Warburton David, Gauldie Jack, Bellusci Saverio, Shi Wei
Saban Research Institute Children's Hospital-Los Angeles, 4650 Sunset Blvd. #35, Los Angeles, CA 90027, USA.
Proc Am Thorac Soc. 2006 Nov;3(8):668-72. doi: 10.1513/pats.200605-122SF.
Chronic obstructive pulmonary disease with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, because only a proportion ( approximately 15%) of smokers develop chronic obstructive pulmonary disease 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. Likewise, null mutants that interfere with matrix assembly and/or integrity, such as elastin, lysyl oxidase, or fibrillin, also result in alveolar dysplasia. Importantly, null mutation of Smad3, which encodes a receptor-activated Smad in the transforming growth factor-beta signaling pathway, results in a more subtle failure to correctly organize the alveolar matrix, which is in turn antecedent to early-onset emphysema mediated by matrix metalloproteinase-9. Furthermore, exposure to side-stream smoke profoundly exacerbates and accelerates alveolar destruction, leading to more severe early-onset emphysema in young Smad3-null mice (unpublished data). Interestingly, polymorphisms in the fibrillin, transforming growth factor-beta type II receptor, and matrix metalloproteinase-9 genes have been described in humans with emphysema. Thus, dysplastic or degraded matrix cannot provide the structural niche for alveolar stem/progenitor cells to assume the correct phenotype and/or repair the alveolar cell lineage niche. The hope is that providing the correct exogenous signals can coax them into doing so.
慢性阻塞性肺疾病合并肺气肿一直被认为是老年吸烟者加速性的退行性疾病。然而，由于只有一部分（约15%）吸烟者会患上慢性阻塞性肺疾病合并肺气肿，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、功能获得或丧失来干扰关键基因，若结构效应严重则会导致包括新生儿致死性呼吸窘迫的表型，若效应较轻微则会导致肺泡化减少和/或早发性肺气肿。同样，干扰基质组装和/或完整性的无效突变体，如弹性蛋白、赖氨酰氧化酶或原纤蛋白，也会导致肺泡发育异常。重要的是，编码转化生长因子-β信号通路中受体激活型Smad的Smad3无效突变，会导致更细微的无法正确组织肺泡基质的情况，进而引发由基质金属蛋白酶-9介导的早发性肺气肿。此外，接触侧流烟雾会严重加剧并加速肺泡破坏，导致年轻的Smad3基因敲除小鼠出现更严重的早发性肺气肿（未发表数据）。有趣的是，在患有肺气肿的人类中已发现原纤蛋白、转化生长因子-β II型受体和基质金属蛋白酶-9基因存在多态性。因此，发育异常或降解的基质无法为肺泡干/祖细胞提供结构微环境，使其呈现正确的表型和/或修复肺泡细胞谱系微环境。希望是提供正确的外源性信号能促使它们这样做。
