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Sci. STKE, 18 December 2007
Vol. 2007, Issue 417, p. tw461
[DOI: 10.1126/stke.4172007tw461]

EDITORS' CHOICE

Lung Disease Loss of Bactericidal Activity Promotes Infection

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Chronic lung disease, including cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), is characterized by high concentrations of interleukin-8 (IL-8) in cells around the airway and accumulation of neutrophils, yet the lungs of these patients are frequently colonized by bacteria, such as Pseudomonas aeruginosa. Hartl et al. show that IL-8 acts through the CXCR1 receptor, not the CXCR2 receptor, to promote the bactericidal activity of neutrophils. By comparing neutrophils from the peripheral blood and airway (bronchial alveolar lavage and sputum) of healthy individuals with those from patients with cystic fibrosis, bronchiectasis, or COPD, Hartl et al. found that the airway neutrophils from the diseased lungs had decreased CXCR1 at the surface and exhibited impaired bactericidal activity. The protease elastase is increased in abundance in airway fluids from patients with cystic fibrosis. Further statistical analysis of various factors associated with cystic fibrosis, including infection with P. aeruginosa, suggested that the concentration of free elastase correlated with the loss of CXCR1 on the airway neutrophils. Addition of airway fluids from individuals with cystic fibrosis to peripheral neutrophils caused loss of CXCR1 and impaired bacterial killing, and these effects were prevented if the elastase activity was inhibited pharmacologically in the airway fluid prior to addition to the isolated neutrophils. Cleavage of CXCR1 by elastase produced two soluble CXCR1 fragments that were also detected in the airway fluids from patients with cystic fibrosis, bronchiectasis, or COPD. Application of purified soluble CXCR1 fragments stimulated bronchial epithelial cells to produce IL-8 through a mechanism requiring the Toll-like receptor TLR2. Cystic fibrosis patients who inhaled {alpha}1 antitrypsin to inhibit elastase activity for 4 weeks showed increased CXCR1 at the surface of airway neutrophils, decreased abundance of soluble CXCR1 fragments in the airway fluid, and decreased P. aeruginosa in the sputum. In commentary, Sabroe and Whyte describe how failure of mucosal immunity contributes to disease pathogenesis, especially in cystic fibrosis.

D. Hartl, P. Latzin, P. Hordijk, V. Marcos, C. Rudolph, M. Woischnik, S. Krauss-Etschmann, B. Koller, D. Reinhardt, A. A. Roscher, D. Roos, M. Griese, Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat. Med. 13, 1423-1430 (2007). [PubMed]

I. Sabroe, M. K. B. Whyte, Incapacitating the immune system in cystic fibrosis. Nat. Med. 13, 1417-1418 (2007). [PubMed]

Citation: N. R. Gough, Loss of Bactericidal Activity Promotes Infection. Sci. STKE 2007, tw461 (2007).



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