PDF(Pubmed)
Abstract：
Idiopathic pulmonary fibrosis (IPF) is an age-related disease with poor prognosis and limited therapeutic options. Activation of lung fibroblasts and differentiation to myofibroblasts are the principal effectors of disease pathology, but damage and senescence of alveolar epithelial cells, specifically type II (ATII) cells, has recently been identified as a potential trigger event for the progressive disease cycle. Targeting ATII senescence and the senescence-associated secretory phenotype (SASP) is an attractive therapeutic strategy; however, translatable primary human cell models that enable mechanistic studies and drug development are lacking. Here, we describe a novel system of conditioned medium (CM) transfer from bleomycin-induced senescent primary alveolar epithelial cells (AEC) onto normal human lung fibroblasts (NHLF) that demonstrates an enhanced fibrotic transcriptional and secretory phenotype compared to non-senescent AEC CM treatment or direct bleomycin damage of the NHLFs. In this system, the bleomycin-treated AECs exhibit classical hallmarks of cellular senescence, including SASP and a gene expression profile that resembles aberrant epithelial cells of the IPF lung. Fibroblast activation by CM transfer is attenuated by pre-treatment of senescent AECs with the senolytic Navitoclax and AD80, but not with the standard of care agent Nintedanib or senomorphic JAK-targeting drugs (e.g., ABT-317, ruxolitinib). This model provides a relevant human system for profiling novel senescence-targeting therapeutics for IPF drug development.
摘要：
特发性肺纤维化（IPF）是一种与年龄相关的疾病，预后不良，治疗选择有限。肺成纤维细胞的激活和向肌成纤维细胞的分化是疾病病理的主要影响因素，但是肺泡上皮细胞的损伤和衰老，特别是II型（ATII）细胞，最近已被确定为进行性疾病周期的潜在触发事件。靶向ATII衰老和衰老相关分泌表型(SASP)是一种有吸引力的治疗策略;然而,缺乏能够进行机理研究和药物开发的可翻译的原代人类细胞模型。这里,我们描述了一种从博来霉素诱导的衰老原代肺泡上皮细胞（AEC）转移到正常人肺成纤维细胞（NHLF）的条件培养基（CM）转移到正常人肺成纤维细胞（NHLF）的新系统，与非衰老AECCM治疗或NHLF的直接博来霉素损伤相比，该系统显示出增强的纤维化转录和分泌表型。在这个系统中,博来霉素处理的AECs表现出细胞衰老的经典标志，包括SASP和类似于IPF肺异常上皮细胞的基因表达谱。通过用衰老的Navitoclax和AD80预处理衰老的AECs，而不是用标准的护理剂Nintedanib或衰老的JAK靶向药物（例如，ABT-317，鲁索替尼）。该模型提供了相关的人类系统，用于分析IPF药物开发的新型衰老靶向治疗剂。
