醛脱氢酶(ALDHs)在醛的解毒中起主要作用。ALDHs的高表达是包括肺在内的许多器官的干细胞的标志物。ALDH2基因(ALDH2*2)的常见多态性导致酶失活,并与酒精潮红综合征和心血管和阿尔茨海默病以及某些癌症的风险增加有关。尚未彻底检查这种ALDH2多态性对肺及其干细胞的影响。
我们检查了健康个体群体中ALDH2*2等位基因与肺功能参数之间的关联。我们还研究了其与患者队列中哮喘和COPD发病率的关系。我们使用体外集落形成测定法来检测多态性对来自原代人手术样品和Aldh2*2转基因(Tg)和Aldh2-/-小鼠的肺上皮干细胞的影响。比较野生型(WT)对急性和慢性肺损伤的反应,Aldh2*2Tg和Aldh2-/-小鼠。
在人类中,ALDH2*2等位基因在普通人群中与较低的FEV1/FVC相关,但与哮喘或COPD的发展无关。与ALDH2等位基因相比,携带ALDH2*2等位基因的支气管和肺上皮均显示出较低的集落形成效率(CFE)的趋势。在老鼠身上,气管上皮厚度,核密度,Aldh2-/-和Aldh2*2Tg成年小鼠的基底干细胞数量明显低于WT。电子显微镜显示Aldh2-/-小鼠气管中形态异常的线粒体数量显着增加。与WT小鼠相比,Aldh2-/-气管和肺细胞显示出更高的ROS水平和更少的功能线粒体。当检查气管和肺上皮干细胞的体外CFE时,没有检测到显着差异。当暴露于慢性香烟烟雾时,Aldh2*2Tg小鼠对肺气肿发展有抗性,而流感感染在Aldh2-/-小鼠中引起的上皮损伤比WT小鼠更多。
ALDH2多态性对肺有一些微妙的影响,其中一些类似于正常衰老过程中观察到的变化,提示“肺早衰”效应。
Aldehyde 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.
We 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.
In 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.
ALDH2 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.