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Departments of Internal Medicine and Pediatrics, University of Iowa Carver College of Medicine, and Veterans Administration Medical Center, Iowa City, Iowa; Department of Medicine, University at Buffalo, State University of New York; and Department of Veterans Affairs Western New York Healthcare System, Buffalo, New York
Correspondence and requests for reprints should be addressed to Dwight C. Look, M.D., University of Iowa Carver College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, C33-GH, Iowa City, IA 52242. E-mail: dwight-look{at}uiowa.edu
Key Words: airway epithelial cells • bacterial adherence • interleukin-8 • nuclear factor-
B • p38 mitogen-activated protein kinase
Chronic obstructive pulmonary disease (COPD) is associated with periodic exacerbations that manifest as worsening of lung function and increased dyspnea, cough, sputum production, and sputum purulence. COPD exacerbations are associated with increased markers of inflammation in the airway, including neutrophils, interleukin(IL)-6, and IL-8 (1, 2). These observations led to the hypothesis that factors that promote airway inflammation lead to worsening airway function in patients with COPD. Although infection clearly has the ability to induce airway inflammation, the role that bacteria play in COPD exacerbations remains controversial (3, 4). Bacteria commonly colonize the airway of patients with COPD at baseline, making the presence of bacteria insufficient to explain worsening airway function (5–7). However, COPD exacerbation could be precipitated by an increase in bacterial number; change in the airway compartment in which bacteria are located; or acquisition of new, more virulent, and/or more proinflammatory bacterial species or strain (3, 8, 9). Nontypeable Haemophilus influenzae is the bacterial species most commonly isolated from airway samples during COPD exacerbations (9, 10). The ability of this bacteria to cause intense airway inflammation and the association of exacerbations with development of humoral immune responses to H. influenzae acquired for the first time supports a potential role for infection by this organism in causing COPD exacerbations (11). However, patient and bacterial factors that determine whether airway infection results in worsening of airway function are poorly defined.
We have previously reported an initial comparative study of H. influenzae isolates from patients with COPD who were followed as part of a prospective, longitudinal study at the Buffalo Veterans Affairs Medical Center (12). For this study, 17 bacterial isolates were obtained from 15 patients with COPD who underwent serial assessment of clinical status, sputum microbiology, and serum antibacterial antibody production. Exacerbation strains were defined as new isolates cultured from sputum during exacerbation of clinical symptoms with subsequent development of a homologous bactericidal serum antibody response. Colonization strains were not associated with an increase in symptoms or new antibody production. We found that strains of H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in an in vivo mouse model of airway infection. Experiments using an in vitro model of human primary airway epithelial cells revealed that exacerbation strains adhered significantly more to epithelial cells. In addition, exacerbation isolates induced greater release of IL-8 compared with colonization strains, a response likely mediated by increased activation of both the nuclear factor-B and p38 mitogen-activated protein kinase signaling pathways. The results indicate that H. influenzae isolated from patients with exacerbations of COPD induce more airway inflammation, and likely have differences in virulence compared with colonizing strains.
We have gone on to investigate selected characteristics of the interaction between H. influenzae and airway epithelial cells that could account for bacterial strain differences in induction of IL-8. Previous experiments in our laboratory indicate that multiple soluble factors are released during epithelial cell interaction with H. influenzae that augment both IL-8 release and expression of other inflammatory mediators. Accordingly, we questioned whether these factors might disproportionately augment epithelial cell IL-8 levels in experiments using exacerbation strains or suppress IL-8 levels after epithelial cell interaction with colonization strains. However, we found that differences between H. influenzae isolates associated with exacerbation versus colonization in patients with COPD were not attributable to the presence of soluble factors generated after epithelial cell–bacterial interaction. Interestingly, induction of IL-8 expression by airway epithelial cell interaction with both exacerbation and colonization strains of H. influenzae was inhibited by exposure of epithelial cells to the macrolide antibiotics erythromycin and azithromycin. This effect was not due to antibacterial properties of these antibiotics, as inhibition of IL-8 expression was seen when bacteria were killed before experiments by pretreatment with gentamicin. Taken together, our findings support the concept that H. influenzae infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function. Furthermore, inflammatory mediator generation by epithelial cells exposed to bacteria in the airway may be modulated pharmacologically, and this strategy could improve airway function in patients with COPD.
FOOTNOTES
Supported by grants from the National Institutes of Health: R01 HL065752 (D.C.L.) and R01 HL082505 (D.C.L.).
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 17, 2006; accepted in final form April 12, 2006)
REFERENCES
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