Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD
Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD
复制标题
DOI：
10.1152/ajplung.00135.2016
复制
发表时间：
2016-11-01
影响因子：
4.9
通讯作者：
Heijink, Irene H.
中科院分区：
文献类型：
--
作者：
Pouwels, Simon D.;Hesse, Laura;Heijink, Irene H.
香烟烟雾(CS)暴露是慢性阻塞性肺疾病(COPD)的主要危险因素。我们研究了CS诱导的损伤相关分子模式(DAMP)释放或DAMP介导的炎症是否有助于COPD的易感性。包括支气管刷在内的样本来自吸烟前后对COPD易感和不易感的年轻人和老年人，并用于基因图谱和呼吸道上皮细胞(AEC)培养。血管内皮细胞暴露于CS提取物(CSE)或特定的阻滞剂。BALB/cByJ和DBA/2J小鼠鼻腔暴露于LL-37和线粒体(Mt)抑制物。功能基因集浓缩分析显示，CS显著上调COPD患者气道上皮细胞DAMPS及DAMP受体基因表达。在培养的血管内皮细胞中，我们观察到CSE诱导坏死和潮湿的释放，尤其是COPD来源的细胞比对照来源的细胞释放更高的Galectin-3。Galectin-3、IL-37和mtDAMPs促进AEC分泌CXCL8。IL-37和mtDAMPs诱导中性粒细胞气道炎症，仅在易感CS诱导的气道炎症的小鼠中发生。综上所述，我们发现在COPD患者的呼吸道上皮中，CS在体内诱导的DAMPS及其受体的表达以及在体外对Galectin-3的释放被夸大。此外，我们的研究表明，释放湿气的倾向和随后的炎症诱导可能有助于COPD的发展。
Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings, were collected from young and old individuals, susceptible and nonsusceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intranasally exposed to LL-37 and mitochondrial (mt) DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared with control-derived cells. Galectin-3, LL-37, and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Furthermore, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD.