Role of Senescent Cells in Radiation-induced Pulmonary Fibrosis

衰老细胞在辐射诱发的肺纤维化中的作用

• 批准号: 10226299
• 负责人: DAOHONG ZHOU
• 金额: $ 19.21万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226299
• 关键词: Adult; Alveolar; Antineoplastic Agents; Area; Automobile Driving; BCL2 gene; Bleomycin; Blood Platelets; Cancer Patient; Cardiovascular Diseases; Cell Aging; Cells; Chest; Chronic; Defect; Development; Disease; Dose-Limiting; Effectiveness; Epithelial; Epithelial Cells; Failure; Fibrosis; Ganciclovir; Genetic; Impaired wound healing; Individual; Inflammation; Ionizing radiation; Late Effects; Lung; Maintenance; Malignant neoplasm of lung; Mus; Normal tissue morphology; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Play; Process; Progressive Disease; Protac; Pulmonary Fibrosis; Pulmonary Inflammation; Radiation; Radiation therapy; Reactive Oxygen Species; Role; Safety; Simplexvirus; Structure; TERF2 gene; Testing; Thymidine Kinase; Tissues; Toxic effect; Transgenic Mice; Ubiquitination; aged; alveolar epithelium; base; design; idiopathic pulmonary fibrosis; improved; inhibitor/antagonist; innovation; irradiation; lung injury; lung small cell carcinoma; mouse model; novel; premature; prevent; promoter; repaired; response; self-renewal; senescence; skin fibrosis; stem cell function; stem cell niche; stem cells; tissue injury; tissue stem cells; ubiquitin-protein ligase; wound healing

PROJECT SUMMARY / ABSTRACT This application is in response to NCI Provocative Question (PQ) 9 to test an innovative hypothesis that senescent cells (SCs) induced by ionizing radiation (IR), particularly senescent type 2 alveolar epithelial cells (AEC2s), are the perpetuators primarily responsible for initiating pathogenesis and driving progression of radiation-induced pulmonary fibrosis (RIPF); therefore, clearance of SCs with a senolytic drug that selectively kills SCs can prevent RIPF and/or delay its progression and, more importantly, reverse existing tissue fibrosis, even after RIPF becomes a progressive disease. This hypothesis is based on the long-term understanding of tissue fibrosis pathogenesis and the exciting new findings about the role of SCs in pulmonary fibrosis, including RIPF. Specifically, pulmonary fibrosis is a disease caused by aberrant wound healing responses that are presumably initiated by cellular senescence induction in AEC2s, which are considered alveolar stem cells (ASCs). This process causes AEC2 defects in self-renewal and differentiation and an inability to generate AECs for maintenance of the alveolar epithelial barrier and to repair damaged lung epithelium. Senescent AEC2s also produce increased levels of reactive oxygen species and release an array of proinflammatory and profibrotic factors, as a result of senescence-associated secretory phenotype (SASP) expression, which may initiate and perpetuate pulmonary fibrosis development by inducing chronic oxidative stress and inflammation and promoting abnormal repair of tissue injury. This is supported by the findings that (1) AEC2 senescence, induced by AEC2-specific deletion of telomeric repeat-binding factor 2 (Trf2), in adult mice causes ASC failure, provokes pulmonary inflammation and fibrotic responses, and sensitizes mice to bleomycin- induced pulmonary fibrosis and (2) cellular senescence inhibition can prevent RIPF and delay bleomycin-induced pulmonary fibrosis progression. Our preliminary studies showed that treatment of the thoracic irradiated mice with ABT-263, a specific Bcl-2/xl inhibitor and a newly discovered senolytic drug by our group, almost completely reversed RIPF, even when ABT-263 treatment was delayed until RIPF was established. To our knowledge, this is the first study to demonstrate that RIPF can be reversed by a drug after it becomes a progressive disease. From these novel findings, we will test our hypothesis through the following specific aims using our well- established thoracic irradiation mouse model: (1) validate that SCs are the perpetuators primarily responsible for initiating pathogenesis and driving progression of RIPF; (2) elucidate the mechanisms by which clearance of SCs prevents and reverses RIPF; and (3) develop a safer and more effective senolytic drug treatment for RIPF. RIPF is one of the most deleterious late effects of thoracic radiotherapy. Our proposed studies will lead to the identification of the underlying mechanisms whereby IR causes pulmonary fibrosis and development of an innovative mechanism-based therapy that can not only prevent and/or delay RIPF but also reverse RIPF.

项目概要/摘要 此应用程序是为了回应 NCI 挑衅性问题 (PQ) 9，以测试一个创新假设： 电离辐射 (IR) 诱导的衰老细胞 (SC)，特别是衰老的 2 型肺泡上皮细胞 细胞（AEC2）是主要负责启动发病机制和驱动的永续细胞 放射性肺纤维化（RIPF）的进展；因此，用 senolytic 清除 SC 选择性杀死 SC 的药物可以预防 RIPF 和/或延缓其进展，更重要的是， 即使在 RIPF 成为一种进行性疾病之后，也能逆转现有的组织纤维化。这个假设是基于 对组织纤维化发病机制的长期了解以及关于组织纤维化作用的令人兴奋的新发现 肺纤维化中的 SC，包括 RIPF。具体来说，肺纤维化是一种由异常的肺纤维化引起的疾病。 伤口愈合反应可能是由 AEC2 中的细胞衰老诱导启动的，AEC2 是 被认为是肺泡干细胞（ASC）。该过程导致AEC2自我更新和分化缺陷 无法产生 AEC 来维持肺泡上皮屏障和修复受损的肺 上皮。衰老的 AEC2 还会产生更高水平的活性氧并释放一系列 衰老相关分泌表型 (SASP) 导致的促炎和促纤维化因子 表达，可能通过诱导慢性氧化来启动并维持肺纤维化的发展 应激和炎症并促进组织损伤的异常修复。以下研究结果支持了这一点：(1) 成年小鼠中，AEC2 特异性删除端粒重复结合因子 2 (Trf2) 诱导 AEC2 衰老 导致 ASC 衰竭，引发肺部炎症和纤维化反应，并使小鼠对博来霉素敏感 诱导的肺纤维化和（2）细胞衰老抑制可以预防 RIPF 并延缓博莱霉素诱导的肺纤维化 肺纤维化进展。我们的初步研究表明，对胸部照射的小鼠进行治疗 ABT-263是一种特异性Bcl-2/xl抑制剂，也是我们团队新发现的一种抗衰老药物，几乎完全 即使 ABT-263 治疗被推迟到 RIPF 建立后，也能逆转 RIPF。据我们所知，这 这是第一项证明 RIPF 在成为进行性疾病后可以通过药物逆转的研究。 根据这些新颖的发现，我们将利用我们的良好基础，通过以下具体目标来检验我们的假设： 建立胸部照射小鼠模型：（1）验证SCs是主要负责的持续者 启动 RIPF 的发病机制并驱动其进展； (2) 阐明清除机制 SC 预防并逆转 RIPF； (3) 开发更安全、更有效的 RIPF 抗衰老药物治疗。 RIPF 是胸部放射治疗最有害的晚期效应之一。我们提出的研究将导致 确定 IR 导致肺纤维化和发展的潜在机制 基于机制的创新疗法不仅可以预防和/或延迟 RIPF，还可以逆转 RIPF。