Idiopathic pulmonary fibrosis: update on genetic discoveries.
Idiopathic pulmonary fibrosis: update on genetic discoveries.
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DOI：
10.1513/pats.201008-056ms
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发表时间：
2011-05-01
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影响因子：
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通讯作者：
Garcia, Christine Kim
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文献类型：
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作者：
Garcia, Christine Kim
特发性肺纤维化（IPF）是一种进行性肺纤维化疾病，其患病率随年龄增长而增加。最近的证据表明，两种不同生物学途径的基因突变导致家族性肺纤维化（FPF）和散发性IPF的共同表型。编码肺表面活性蛋白C和A2（分别为SFTPC和SFTPA2）的基因突变导致II型肺泡上皮细胞内质网应激增加。编码端粒酶（TERT和TERC）的基因突变通过缩短端粒长度和可能的肺干细胞耗竭引起IPF。所有的突变都是罕见的，但总的来说，TERT突变是FPF中最常见的遗传缺陷。在平均年龄为51岁的受试者中，TERT突变携带者肺纤维化的总体发生率为40%。外显率随着年龄的增长而增加，男性比女性更高，并且与纤维化环境暴露呈正相关。在无端粒酶突变的FPF和散发性IPF患者中发现短端粒长度，表明端粒酶功能障碍的生物学途径为IPF的年龄相关患病率提供了生物学解释。两个看似无关的生物学途径-肺泡上皮细胞内质网应激和端粒酶功能障碍-的分子数据开始阐明IPF的发病机制。这些结果具有潜在的预测和治疗价值。
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lungs that increases in prevalence with advanced age. Recent evidence indicates that mutations in genes of two different biologic pathways lead to the common phenotype of familial pulmonary fibrosis (FPF) and sporadic IPF. Mutations in the genes encoding the lung surfactant proteins C and A2 (SFTPC and SFTPA2, respectively) cause increased endoplasmic reticulum stress in type II alveolar epithelial cells. Mutations in the genes encoding telomerase (TERT and TERC) cause IPF through shortening of telomere lengths and probable exhaustion of lung stem cells. All of the mutations are individually rare, but, collectively, TERT mutations are the most common genetic defect found in FPF. The overall penetrance of pulmonary fibrosis in TERT mutation carriers is 40% in subjects with a mean age of 51 years. Penetrance increases with advanced age, is greater in males than in females, and is positively associated with fibrogenic environmental exposures. Short telomere lengths are found in patients with FPF and sporadic IPF without mutations in telomerase, suggesting that the biologic pathway of telomerase dysfunction provides a biologic explanation for the age-related prevalence of IPF. The molecular data of two seemingly unrelated biologic pathways-alveolar epithelial endoplasmic reticulum stress and telomerase dysfunction-are beginning to elucidate the pathogenesis of IPF. These results have potentially predictive and therapeutic value.