Alveolar macrophages from COPD patients exhibit reduced bacterial phagocytosis compared to those from healthy controls and this defect is associated with increased exacerbation frequency. The defective phagocytosis extends to different bacterial species, fungal spores and apoptotic cells, suggesting a common defective mechanism, and is replicated in monocyte-derived macrophages (MDM) providing a useful cell model. Phagocytosis requires cytoskeletal rearrangements involving protein transporters such as dynein. We hypothesised that regulation of dynein motors is aberrant in COPD and related to reduced phagocytosis and increased pro-inflammatory cytokine release. To test this, the effect of a dynein motor inhibitor, ciliobrevin D, on macrophage phagocytosis was examined. Monocytes from non-smokers (n=8), smokers (n=3) and COPD patients (n=4) were incubated in GM-CSF for 12 days to generate MDM. MDM were treated with ciliobrevin D (1-100µM) for 30 min prior to 4h incubation with fluorescently-labelled H. influenzae (HI) or S. pneumoniae (SP), and phagocytosis measured by fluorimetry. Cytokine release was measured by ELISA (IL-10, TNFα and CXCL8). Ciliobrevin D caused a concentration-dependent increase in phagocytosis of HI in COPD macrophages that was maximal (↑86±36%) in COPD MDM at 100µM (p<0.05). A similar trend was seen with non-smokers and smokers. There was also a trend for a concentration-dependent increase in phagocytosis of SP by MDM from all subjects. However, there was no effect on bacterial-stimulated cytokine release.
Discussion(0)
No comments yet. Be the first to comment.