Developmental Biology and Regenerative Medicine, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
Craniofacial Biology Graduate Program, Herman Ostrow School of Dentistry of University of Southern California, Los Angeles, California, USA.
Thorax. 2017 May;72(5):451-459. doi: 10.1136/thoraxjnl-2016-208964. Epub 2017 Jan 9.
Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc-/-) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally. Here, we tested whether inhaled RSL could protect young, terc-/- mice from accelerated ageing of the lung.
terc-/- mice aged 2 months inhaled 1 mg/kg RSL that was instilled intratracheally once per month for 3 months. One month after the last inhalation, whole lung function, structure and cellular DNA damage were evaluated and AEC2 survival was assessed by western blotting for survival pathway gene expression.
RSL treatments delayed the loss of lung compliance (p<0.05), maintained lung structure (p<0.001) and blocked parenchymal cell DNA damage as measured by TdT Nick-End Labeling (TUNEL). RSL, a known agonist of deacetylase SIRT1, supported AEC2 survival by stimulating SIRT1 expression, promoting p53 destabilisation and decreasing Bax expression and by maintaining expression levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), activated p-Akt and p-Mdm2 and inactivated Phospho-Phosphatase and tensin homolog (p-PTEN).
RSL prophylaxis by inhalation is a potential approach for slowing ageing-related deterioration of lung function and structure by maintaining AEC2 integrity.
肺部衰老，是慢性人类肺部疾病（如 COPD 和肺气肿）的一个重要风险因素，其特征是肺泡空间扩大和肺功能下降。同样，在过早衰老的端粒酶缺失（terc-/-）小鼠中，随着肺泡上皮 2 型细胞（AEC2）数量的减少，p53 稳定化伴随着肺功能下降。白藜芦醇（RSL）是一种植物抗毒素，先前已显示出通过口服给药可提高无脊椎动物的寿命并支持哺乳动物肌肉代谢的功效。在这里，我们测试了吸入 RSL 是否可以保护年轻的 terc-/- 小鼠免受肺部加速衰老的影响。
2 个月大的 terc-/- 小鼠每月经气管内滴注 1mg/kg RSL 一次，共 3 个月。最后一次吸入后 1 个月，评估全肺功能、结构和细胞 DNA 损伤，并通过 Western 印迹评估 AEC2 存活情况以评估存活途径基因表达。
RSL 治疗延缓了肺顺应性的丧失（p<0.05），维持了肺结构（p<0.001）并阻止了 TdT 末端标记（TUNEL）测量的实质细胞 DNA 损伤。RSL 是去乙酰化酶 SIRT1 的已知激动剂，通过刺激 SIRT1 表达、促进 p53 失稳、降低 Bax 表达以及维持过氧化物酶体增殖物激活受体 γ共激活因子 1-α（PGC-1α）、激活的 p-Akt 和 p-Mdm2 和失活的磷酸磷酸酶和张力蛋白同源物（p-PTEN）的表达水平来支持 AEC2 的存活。
通过吸入进行 RSL 预防是一种通过维持 AEC2 完整性来减缓与衰老相关的肺功能和结构恶化的潜在方法。
