Shi Wei, Bellusci Saverio, Warburton David
Developmental Biology Program, Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Blvd MS35, Los Angeles, CA 90027, USA.
Chest. 2007 Aug;132(2):651-6. doi: 10.1378/chest.06-2663.
Adult respiratory diseases are caused by many factors, including genetic-environmental interaction. Genetic abnormalities can impact early fetal lung development, postnatal lung maturation, as well as adult lung injury and repair. Studies suggest that abnormally developed lung structure and function may contribute as a susceptibility factor for several adult lung diseases. This review focuses on the relationship between lung development and pathogenesis of several lung diseases including COPD, cystic fibrosis (CF), and asthma. COPD with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, since only a proportion (approximately 15%) of smokers get COPD with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes either by null mutation, hypomorphism, or gain or loss of function results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early onset emphysema if the effect is milder. Reported susceptibility candidate genes are therefore discussed in some detail, including elastin, lysyl oxidase, fibrillin, the transforming growth factor-beta-Smad3 pathway, as well as extracellular matrix proteases. In the case of CF, the Cftr gene has been shown to regulate fetal lung epithelial cell differentiation and maturation. Subtle abnormalities of lung structure and function are found in clinically asymptomatic CF infants. Finally, airway remodeling due to chronic inflammation is important in infants who later acquire asthma.
成人呼吸系统疾病由多种因素引起，包括基因与环境的相互作用。基因异常可影响胎儿早期肺发育、出生后肺成熟以及成人肺损伤与修复。研究表明，异常发育的肺结构和功能可能是多种成人肺部疾病的易感因素。本综述重点关注肺发育与几种肺部疾病（包括慢性阻塞性肺疾病、囊性纤维化（CF）和哮喘）发病机制之间的关系。伴有肺气肿的慢性阻塞性肺疾病被认为是老年吸烟者加速出现的退行性疾病。然而，由于只有一部分（约15%）吸烟者会患伴有肺气肿的慢性阻塞性肺疾病，显然遗传易感性在决定发病年龄和肺功能下降速度方面必定起着重要作用。在小鼠中，通过无效突变、亚效等位基因、功能获得或丧失对关键基因进行干扰，若结构效应严重则会导致新生儿致命性呼吸窘迫的表型，若效应较轻微则会导致肺泡化减少和/或早发性肺气肿。因此，将详细讨论已报道的候选易感基因，包括弹性蛋白、赖氨酰氧化酶、原纤维蛋白、转化生长因子-β-Smad3信号通路以及细胞外基质蛋白酶。就囊性纤维化而言，已证明Cftr基因可调节胎儿肺上皮细胞的分化和成熟。在临床上无症状的囊性纤维化婴儿中发现了肺结构和功能的细微异常。最后，慢性炎症导致的气道重塑在后来患哮喘的婴儿中很重要。
