Pouwels Simon D, Hesse Laura, Faiz Alen, Lubbers Jaap, Bodha Priya K, Ten Hacken Nick H T, van Oosterhout Antoon J M, Nawijn Martijn C, Heijink Irene H
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Am J Physiol Lung Cell Mol Physiol. 2016 Nov 1;311(5):L881-L892. doi: 10.1152/ajplung.00135.2016. Epub 2016 Sep 9.
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.
接触香烟烟雾（CS）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介导的炎症是否会导致COPD易感性。在吸烟前后，从对COPD发展易感和不易感的年轻和老年个体中收集包括支气管刷检物在内的样本，用于基因谱分析和气道上皮细胞（AEC）培养。将AEC暴露于CS提取物（CSE）或特定的DAMPs。将BALB/cByJ和DBA/2J小鼠经鼻暴露于LL-37和线粒体（mt）DAMPs。功能基因集富集分析表明，CS显著增加了COPD患者气道上皮中DAMPs和DAMP受体的基因表达。在培养的AEC中，我们观察到CSE诱导坏死和DAMP释放，与对照来源的细胞相比，COPD来源的细胞中半乳糖凝集素-3释放特别高。半乳糖凝集素-3、LL-37和mtDAMPs增加了AEC中CXCL8的分泌。LL-37和mtDAMPs仅在对CS诱导的气道炎症易感的小鼠中诱导嗜中性气道炎症。总体而言，我们表明，在COPD患者的气道上皮中，CS在体内诱导的DAMPs和DAMP受体表达以及在体外诱导的半乳糖凝集素-3释放都被夸大了。此外，我们的研究表明，释放DAMPs的易感性以及随后炎症的诱导可能有助于COPD的发展。
