National Heart and Lung Institute, Imperial College London, UK.
Int J Biochem Cell Biol. 2019 Nov;116:105598. doi: 10.1016/j.biocel.2019.105598. Epub 2019 Sep 6.
Chronic obstructive pulmonary disease (COPD) is characterised by an accelerated decline in airway function with age compared to age-matched non-smokers. There is increasing evidence that this is due to small airway disease rather than from emphysema, especially in the early stages of the disease. Small airways (<2 mm internal diameter) are narrowed in COPD with thickening and distortion of the airway wall and peribronchiolar fibrosis. In addition, loss of elasticity in alveolar attachments and mucus hypersecretion contribute to the airway narrowing and closure, leading to air trapping. The mechanisms of peribronchiolar fibrosis are poorly understood and small airway fibroblasts have not been characterised. In small airways of COPD patients the fibroblasts are profibrotic, pro-inflammatory and senescent. There is a reduction in the anti-ageing molecules sirtuin-1 and -6, which are regulated by specific microRNAs that are increased in COPD cells. It is plausible that extracellular vesicles from senescent airway epithelium transmit senescent signals to airway fibroblasts to stimulate fibrosis and inflammation. Small airways fibrosis is a target for new drug development that inhibit growth factor receptors, new antioxidants and particularly those that are targeted to mitochondria and inhibitors of cellular senescence or senolytic therapies.
慢性阻塞性肺疾病（COPD）的特征是气道功能随年龄的增长而加速下降，与年龄匹配的不吸烟者相比。越来越多的证据表明，这是由于小气道疾病而不是肺气肿引起的，尤其是在疾病的早期阶段。小气道（<2mm 内径）在 COPD 中变窄，气道壁和细支气管周围纤维化增厚和变形。此外，肺泡附着的弹性丧失和黏液分泌过多导致气道狭窄和闭塞，导致空气滞留。细支气管周围纤维化的机制尚不清楚，小气道成纤维细胞尚未被描述。在 COPD 患者的小气道中，成纤维细胞具有促纤维化、促炎和衰老的特性。抗衰老分子 Sirtuin-1 和 -6 的减少，这些分子受 COPD 细胞中增加的特定 microRNAs 调节。衰老的气道上皮细胞通过细胞外囊泡向气道成纤维细胞传递衰老信号，从而刺激纤维化和炎症，这是合理的。小气道纤维化是新药物开发的目标，这些药物可以抑制生长因子受体、新型抗氧化剂，特别是靶向线粒体的药物以及抑制细胞衰老或衰老细胞疗法。
