Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Respir Cell Mol Biol. 2011 Apr;44(4):474-82. doi: 10.1165/rcmb.2009-0463OC. Epub 2010 Jun 4.
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 the mechanism by which CS impairs the macrophage uptake of apoptotic PMNs, we did not detect altered surface expression of receptors associated with apoptotic cell clearance. We did observe the impaired phosphorylation of the guanine 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 impaired ruffling 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 the macrophage clearance of apoptotic cells.
接触香烟烟雾（CS）已被证明会损害巨噬细胞清除细菌和凋亡细胞的能力。在这里，我们表明，巨噬细胞在体外暴露于香烟烟雾提取物（CSE）以及体内急性单次接触 CS，都会损害巨噬细胞清除凋亡多形核白细胞（PMN）的能力。在体内更长时间（4-12 周）暴露于烟雾后，巨噬细胞清除凋亡细胞的能力在停止吸烟后仍然受损，在 4 周后观察到缓慢恢复正常。至于 CS 损害巨噬细胞摄取凋亡 PMN 的机制，我们没有检测到与清除凋亡细胞相关的受体表面表达的改变。我们确实观察到鸟嘌呤核苷酸交换因子 Vav1 的磷酸化受损，以及 Ras 相关 C3 肉毒杆菌毒素底物 1（Rac1）激活的下游抑制。与这些发现一致，CS 损害了刺激凋亡细胞后观察到的巨噬细胞细胞骨架变化。在前沿处发生肌动蛋白损失，表现为细胞膜皱襞减少，吞噬凋亡细胞的能力降低。不能清除 PMN 会导致破坏性 PMN 产物的释放增加，并会降低巨噬细胞清除凋亡细胞诱导的修复表型。
