The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair.
The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair.
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DOI：
10.1007/s00408-009-9158-2
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发表时间：
2009-09
期刊：
影响因子：
5
通讯作者：
Torday JS
中科院分区：
文献类型：
--
作者：
Rehan VK;Asotra K;Torday JS
动物和人类研究中有大量的流行病学和实验证据表明，怀孕期间吸烟的母亲的后代会产生有害的长期肺部结果。然而，这些关联的分子机制尚不清楚。因此，没有有效的干预措施来预防围产期烟雾暴露的破坏性影响也就不足为奇了。使用肺发育、稳态和修复的生物学模型，我们已经确定子宫内尼古丁暴露破坏上皮和肺间质之间由甲状旁腺相关蛋白和过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）γ驱动的特异性分子旁分泌通讯，导致肺脂肪成纤维细胞转分化为肌成纤维细胞，即，脂肪成纤维细胞表型转化为不利于肺泡内环境稳定的细胞类型，是慢性肺病（包括哮喘）的细胞标志。此外，我们已经表明，通过分子靶向PPARγ表达，尼古丁诱导的肺损伤不仅可以显着避免，它也可以恢复。我们概述的概念不同于过去提出的烟草烟雾致畸和毒理学影响的传统范式。我们认为，由于尼古丁改变了发育中肺泡中正常的稳态上皮-间充质旁分泌信号，而不是引起完全破坏性的结构变化，因此它提供了一个独特的机会，通过靶向分子操作来预防，停止和/或逆转这一过程。
There is extensive epidemiologic and experimental evidence from both animal and human studies that demonstrates detrimental long-term pulmonary outcomes in the offspring of mothers who smoke during pregnancy. However, the molecular mechanisms underlying these associations are not understood. Therefore, it is not surprising that that there is no effective intervention to prevent the damaging effects of perinatal smoke exposure. Using a biologic model of lung development, homeostasis, and repair, we have determined that in utero nicotine exposure disrupts specific molecular paracrine communications between epithelium and interstitium that are driven by parathyroid hormone-related protein and peroxisome proliferator-activated receptor (PPAR)γ, resulting in transdifferentiation of lung lipofibroblasts to myofibroblasts, i.e., the conversion of the lipofibroblast phenotype to a cell type that is not conducive to alveolar homeostasis, and is the cellular hallmark of chronic lung disease, including asthma. Furthermore, we have shown that by molecularly targeting PPARγ expression, nicotine-induced lung injury can not only be significantly averted, it can also be reverted. The concept outlined by us differs from the traditional paradigm of teratogenic and toxicological effects of tobacco smoke that has been proposed in the past. We have argued that since nicotine alters the normal homeostatic epithelial-mesenchymal paracrine signaling in the developing alveolus, rather than causing totally disruptive structural changes, it offers a unique opportunity to prevent, halt, and/or reverse this process through targeted molecular manipulations.
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影响因子：
10
作者：
Gilliland, FD;Berhane, K;Peters, JM
通讯作者：
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影响因子：
4.8
作者：
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作者：
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DOI：
10.1124/jpet.301.2.594
发表时间：
2002-05-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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作者：
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