Vandivier R William, Richens Tiffany R, Horstmann Sarah A, deCathelineau Aimee M, Ghosh Moumita, Reynolds Susan D, Xiao Yi-Qun, Riches David W, Plumb Jonathan, Vachon Eric, Downey Gregory P, Henson Peter M
Division of Pulmonary Sciences and Critical Care Medicine, Univ. of Colorado Denver, Research Bldg. 2, 12700 E. 19th Ave. Box C272, Aurora, CO 80045, USA.
Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L677-86. doi: 10.1152/ajplung.00030.2009. Epub 2009 Jul 24.
Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.
囊性纤维化（CF）由突变的CF跨膜电导调节因子（CFTR）引起，其特征是气道炎症强烈且凋亡细胞积聚。凋亡细胞的吞噬作用（胞葬作用）是炎症的关键调节因子，因为它可防止凋亡后坏死，并积极抑制多种促炎介质（包括IL-8）的释放。由于CF与凋亡细胞积聚、IL-8水平异常以及强烈炎症相关，我们试图确定CFTR缺乏是否会特异性损害胞葬作用及其对炎症介质释放的调节。我们在此表明，CFTR缺乏直接干扰气道上皮细胞的胞葬作用，这种作用并非由于凋亡细胞与上皮细胞的结合改变或胞葬作用受体的表达改变所致。相反，已知的胞葬作用负调节因子RhoA在CFTR缺乏的细胞中表达大幅增加，RhoA或其下游效应物Rho激酶的抑制剂可使这些细胞中的胞葬作用恢复正常。胞葬作用受损似乎是通过一种氨氯地平敏感的离子通道介导的，因为氨氯地平可恢复CFTR缺乏细胞的吞噬能力。最后，CFTR缺乏细胞中无效的胞葬作用似乎具有促炎后果，因为凋亡细胞可增强这些细胞释放IL-8，但野生型对照细胞则不会。因此，在CF中，胞葬作用失调可能导致凋亡细胞积聚和炎症反应调节受损，最终可能提示一个新的治疗靶点。
