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Published ahead of print on March 30, 2006, doi:10.1164/rccm.200509-1461OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 1, July 2006, 31-40

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Submitted on September 19, 2005
Accepted on March 27, 2006

Impaired Alveolar Macrophage Response to Haemophilus Antigens in Chronic Obstructive Lung Disease

Charles S Berenson1*, Catherine T Wrona1, Lori J Grove1, Jane Maloney1, Mary Alice Garlipp1, Paul K Wallace2, Carleton C Stewart2, and Sanjay Sethi1

1 Department of Veterans Affairs Western New York Healthcare System, Infectious Disease Division, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA, 2 Laboratory of Flow Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA

* To whom correspondence should be addressed. E-mail: berenson{at}acsu.buffalo.edu.

Rationale: Interactions of nontypeable Haemophilus influenzae (NTHI) with macrophages are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immunologic mechanisms that mediate NTHI-macrophage inflammation are poorly understood. Outer membrane protein (OMP) P6 and lipooligosaccharide (LOS) of NTHI are potent immunomodulators. We theorized that alveolar macrophages in COPD possess fundamental immune defects that permit NTHI to evade host responses. Objective: To test this hypothesis, we obtained human alveolar and blood macrophages from: 1) ex-smokers with COPD, 2) ex-smokers without COPD and 3) nonsmokers. Methods: Alveolar and blood macrophages of each donor were incubated with purified LOS and OMP P6, as well as OMP P2 and the total outer membrane (OM) preparation (0.1-1ug/ml). Measurements: Supernatants (24 hours) were assayed for IL-1{beta}, TNF-{alpha}, IL-10, IL-12 and IL-8 by multianalyte multiplexed flow cytometry. Results: Comparative induction of COPD and nonCOPD alveolar macrophages by LOS and OMP P6 revealed diminished IL-8, TNF-{alpha} and IL-1{beta} responses of COPD alveolar macrophages (p≤0.03 for each). COPD alveolar macrophages also had diminished responses to total OMs (p≤0.03 for each). In contrast, COPD blood macrophages had no significant differences among donor groups in IL-8, TNF-{alpha} or IL-1{beta} responsiveness to NTHI antigens. Diminished IL-12 responses of COPD blood macrophages to NTHI antigens, compared with nonsmokers, could not be independently dissociated from group differences in age and pack-years. Conclusions: These findings support a paradigm of defective immune responsiveness of alveolar macrophages, but not blood macrophages, in COPD.
Key words: nontypeable Haemophilus influenzae; macrophage; alveolar; cytokine; COPD




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