Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung

Respiratory Research

Research

Gao Jingtao¹  Shuji Yamashita²  Tohru Sakamoto³  Nobuyuki Hizawa³  Hideyasu Yamada³  Satoshi Suzuki⁴  Hiroyuki Yasuda⁵  Aoi Kuroda⁵  Kenzo Soejima⁵  Mari Ozaki⁵  Ahmed E. Hegab⁵  Makoto Ishii⁵  Junko Hamamoto⁵  Shizuko Kagawa⁵  Tomoko Betsuyaku⁵  Takanori Asakura⁵  Ho Namkoong⁵ 

[1] Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, 101149, Beijing, China;Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan;Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, 305-8575, Ibaraki, Japan;Department of Thoracic Surgery, Japanese Red Cross Ishinomaki Hospital, 71 Nishimichishita, Hebita, 986-8522, Ishinomaki, Japan;Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku Ku, Shinanomachi 35, 160-8582, Tokyo, Japan;

关键词: ALDH2;    Aldehyde;    Epithelial cell;    Basal cell;    Club cell;    Trachea;    Lung;    Stem cell;    Mitochondria;   

DOI  :  10.1186/s12931-017-0554-5

 received in 2016-12-21, accepted in 2017-04-13,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundAldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer’s diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined.MethodsWe examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2−/− mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2−/− mice.ResultsIn humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2−/− and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2−/− mice. Aldh2−/− tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2−/− mice than in WT mice.ConclusionsALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a “premature lung aging” effect.

【 授权许可】

CC BY   
© The Author(s). 2017