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Published ahead of print on December 20, 2007, doi:10.1165/rcmb.2007-0366OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 6, June 2008, 629-638

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Submitted on October 5, 2007
Revised on December 20, 2007

Haemophilus influenzae Lysate Induces Aspects of the Chronic Obstructive Pulmonary Disease Phenotype

Seyed Javad Moghaddam1, Cecilia G Clement1, M. Miguelina De la Garza2, Xiaoyan Zou1, Elizabeth L Travis3, Hays W. J. Young1, Christopher M Evans4, Michael J Tuvim4, and Burton F Dickey4*

1 Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Tecnologico de Monterrey School of Medicine, Monterrey, Nuevo Leon, Mexico, 3 Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 4 Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute of Biosciences and Technology, Center for Lung Inflammation and Infection, Houston, TX, USA

* To whom correspondence should be addressed. E-mail: bdickey{at}mdanderson.org.

Non-typeable Haemophilus influenzae (NTHi) commonly colonizes the lower airways of patients with chronic obstructive pulmonary disease (COPD). Whether it contributes to COPD progression is unknown. Here, we determined which aspects of the COPD phenotype can be induced by repetitive exposure to NTHi products. Mice were exposed weekly to an aerosolized NTHi lysate, and inflammation was evaluated by measurement of cells and cytokines in bronchoalveolar lavage fluid (BALF) and immunohistochemical staining: structural changes were evaluated histochemically by PAFS, Masson's trichrome and Picrosirius red staining: mucin gene expression was measured by quantitative RT-PCR; and role for TNF-{alpha} was examined by transgenic airway overexpression and use of an inhibitory antibody. NTHi lysate induced activation of NF-{kappa}B in airway cells and increases of inflammatory cytokines and neutrophils in BALF. Repetitive exposure induced infiltration of macrophages, CD8+ T cells, and B cells around airways and blood vessels, and collagen deposition in airway and alveolar walls, but airway mucin staining and gel-forming mucin transcripts were not increased. Transgenic overexpression of TNF-{alpha} caused BALF neutrophilia and inflammatory cell infiltration around airways, but not fibrosis, and TNF-{alpha} neutralization did not reduce BALF neutrophilia in response to NTHi lysate. In conclusions, NTHi products elicit airway inflammation in mice with a cellular and cytokine profile similar to that in COPD, and cause airway wall fibrosis but not mucous metaplasia. TNF-{alpha} is neither required for inflammatory cell recruitment nor sufficient for airway fibrosis. Colonization by NTHi may contribute to the pathogenesis of small airways disease in COPD patients.




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