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A7440 - Experimental Modeling of Infectious Exacerbationss in a Cigarette Smoke-Induced Ferret Model of COPD
Author Block: B. Hunt1, D. Stanford1, N. Kaza1, S. Byzek1, J. LaFontaine1, S. M. Rowe2, S. Raju3, W. E. Swords4; 1University of Alabama at Birmingham, Birmingham, AL, United States, 2Univ of Alabama At Birmingham, Birmingham, AL, United States, 3Pulmonary, University of Alabama at Birmingham, Birmingham, AL, United States, 4Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Introduction. Patients with chronic obstructive pulmonary disease (COPD) have persistent airway infections that are typically caused by opportunistic pathogens that normally reside within the nasopharyngeal microbiome. The population dynamics of the microbial populations within the lungs of COPD patients are dynamic and subject to rapid change, and the introduction of newly colonizing strains/species has been associated with onset of exacerbations in patient studies. There have also been some indications that bacterial subpopulations may differ in virulence. However, the absence of a physiologically relevant animal model has precluded experimentation on the impact of infection in the clinical context of COPD exacerbations. Methods. We utilized a novel chronic smoke-induced ferret model of COPD that is physiologically reminiscent of the human condition, including chronic mucus hypersecretion, defective mucociliary transport, mucus obstruction and development of opportunistic infections. These ferrets spontaneously develop dysbiotic infections with many of the same bacterial phylotypes that are observed in human patients, and have increased prevalence of Haemophilus and Staphylococcus. Smoke-exposed ferrets with confirmed COPD disease (and control animals) were infected via the intratracheal route with nontypeable Haemophilus influenzae bacteria, and the presence, density and persistence of the bacterial populations were longitudinally monitored for 21 days by plate count and quantitative PCR of bronchoalveolar lavages obtained by bronchoscopy. Results. The results indicate that experimentally instilled nontypeable H. influenzae bacteria persist within the lungs of ferrets with COPD. As there were no significant changes in total bacterial loads, these bacterial populations supplanted rather than augmented othern bacterial subpopulations within the existing community. In vivo micro-resolution CT imaging, histopathologic and cytokine analyses were also performed in order to quantify the host inflammatory response following infection. Conclusions. We conclude that COPD ferrets are susceptible to persistent infections with H. influenzae, and potentially other COPD related opportunists. As has been reported in human longitudinal patient studies, the bacterial populations within the COPD ferret lung are dynamic in composition, and subject to bacterial replacement by new incoming strains. Moreover, the data support the conclusion that infection initiates a robust inflammatory response that is a hallmark of exacerbation of COPD disease.