The role of PUMA in the progression of cigarette smoking-induced COPD

PUMA 在吸烟引起的 COPD 进展中的作用

• 批准号: 10930186
• 负责人: Dongshi Chen
• 金额: $ 41.4万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930186
• 关键词: Air; Alveolar; Animal Model; Apoptosis; Apoptosis Inhibitor; Apoptotic; Attenuated; BCL2 gene; Bronchoalveolar Lavage; Cause of Death; Cell Death; Cell Death Induction; Cell Death Inhibition; Cells; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Cigarette smoke-induced emphysema; Data; Databases; Development; Disease Progression; Elasticity; Epithelial Cells; Etiology; Evaluation; Exposure to; Family member; Foundations; Genomics; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Investigation; Knockout Mice; Liquid substance; Lung; Lung diseases; Macrophage; Macrophage Activation; Mediating; Mitochondria; Modeling; Molecular; Molecular Weight; Mus; Organoids; Pathogenesis; Patients; Pattern; Play; Pre-Clinical Model; Process; Pulmonary Emphysema; Pulmonary Inflammation; Reporting; Research; Role; Signal Pathway; Smoking; Structure of parenchyma of lung; TNF gene; TP53 gene; Testing; Therapeutic Uses; Tissues; airway obstruction; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced COPD; cigarette smoking; cytokine; design; effective therapy; experimental study; exposure to cigarette smoke; improved; in vivo; inhibitor; knock-down; loss of function; mortality; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; prevent; pulmonary function; small molecule inhibitor; smoking cessation; targeted treatment; therapeutic target

Abstract Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of mortality worldwide. The causes of COPD are usually determined by multiple factors, among which exposure to cigarette smoke (CS) is the most common cause of COPD. CS exposure has been reported to induce epithelial cell death by apoptosis and necroptosis, and trigger lung inflammation. Most previous studies on cell death focus on the mechanism of apoptosis. Necroptosis, a new form of cell death, has emerged as another important mechanism for COPD pathogenesis. Therefore, revealing a novel target for both apoptosis and necroptosis will help the development of new treatments for COPD. Our preliminary data show that p53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BH3-only Bcl-2 family member, is markedly induced in the lung tissues of COPD patients and mice exposed to CS treatment, as well as in lung epithelial cells treated with air-liquid interface (ALI) CS exposure or cigarette smoking extract (CSE). PUMA deficiency protected against CSE-induced apoptosis and necroptosis in the lung epithelial cells, and mouse alveolar organoids. Depletion of PUMA in the lung epithelial cells also attenuated the macrophage inflammatory profile. Moreover, knockdown of PUMA has higher suppressive effect on pro-inflammatory cytokines induction by CSE exposure than inhibition of cell death, indicating that PUMA might have a new function in triggering inflammation besides cell death. PUMA knock-out mice showed decreased lung inflammation, apoptosis, and necroptosis after 2 months of CS exposure, and rescued lung function loss after 6 months of CS exposure. Based on these preliminary findings, we hypothesize that PUMA mediates CS-induced apoptosis and necroptosis, and contributes to lung inflammation in the pathogenesis of COPD. We further hypothesize that PUMA can be pharmacologically targeted as a novel therapy against COPD. Specifically, we will investigate the functional role of PUMA in CS-induced lung epithelial cell death, as well as inflammatory macrophage activation, and test whether PUMA deletion or inhibition by a first-in-class small molecule inhibitor can protect the lung from CS-induced emphysema. In the proposed studies, we will pursue these three specific aims: (1) Test the hypothesis that PUMA orchestrates CS-induced apoptosis and necroptosis. (2) Test the hypothesis that PUMA induction in lung epithelial cells triggers pro-inflammatory cytokines expression and causes cell death independent lung inflammation. (3) Test the hypothesis that inhibition of PUMA by small molecular weight inhibitors prevents the development of cigarette smoke-induced emphysema in mice. This project is expected to reveal a new function of PUMA in the pathogenesis of COPD, especially its novel function in the induction of inflammatory cytokines. The completion of the proposed studies will provide proof-of- principle evidence for targeting PUMA as a novel therapeutic approach for COPD treatment.

抽象的 慢性阻塞性肺疾病（COPD）是全球死亡率的第四个领先原因。原因 COPD的通常由多种因素确定，其中暴露于香烟烟雾（CS）中最多 COPD的常见原因。据报道，CS暴露会通过细胞凋亡诱导上皮细胞死亡 坏死性，并触发肺部炎症。先前关于细胞死亡的大多数研究都集中在 凋亡。坏死性是一种新的细胞死亡形式，已成为COPD的另一种重要机制 发病。因此，揭示凋亡和坏死的新靶标将有助于发展 COPD的新治疗方法。我们的初步数据表明，p53上调的凋亡调节剂（PUMA）， COPD患者的肺组织中明显诱导了促凋亡的BH3仅BH3家庭成员 暴露于CS治疗的小鼠以及在用空气界面（ALI）CS暴露处理的肺上皮细胞中 或吸烟提取物（CSE）。 PUMA缺乏症免受CSE诱导的细胞凋亡和坏死性的影响 在肺上皮细胞和小鼠牙槽器官中。肺部上皮细胞中的PUMA耗尽 减弱了巨噬细胞炎症性。此外，PUMA的敲低具有更高的抑制作用 关于通过CSE暴露诱导促炎性细胞因子而不是细胞死亡的抑制，表明PUMA 除细胞死亡外，可能在触发炎症方面具有新功能。彪马敲除小鼠显示 CS暴露2个月后，肺部炎症，细胞凋亡和坏死病减少，并营救了肺 CS暴露6个月后的功能损失。基于这些初步发现，我们假设PUMA 介导CS诱导的凋亡和坏死性，并导致肺部炎症 COPD。我们进一步假设PUMA可以在药理学上是针对COPD的新疗法。 具体而言，我们将研究PUMA在CS诱导的肺上皮细胞死亡中的功能作用，以及 炎症性巨噬细胞激活，并测试一流小的puma缺失或抑制 分子抑制剂可以保护肺部免受CS诱导的肺气肿。在拟议的研究中，我们将追求 这三个具体目的：（1）检验PUMA策划CS诱导的凋亡和的假设 坏死性。 （2）检验以下假设：肺上皮细胞中的PUMA诱导会触发促炎症 细胞因子表达并引起细胞死亡独立的肺部炎症。 （3）检验抑制的假设 小分子量抑制剂的puma防止了香烟烟雾引起的肺气肿的发展 在老鼠中。 预计该项目将在COPD的发病机理中揭示PUMA的新功能，尤其是其新颖的新功能 诱导炎症细胞因子的功能。拟议研究的完成将提供证明 将PUMA作为COPD治疗的新型治疗方法的主要证据。