title: Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.
abstract: Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-0688, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Ganesan
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Faris
authors.forename: Adam T
authors.initials: AT
authors.lastname: Comstock
authors.forename: Joanne
authors.initials: J
authors.lastname: Sonstein
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.forename: Uma S
authors.initials: US
authors.lastname: Sajjan
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006192:Haemophilus Infections / Q000276:immunology* / Q000503:physiopathology; D006193:Haemophilus influenzae / Q000276:immunology; D007113:Immunity, Innate / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008176:Lung Volume Measurements; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D010196:Pancreatic Elastase / Q000494:pharmacology*; D010587:Phagocytosis / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000276:immunology / Q000382:microbiology; D051117:Scavenger Receptors, Class A / Q000502:physiology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D051117:Scavenger Receptors, Class A; D010196:Pancreatic Elastase
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