Alveolar Septal Fibroblast Loss and The Pathogenesis of Emphysema

肺泡间隔成纤维细胞丢失与肺气肿的发病机制

• 批准号: 10367957
• 负责人: David W. Riches
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367957
• 关键词: Ablation; Address; Affect; Alveolar; Alveolar wall; Apoptosis; Apoptotic; Attention; Award; BCL2 gene; Blood capillaries; Capillary Endothelial Cell; Cell Death; Cells; Chronic; Chronic lung disease; Cigarette smoke-induced emphysema; Collagen; Development; Diagnosis; Disease; Elastin; Elderly; Endothelial Cells; Endothelium; Epithelial Cells; Event; Extracellular Matrix; Fibroblasts; Gases; Genes; Genetic; Goals; Health; Heterogeneity; Histologic; Homeostasis; Impairment; Knowledge; Lead; Location; Lung; Lung diseases; Mesenchymal; Methods; Modeling; Mus; Myofibroblast; Pathogenesis; Pathologic; Pathway interactions; Pericytes; Phase; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Play; Positioning Attribute; Process; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary alveolar structure; RIPK3 gene; Recording of previous events; Research; Respiratory Insufficiency; Risk Factors; Role; Structure of parenchyma of lung; Testing; Therapeutic; Thinness; Type II Epithelial Receptor Cell; Veterans; airway epithelium; alveolar epithelium; base; cigarette smoke; cigarette smoke-induced; cigarette smoking; exposure to cigarette smoke; functional disability; functional loss; genetic approach; interstitial; loss of function; lung development; lung injury; male; mouse model; novel; prevent; pulmonary function; response; sex

Commonly diagnosed among male US Veterans of advancing age and with prior history of cigarette smoking, emphysema is a chronic lung disease in which loss of the alveolar-capillary gas exchange units ultimately leads to end-stage respiratory insufficiency. Thus, understanding the mechanisms underlying lung function impairment in emphysema and developing strategies to mitigate its development remains at the forefront of research into US Veteran’s health. Emphysema is associated with alveolar septal thinning, loss of extracellular matrix (ECM), especially elastin and collagen, and alveolar simplification due to loss of alveolar epithelial cells, endothelial cells and fibroblasts. While considerable attention has been focused on understanding how cigarette smoke (CS) exposure adversely impacts alveolar epithelial cells and endothelial cells, little is known about its effect on alveolar septal fibroblasts, which provide essential trophic and structural support to the alveolar epithelium. Using 2 validated mouse models of emphysema, we have observed that PDGFRα+ alveolar fibroblasts are eliminated from alveolar walls and septa prior to the pathologic development of airspace enlargement, raising the question of whether this event may play a causal and previously unexplored role in emphysema. Therefore, the goal of this VA Merit Award application is to test the hypothesis that emphysema is initiated by programmed cell death and loss of alveolar fibroblasts, which in turn leads to loss of trophic support to the alveolar epithelium. Through the use of genetic cell ablation and gain- and loss-of-function approaches in mice, we propose testing this hypothesis with three Specific Aims. Aim 1 will test the hypothesis that alveolar wall and septal fibroblast programmed cell death precedes the development of emphysema and leads to disrupted crosstalk with, and support to, alveolar epithelial cells. This hypothesis will be tested by investigating which alveolar fibroblast subsets are lost during emphysema development, when they are lost, the type of programmed cell death that occurs, and how their loss functionally affects alveolar epithelial cells. Aim 2 will test the hypothesis that loss of alveolar fibroblasts is sufficient to initiate the development of emphysema. This hypothesis will be tested using a conditional fibroblast ablation strategy followed by assessment of the rate of alveolar epithelial cell loss and emphysema development. The role of loss of specific alveolar fibroblast subsets in emphysema development will subsequently be determined by conditionally ablating defined lung fibroblast subsets. Lastly, Aim 3 will test the hypothesis that preventing alveolar fibroblast programmed cell death will maintain alveolar structural support and prevent emphysema development. This hypothesis will be tested in two phases. First, we will investigate the mechanisms of programmed cell death, with a focus on apoptosis and necroptosis. Second, based on this information, we will conditionally express the anti-apoptotic gene, Bcl-2, or functionally inactivate the necroptosis pathway by conditional RIPK3 or MLKL inactivation, in defined alveolar fibroblast subsets and determine the ability of the mice to respond to cigarette smoke induced airspace enlargement. Although alveolar septal fibroblasts have long been known to be positioned adjacent to, and in intimate contact with the alveolar epithelium, remarkably little is known about how early fibroblast programmed cell death and functional loss may be necessary and/or sufficient to promote the development of emphysema. The proposed studies will address this key knowledge gap. Additionally, identifying methods to prevent alveolar fibroblast loss could lead to new opportunities to target this process as a strategy to prevent emphysema development.

在美国男性退伍军人中，通常被诊断为促进年龄和先前吸烟史的诊断， 肺气肿是一种慢性肺疾病 终端呼吸不足。这是了解肺功能障碍的基础机制 在肺气肿和制定减轻其发展的策略中，仍处于研究的最前沿 美国退伍军人的健康。 肺气肿与牙槽间隔稀疏，细胞外基质（ECM）的丧失有关，尤其是弹性蛋白和 由于肺泡上皮细胞，内皮细胞和成纤维细胞的丧失，胶原蛋白和肺泡简化。 非常关注的重点是了解香烟烟（CS）如何不利 影响肺泡上皮细胞和内皮细胞，对其对肺泡隔膜成纤维细胞的影响知之甚少， 使用2个经过验证的小鼠模型，这些模型为肺泡上皮提供必不可少的营养和结构支持 在肺气肿中，我们观察到PDGFRα+肺泡成纤维细胞从肺泡壁和 在空域扩张的病理发展之前的隔sa，提出了这个事件的问题 可能在肺气肿中起因果关系和以前出乎意料的作用。因此，该VA功绩奖的目标 应用是为了检验以下假设：肺气肿是通过程序性细胞死亡和肺泡丢失引发的 成纤维细胞，进而导致肺泡上皮的营养支撑丧失。通过使用通用 细胞消融以及小鼠的功能丧失方法，我们提出了三个假设的测试 具体目标。 AIM 1将检验肺泡壁和成纤维细胞编程细胞死亡的假设 在肺气肿的发展之前，并导致与肺泡的串扰中断并支撑 上皮细胞。该假设将通过调查哪些肺泡成纤维细胞子群进行检验 肺气肿发育，当它们丢失时，发生的编程细胞死亡类型以及如何损失 在功能上影响肺泡上皮细胞。 AIM 2将检验以下假设：肺泡成纤维细胞的丧失是 足以启动肺气肿的发展。该假设将使用条件成纤维细胞进行检验 消融策略，然后评估肺泡上皮细胞损失和肺气肿发育的速率。 特异性肺泡成纤维细胞子集丧失在肺气肿发育中的作用将是 通过有条件消融定义的肺成纤维细胞子群确定。最后，AIM 3将检验以下假设。 防止肺泡成纤维细胞编程的细胞死亡将保持肺泡结构支持并防止 肺气肿发展。该假设将分为两个阶段。首先，我们将研究机制 程序性细胞死亡的重点是细胞凋亡和坏死。第二，根据这些信息，我们将 有条件地表达抗凋亡基因，Bcl-2或通过功能使坏死途径失活 有条件的RIPK3或MLKL灭活，在定义的肺泡成纤维细胞子集中，确定 小鼠应对香烟诱发的空域增强。尽管牙槽间隔成纤维细胞具有 众所周知，长期以来一直位于与牙槽上皮相邻的位置，并且非常接触 关于成纤维细胞编程的细胞死亡和功能损失的早期造成的知之甚少 足以促进肺气肿的发展。拟议的研究将解决这一关键知识 差距。此外，确定防止肺泡成纤维细胞损失的方法可能导致新的机会 这一过程是防止肺气肿发展的策略。