nitrogen intermediates in P. aeruginosaclearance was tested in TNF- $alpha$ and inducible nitric oxide synthase(iNOS) knockout mice. P. aeruginosa clearance was diminished intransgenic TNF- $alpha$ - and iNOS-deficient mice. In contrast to theeffects of TNF- $alpha$ and iNOS, gamma interferon knockout mice retaineda full capacity to eliminate P. aeruginosa from the lung. Malnutritionalso contributed to excessive inflammation in C57BL/6J mice uponchronic challenge with P. aeruginosa. The repeatedly infectedmalnourished host did not produce interleukin-10, a major anti-inflammatorycytokine absent or diminished in the bronchoalveolar fluids ofCF patients. These results are consistent with a model in whichdefective CFTR in the intestinal tract leads to nutritional deficiencywhich in turn contributes to compromised innate lung defenses,bacterial colonization, and excessive inflammation in the CF respiratorytract.

^* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Michigan Medical School, 5641Medical Science Building II, Ann Arbor, MI 48109-0620. Phone:(734) 763-1580. Fax: (734) 647-6243. E-mail: Deretic{at}umich.edu.

Infection and Immunity, April 2000, p. 2142-2147, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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