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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 malnutrition and chronic respiratory infections. Chronic lung infections with Pseudomonas 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 to P. aeruginosa colonization, 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 of P. aeruginosa. This variability was not detected in bitransgenic
CFTRm1Unc
/
(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
of P. aeruginosa. Tumor necrosis factor alpha (TNF-
) and
nitrite levels detected upon exposure to P. aeruginosa
aerosols 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-
and reactive nitrogen intermediates in P. aeruginosa clearance was tested in TNF-
and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was
diminished in transgenic TNF-
- and iNOS-deficient mice. In contrast
to the effects of TNF-
and iNOS, gamma interferon knockout
mice retained a full capacity to eliminate P. aeruginosa
from the lung. Malnutrition also contributed to excessive
inflammation in C57BL/6J mice upon chronic challenge with P. 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 defective CFTR in 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.
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology, University of Michigan Medical School,
5641 Medical 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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