Revealing the Pathogenic and Aging-related Mechanisms of the Enigmatic Idiopathic Pulmonary Fibrosis An Integral Model
Revealing the Pathogenic and Aging-related Mechanisms of the Enigmatic Idiopathic Pulmonary Fibrosis An Integral Model
复制标题
DOI：
10.1164/rccm.201312-2221pp
复制
发表时间：
2014-05-15
影响因子：
24.7
通讯作者：
Pardo, Annie
中科院分区：
文献类型：
--
作者：
Selman, Moises;Pardo, Annie
越来越多的证据表明，老化肺中肺泡上皮细胞和成纤维细胞的异常活化在特发性肺纤维化（IPF）的发病机制中起着关键作用。然而，尚未阐明将衰老与IPF联系起来的生物病理学过程以及导致上皮细胞和成纤维细胞异常活化的机制。衰老的许多标志（例如，基因组不稳定性、端粒磨损、表观遗传改变、线粒体功能障碍和细胞衰老）已被认为是IPF发展的重要机制;然而，这些紊乱不限于IPF，也发生在其他衰老相关的肺部疾病中，主要是慢性阻塞性肺病（COPD）。因此，一个未回答的问题是，为什么一个端粒较短、肺泡上皮衰老、过度氧化应激和线粒体功能障碍的约60岁的当前/既往吸烟者会发生IPF而不是COPD;换句话说，是什么使老年肺特别容易发生IPF？在这个角度来看，我们提出了一个完整的模型，其中一些基因变异和/或基因表达的组合在老化的肺导致上皮完整性的损失，因此在肺泡的失败，以正确地响应损伤和面对与机械拉伸相关的应力。之后，影响上皮细胞和成纤维细胞的独特的表观遗传“重编程”引起发育途径的重演以及两种细胞类型之间的异常激活和错误沟通，导致细胞外基质的过度产生和积累以及随后的肺结构破坏。
A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Many of the hallmarks of aging (e.g., genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, and cellular senescence) have been proposed as essential mechanisms for the development of IPF; however, these disturbances are not restricted to IPF and also occur in other aging-related lung disorders, primarily chronic obstructive pulmonary disease (COPD). Therefore, an unanswered question is why a current/former smoker of about 60 years of age with shorter telomeres, alveolar epithelial senescence, excessive oxidative stress, and mitochondrial dysfunction develops IPF and not COPD; in other words, what makes old lungs specifically susceptible to develop IPF? In this Perspective, we propose an integral model in which the combination of some gene variants and/or gene expression in the aging lung results in the loss of epithelial integrity and consequently in the failure of the alveoli to correctly respond to injury and to face the stress associated with mechanical stretch. Afterward, a distinctive epigenetic "reprogramming" that affects both epithelial cells and fibroblasts provokes, among others, the recapitulation of developmental pathways and the aberrant activation and miscommunication between both cell types, resulting in the exaggerated production and accumulation of extracellular matrix and the subsequent destruction of the lung architecture.