Chronic Expression of a Clinical SFTPC Mutation Causes Murine Lung Fibrosis with Idiopathic Pulmonary Fibrosis Features.
Chronic Expression of a Clinical SFTPC Mutation Causes Murine Lung Fibrosis with Idiopathic Pulmonary Fibrosis Features.
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临床 SFTPC 突变的慢性表达导致具有特发性肺纤维化特征的小鼠肺纤维化。
DOI：
10.1165/rcmb.2022-0203ma
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发表时间：
2023
影响因子：
6.4
通讯作者：
Katzen,Jeremy
中科院分区：
文献类型：
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作者：
Rodriguez,Luis;Tomer,Yaniv;Carson,Paige;Dimopoulos,Thalia;Zhao,Ming;Chavez,Katrina;Iyer,Swati;Huang,Li;Ebert,Christina;Sereda,Larisa;Murthy,Aditi;Trujillo,Glenda;Beers,MichaelF;Katzen,Jeremy
特发性肺纤维化（IPF）是一种慢性进行性纤维化间质性肺疾病。开发更有效的IPF治疗方法的一个障碍是缺乏概括该疾病早期病理生物学的临床前模型。气管内博莱霉素是IPF的常规临床前小鼠模型，不能重现肺泡上皮2型细胞（AEC2）的内在功能障碍，这被认为是IPF发病的近端事件。在间质性肺病患者中发现的基于sftpc（表面活性蛋白C基因）突变的小鼠纤维化模型导致AEC2未折叠蛋白反应和内质网应激的激活，这是在IPF中观察到的AEC2功能障碍表型。尽管这些模型实现了自发性纤维化，但它们是在既往肺损伤的情况下实现的，因此难以对ipf患者的一般临床过程进行表型模拟——逐渐进行性纤维化和肺功能丧失。在这里，我们报告了一种改进的小鼠esftpcmutation模型，以概括IPF的临床过程、生理损伤、实质细胞组成和生物标志物。该平台为了解IPF发病机制和临床前治疗候选指标提供了一个创新的模型。
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease. A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is believed to be a proximal event in the pathogenesis of IPF. Murine fibrosis models based onSFTPC(Surfactant Protein C gene) mutations identified in patients with interstitial lung disease cause activation of the AEC2 unfolded protein response and endoplasmic reticulum stress—an AEC2 dysfunction phenotype observed in IPF. Although these models achieve spontaneous fibrosis, they do so with precedent lung injury and thus are challenged to phenocopy the general clinical course of patients with IPF—gradual progressive fibrosis and loss of lung function. Here, we report a refinement of a murineSftpcmutation model to recapitulate the clinical course, physiological impairment, parenchymal cellular composition, and biomarkers associated with IPF. This platform provides the field with an innovative model to understand IPF pathogenesis and index preclinical therapeutic candidates.