Smad3 signaling involved in pulmonary fibrosis and emphysema.
Smad3 signaling involved in pulmonary fibrosis and emphysema.
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DOI：
10.1513/pats.200605-125sf
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发表时间：
2006-11-01
期刊：
影响因子：
--
通讯作者：
Warburton, David
中科院分区：
文献类型：
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作者：
Gauldie, Jack;Kolb, Martin;Warburton, David
在同一患者中同时发现肺气肿和肺纤维化证据的发生率已受到越来越多的关注。一些研究者在活检中发现肺上部区域存在肺气肿，肺下部区域存在弥漫性实质性疾病伴纤维化，尤其与当前或既往重度吸烟者有关。以前被认为是两种不同的疾病机制，现在有数据表明细胞和分子活化的一些共同途径导致不同的形态和生理结果。根据目前的观点，肺气肿可能起源于蛋白酶/抗蛋白酶失衡，而抗蛋白酶在纤维化的调节中的作用已被提出。在实验啮齿动物模型中，转化生长因子β（TGF-β）的过表达导致进行性肺纤维化，伴随蛋白酶抑制剂（如金属蛋白酶组织抑制剂（TIMP）和纤溶酶原激活物抑制剂-1（派-1）基因）的显著上调，沿着过度基质蓄积。可能是“基质降解”肺微环境，其中金属蛋白酶活性占优势，有利于肺气肿的发展，而“基质非降解”微环境，随着TIMP的存在增强，将导致基质积累和纤维化。令人惊讶的是，尽管TGF-β信号传递缺陷的Smad 3缺失小鼠对博来霉素和TGF-β介导的纤维化具有抗性，但它们发生自发的年龄相关的空域扩大，与肺气肿一致，缺乏适当修复组织损伤的能力。一个共同的因素是组织损伤和修复，TGF-β和Smad信号通路发挥着重要的分子作用。这两种变化都可以在实验模型中进行无创成像和生理测量。
The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor beta (TGF-beta) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked up-regulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-beta and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.