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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

基本信息

批准号：
10609797
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
项目类别：
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/10609797
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 Inhibition of Apoptosis Knowledge Location Lung Lung diseases Mesenchymal Methods Microanatomy 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 cigarette smoke cigarette smoke-induced cigarette smoking exposure to cigarette smoke functional disability functional loss gain of function genetic approach interstitial loss of function lung development lung injury male mouse model novel postnatal prevent pulmonary function response sex

项目摘要

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.

该病常见于老年男性美国退伍军人和既往吸烟史，