Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function.

摘要: Inhaled corticosteroids (ICS) increase community-acquired pneumonia (CAP) incidence in patients with chronic obstructive pulmonary disease (COPD) by unknown mechanisms. Apoptosis is increased the lungs of COPD patients. Uptake apoptotic cells (ACs) (“efferocytosis”) alveolar macrophages (AMos) reduces their ability to combat microbes, including Streptococcus pneumoniae, most common cause CAP Having shown that ICS significantly AMo efferocytosis, we hypothesized this process, termed glucocorticoid-augmented might explain association therapy COPD. To test hypothesis, studied effects fluticasone, AC, or both on AMos C57BL/6 mice vitro and an established model pneumococcal pneumonia. Fluticasone plus AC reduced TLR4-stimulated IL-12 production, relative either treatment alone, decreased TNF-α, CCL3, CCL5, keratinocyte-derived chemoattractant/CXCL1, AC. Mice treated fluticasone before infection viable pneumococci developed more lung CFUs at 48 h. However, none pretreatments altered inflammatory cell recruitment h postinfection, less markedly mediator production heat-killed pneumococci. killing pneumococci, other conditions, part delaying phagolysosome acidification without affecting reactive oxygen nitrogen species. These results support efferocytosis as a potential explanation for epidemiological risk CAP, establish murine experimental models dissect underlying molecular