Cardiovascular , Pulmonary , and Renal Pathology Elastase / LPS-Exposed Mice Exhibit Impaired Innate Immune Responses to Bacterial Challenge Role of Scavenger Receptor A

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 (SRA). 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. (Am J Pathol 2012, 180:61–72; DOI: 10.1016/j.ajpath.2011.09.029) Chronic obstructive pulmonary disease (COPD) is a progressive disorder of the lung parenchyma and airways that became the third-leading cause of death in the United States in 2008. Acute exacerbations are associated with disease progression and are also a major cause of morbidity and mortality in COPD patients. Approximately two thirds of all of the infectious exacerbations are associated with bacterial infection, alone or in combination with respiratory viruses. Acute exacerbations are associated with the acquisition of new strains of nontypeable Haemophilus influenzae (NTHi), Moraxella catarrhalis, and Streptococcus pneumoniae and, in patients with severely reduced lung function, Enterobacteriaceae and Pseudomonas species. The lower airways of some COPD patients are also chronically colonized with bacteria readily detectable by conventional culture-dependent methods; these patients show elevated markers of inflammation, compared with individuals who do not show bacterial colonization by this methodology. NTHi is the most frequently isolated bacterial pathogen from sputum of COPD patients under stable conditions. Impaired innate immune defense mechanisms are thought to contribute to the bacterial infection and persistence of bacteria in these patients. Alveolar macrophages are professional phagocytes that play a critical role in the clearance of infecting bacteria while preventing excessive pulmonary inflammation. Alveolar macrophages express a variety of cell surface receptors that are crucial for recognition and phagocytosis of pathogens and stimulating the appropriate immune response to infection. Compared with alveolar macrophages from healthy nonsmokers, alveolar and monocyte-derived mac-