Phagocytic Dysfunction of Human Alveolar Macrophages and Severity of Chronic Obstructive Pulmonary Disease

The paradigm of bacterial colonization of the lower airways in COPD contributing to progressive lung disease is supported by the association of bacterial colonization with advanced airway inflammation, increased frequency of exacerbations, and accelerated decline in lung function [1–3]. Once initiated, chronic inflammation and failure to clear bacteria of the lower airways may promote progression of COPD [4, 5]. Moreover, bacterial colonization of the airways is associated with increased risk of exacerbation of COPD [6]. Our previous studies identified a fundamental phagocytic defect of alveolar macrophages in COPD to 3 clinical strains of NTHI that is not attributable to active smoking [7]. However, macrophages derived from peripheral blood monocytes of COPD donors had no phagocytic impairment, suggesting a compartmentalized immunologic defect. Intracellular survival of NTHI in macrophages after phagocytosis has been theorized to play a role in bacterial persistence [8, 9]. However, we found no increase in intracellular viability of bacteria in COPD alveolar macrophages. Instead, failure to evoke a phagocytic response by alveolar macrophages in COPD may permit evasion of immune clearance by bacterial pathogens, providing a source for perpetuating inflammation. Our related findings of impaired cytokine responsiveness to outer membrane protein P6 and to lipooligosaccharide of NTHI further indicated that intrinsic alveolar macrophage impairment in COPD is not limited to a single intracellular signaling pathway [10]. Collectively, these studies support an immunologic basis for persistence of NTHI in the respiratory tract of adults with COPD. However, our previous investigation was limited to study of NTHI and did not determine if defective phagocytosis discriminated among respiratory targets [7]. Further, the impact of active smoking on alveolar macrophage dysfunction in COPD was not explored. Each bacterial species that causes infection in adults with COPD displays unique dynamics of colonization and immune interaction with human cells. Nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis are the 2 most prevalent bacteria associated with exacerbations of COPD [11, 12]. Host acquisition of new strains of NTHI and host lymphocyte and antibody responses to NTHI antigens are associated with exacerbations of COPD [13–15]. Host antibody responses to outer membrane antigens of M. catarrhalis are also associated with respiratory clearance [16]. Moreover, M. catarrhalis strains have conserved genes whose proteins are expressed during infection in COPD [17]. NTHI and M. catarrhalis are predominantly mucosal pathogens [15, 18]. Although Streptococcus pneumoniae is also a mucosal pathogen, it is a leading cause of community-acquired pneumonia in COPD [19, 20]. Each of these bacterial pathogens presents a unique set of potential immunologic triggers for different host pathways. Beyond this, the link between impaired alveolar macrophage innate defense and severity of COPD has only been explored to a limited degree. We hypothesized that the impaired immunologic responses of COPD alveolar macrophages to NTHI extend to other respiratory pathogens, and that responses to pathogen-associated molecular motifs of bacteria are different from responses to inert targets. We further theorized that dysfunctional alveolar macrophage phagocytosis in COPD, associated with failure to effectively clear respiratory pathogens, is associated with severity of disease in COPD and performed experiments to test these hypotheses.