Cloonan Suzanne M, Lam Hilaire C, Ryter Stefan W, Choi Augustine M
Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA; Pulmonary and Critical Care Medicine; Weill Cornell Medical College; New York, NY USA.
Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
Autophagy. 2014 Mar;10(3):532-4. doi: 10.4161/auto.27641. Epub 2014 Jan 7.
Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated. Based on observations that increased morphological and biochemical indicators of autophagy correlate with cilia shortening in our models, we posited that autophagy might regulate cilia length in response to CS in the lung. We demonstrate that CS-induced cilia shortening occurs through an autophagy-dependent mechanism mediated by the deacetylase HDAC6 (histone deacetylase 6). Autophagy-impaired (Becn1(+/-), map1lc3b(-/-), or Hdac6(-/Y)) mice resist CS-induced cilia shortening. Furthermore, cilia components are identified as autophagic substrates during CS exposure. Assessment of airway cilia function using a 3D MCC assay demonstrates that Becn1(+/-), map1lc3b(-/-), and Hdac6(-/Y) mice or mice injected with the HDAC6 inhibitor tubastatin A are protected from CS-associated mucociliary dysfunction. We concluded that an autophagy-dependent pathway regulates cilia length during CS exposure, which identifies new pathways and targets in COPD.
慢性阻塞性肺疾病（COPD）涉及对香烟烟雾（CS）的异常气道炎症反应，这与呼吸道上皮细胞纤毛缩短和黏液纤毛清除功能（MCC）受损有关。CS相关纤毛缩短的潜在细胞和分子机制仍未完全明了。我们之前已证明COPD患者肺部自噬增加；然而，该过程是否对肺中特定的自噬靶点具有选择性尚未阐明。基于在我们的模型中自噬的形态学和生化指标增加与纤毛缩短相关的观察结果，我们推测自噬可能在肺中响应CS调节纤毛长度。我们证明CS诱导的纤毛缩短通过去乙酰化酶HDAC6（组蛋白去乙酰化酶6）介导的自噬依赖性机制发生。自噬受损（Becn1(+/-)、map1lc3b(-/-)或Hdac6(-/Y)）的小鼠抵抗CS诱导的纤毛缩短。此外，在CS暴露期间，纤毛成分被鉴定为自噬底物。使用三维MCC测定法评估气道纤毛功能表明，Becn1(+/-)、map1lc3b(-/-)和Hdac6(-/Y)小鼠或注射HDAC6抑制剂tubastatin A的小鼠免受CS相关的黏液纤毛功能障碍影响。我们得出结论，在CS暴露期间，一条自噬依赖性途径调节纤毛长度，这为COPD确定了新的途径和靶点。
