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

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

Correspondence and requests for reprints should be addressed to Burton F. Dickey, M.D., Clifton D. Howe Distinguished Professor of Pulmonary Medicine, Chair, Department of Pulmonary Medicine, Unit 403, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. E-mail: bdickey{at}mdanderson.org

Nontypeable 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 periodic acid fluorescent Schiff's reagent, Masson's trichrome, and Picrosirius red staining; mucin gene expression was measured by quantitative RT-PCR; and the role of TNF- was examined by transgenic airway overexpression and use of an inhibitory antibody. NTHi lysate induced rapid activation of NF-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- caused BALF neutrophilia and inflammatory cell infiltration around airways, but not fibrosis, and TNF- neutralization did not reduce BALF neutrophilia in response to NTHi lysate. In conclusion, 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- 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 patients with COPD.

Key Words: pulmonary disease, chronic obstructive • Haemophilus influenzae • bronchiolitis • inflammation • fibrosis

CLINICAL RELEVANCE Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the airways of patients with chronic obstructive pulmonary disease (COPD). Whether NTHi colonization contributes to COPD progression is unknown. Our findings define which aspects of COPD might be induced by repetitive exposure to NTHi to help future clinical research.