Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 44, Issue 4, Pages 474-482Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2009-0463OC
Keywords
cigarette smoke; alveolar macrophage; phagocytosis and engulfment of apoptotic cells; actin rearrangements; small GTP protein Rac1
Funding
- National Institutes of Health [RO1 HL082541]
- Japanese Respiratory Foundation Pfizer
- American Thoracic Society/Alpha-1 Foundation
- Japanese Respiratory Foundation
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Exposure to cigarette smoke (CS) was shown to impair the capacity of macrophages to clear bacteria and apoptotic cells. Here, we show that both the exposure of macrophages to cigarette smoke extract (CSE) in vitro and an acute single exposure to CS in vivo impair the macrophage clearance of apoptotic polymorphonuclear leukocytes (PMNs). Upon longer periods of exposure to smoke in vivo (4-12 weeks), the impaired capacity of macrophages to clear apoptotic cells persisted after the cessation of smoking, with slow recovery to normality observed 4 weeks later. With respect to themechanism by which CS impairs themacrophage uptake of apoptotic PMNs, we did not detect altered surface expression of receptors associated with apoptotic cell clearance. Wedidobservetheimpairedphosphorylation oftheguanine nucleotide exchange factor Vav1 and the downstream inhibition of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Consistent with these findings, CS impaired the macrophage cytoskeletal changes observed after stimulation with apoptotic cells. A loss of actin occurred at the leading edge, manifested as impairedruffling of the cell membrane and a decreased capacity to engulf apoptotic cells. The inability to clear PMNs would lead to a greater release of destructive PMN products, and would diminish the reparative phenotype induced by themacrophage clearance of apoptotic cells.
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