This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yu, H.
Right arrow Articles by Deretic, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yu, H.
Right arrow Articles by Deretic, V.

 Previous Article  |  Next Article 

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-alpha ) 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-alpha and reactive nitrogen intermediates in P. aeruginosa clearance was tested in TNF-alpha and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-alpha - and iNOS-deficient mice. In contrast to the effects of TNF-alpha 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.


This article has been cited by other articles:

  • Kukavica-Ibrulj, I, Levesque, R C (2008). Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies. Lab Anim 42: 389-412 [Abstract] [Full Text]  
  • Poschet, J. F., Timmins, G. S., Taylor-Cousar, J. L., Ornatowski, W., Fazio, J., Perkett, E., Wilson, K. R., Yu, H. D., de Jonge, H. R., Deretic, V. (2007). Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L712-L719 [Abstract] [Full Text]  
  • Wilson, K. R., Napper, J. M., Denvir, J., Sollars, V. E., Yu, H. D. (2007). Defect in early lung defence against Pseudomonas aeruginosa in DBA/2 mice is associated with acute inflammatory lung injury and reduced bactericidal activity in naive macrophages. Microbiology 153: 968-979 [Abstract] [Full Text]  
  • Guilbault, C., Saeed, Z., Downey, G. P., Radzioch, D. (2007). Cystic Fibrosis Mouse Models. Am. J. Respir. Cell Mol. Bio. 36: 1-7 [Abstract] [Full Text]  
  • Moeller, A, Horak, F Jr, Lane, C, Knight, D, Kicic, A, Brennan, S, Franklin, P, Terpolilli, J, Wildhaber, J H, Stick, S M (2006). Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis. Thorax 61: 514-520 [Abstract] [Full Text]  
  • Yarden, J, Radojkovic, D, De Boeck, K, Macek, M Jr, Zemkova, D, Vavrova, V, Vlietinck, R, Cassiman, J-J, Cuppens, H (2005). Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax 60: 320-325 [Abstract] [Full Text]  
  • Werner, A., Bongers, M. E. J., Bijvelds, M. J., de Jonge, H. R., Verkade, H. J. (2004). No indications for altered essential fatty acid metabolism in two murine models for cystic fibrosis. J. Lipid Res. 45: 2277-2286 [Abstract] [Full Text]  
  • Norkina, O., Kaur, S., Ziemer, D., De Lisle, R. C. (2004). Inflammation of the cystic fibrosis mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 286: G1032-G1041 [Abstract] [Full Text]  
  • Mueller-Ortiz, S. L., Drouin, S. M., Wetsel, R. A. (2004). The Alternative Activation Pathway and Complement Component C3 Are Critical for a Protective Immune Response against Pseudomonas aeruginosa in a Murine Model of Pneumonia. Infect. Immun. 72: 2899-2906 [Abstract] [Full Text]  
  • van Heeckeren, A. M., Scaria, A., Schluchter, M. D., Ferkol, T. W., Wadsworth, S., Davis, P. B. (2004). Delivery of CFTR by adenoviral vector to cystic fibrosis mouse lung in a model of chronic Pseudomonas aeruginosa lung infection. Am. J. Physiol. Lung Cell. Mol. Physiol. 286: L717-L726 [Abstract] [Full Text]  
  • van Heeckeren, A. M., Schluchter, M., Xue, L., Alvarez, J., Freedman, S., St. George, J., Davis, P. B. (2004). Nutritional Effects on Host Response to Lung Infections with Mucoid Pseudomonas aeruginosa in Mice. Infect. Immun. 72: 1479-1486 [Abstract] [Full Text]  
  • Carpagnano, G. E., Barnes, P. J., Geddes, D. M., Hodson, M. E., Kharitonov, S. A. (2003). Increased Leukotriene B4 and Interleukin-6 in Exhaled Breath Condensate in Cystic Fibrosis. Am. J. Respir. Crit. Care Med. 167: 1109-1112 [Abstract] [Full Text]  
  • Arkwright, P. D., Pravica, V., Geraghty, P. J., Super, M., Webb, A. K., Schwarz, M., Hutchinson, I. V. (2003). End-Organ Dysfunction in Cystic Fibrosis: Association with Angiotensin I Converting Enzyme and Cytokine Gene Polymorphisms. Am. J. Respir. Crit. Care Med. 167: 384-389 [Abstract] [Full Text]  
  • Steinkamp, G, Wiedemann, B (2002). Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 57: 596-601 [Abstract] [Full Text]  
  • Hart, C A., Winstanley, C. (2002). Persistent and aggressive bacteria in the lungs of cystic fibrosis children. Br Med Bull 61: 81-96 [Abstract] [Full Text]  
  • Poschet, J. F., Boucher, J. C., Tatterson, L., Skidmore, J., Van Dyke, R. W., Deretic, V. (2001). Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung. Proc. Natl. Acad. Sci. USA 98: 13972-13977 [Abstract] [Full Text]  
  • KHARITONOV, S. A., BARNES, P. J. (2001). Exhaled Markers of Pulmonary Disease. Am. J. Respir. Crit. Care Med. 163: 1693-1722 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»