Epithelial dysfunction in early pulmonary fibrosis

项目1：特发性肺纤维化（IPF）的发病机制仍不明确;然而， 鉴定家族性IPF（FIP）中编码表面活性蛋白C（SP-C）的基因突变， 沿着其他几条证据表明，肺泡上皮细胞（AEC）在 疾病进展。我们的数据表明，AEC对pro-SP-C的异常加工导致内质网 内质网（ER）应激、未折叠蛋白应答的激活和细胞死亡。我们还表明，ER 压力经常发生在IPF的AEC中，证实该途径有助于疾病。此外，我们 表明疱疹病毒通常定位于IPF的AEC，并可能导致ER应激和AEC 损伤最后，我们已经确定了端粒酶基因的功能缺失突变，这些突变与疾病分离 在一些FIP家族中，这表明端粒酶缺陷导致端粒缩短和细胞凋亡。 II型AEC。FIP家族中早期纤维化改变的个体的鉴定将提供有价值的 资源为invesfigafions旨在确定主要疾病的机制。在本研究中，我们将利用CT 扫描以识别存在FIP风险的无症状个体，这些个体的影像学变化符合 早期纤维化早期FIP受试者和对照受试者将接受支气管镜检查以采集样本进行检测 以下假设。增加肺上皮细胞的可移植性的遗传或获得性因素， 损伤和/或凋亡是IPF发病机制的基础。脆弱的上皮细胞暴露于常见的 有害/有毒的环境损伤导致肺泡修复能力有限的广泛损伤， 导致纤维化重塑。以下具体目标将探讨AEC在早期FIP中的作用：1） 评估肺中上皮细胞损伤/凋亡、ER应激标志物和表面活性蛋白的产生 2）研究早期FIP是否发生疱疹病毒感染，有助于 ER应激，并与肺泡上皮细胞损伤有关，3）以确定是否有差异 端粒长度出现在来自患有早期FIP的患者的上皮细胞中，并且与上皮细胞损伤相关。 通过阐明早期疾病的关键成分，我们的研究将确定新的治疗靶点。

PROJECT 1: The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains poorly defined; however, identificafion of mutafions in the gene encoding surfactant protein C (SP-C) in the familial form of IPF (FIP), along with several other lines of evidence, suggests that alveolar epithelial cells (AECs) play a key role in disease progression. Our data indicate that abnormal processing of pro-SP-C by AECs leads to endoplasmic reficulum (ER) stress, acfivafion ofthe unfolded protein response, and cell death. We also show that ER stress occurs frequently in AECs in IPF, suggesfing that this pathway contributes to disease. In addifion, we show that herpesviruses are commonly localized to AECs in IPF and could contribute to ER stress and AEC injury. Finally, we have identified loss-of-funcfion mutations in telomerase genes that segregate with disease in some FIP families, suggesting that defective telomerase leads to telomere shortening and apoptosis of type II AECs. Identificafion of individuals in FIP families with early fibrotic changes will provide a valuable resource for invesfigafions aimed at defining primary disease mechanisms. In this study, we will ufilize CT scanning to identify asymptomafic individuals at risk for FIP who have radiographic changes consistent with early fibrosis. Subjects with eariy FIP and controls will undergo bronchoscopy for sample collecfion to test the following hypothesis. Genefic or acquired factors that increase the suscepfibility of lung epithelial cells to injury and/or apoptosis underiie the pathogenesis of IPF. Exposure of vulnerable epithelial cells to common injurious/toxic environmental sfimuli results in extensive injury with limited capacity for alveolar repair, leading to fibrofic remodeling. The following specific aims will invesfigate the role of AECs in early FIP: 1) to evaluate epithelial cell injury/apoptosis, markers of ER stress, and surfactant protein producfion in the lungs of pafients with eariy FIP, 2) to invesfigate whether herpesvirus infection occurs in eariy FIP, contributes to ER stress, and is associated with alveolar epithelial cell injury and, 3) to determine whether differenfial telomere length occurs in epithelial cells from patients with eariy FIP and correlates with epithelial cell injury. By elucidafing crifical components of eariy stage disease, our study will define novel therapeufic targets.