Impact of alcohol on lung fibroblast regulation of the alveolar epithelial barrier

酒精对肺成纤维细胞调节肺泡上皮屏障的影响

基本信息

批准号：
10263149
负责人：
VIRANUJ SUEBLINVONG
金额：
$ 7.8万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263149
关键词：
Acute Adult Respiratory Distress Syndrome Alcohols Alveolar Alveolar Macrophages Animals Attenuated Automobile Driving Bleomycin Cell Differentiation process Cell physiology Chronic Chronic Obstructive Airway Disease Chronic lung disease Coculture Techniques Collagen Communication Complex Cytokine Signaling Data Deposition Down-Regulation Endotoxins Epithelial Epithelial Cells Ethanol Experimental Models Extracellular Matrix Extracellular Matrix Proteins Failure Fibroblasts Fibronectins Foundations Functional disorder Future Goals Growth Factor Homeostasis Impairment Individual Injury Interstitial Lung Diseases Laboratories Lead Lung Lung diseases Measures Mesenchymal MicroRNAs Modality Molecular Morbidity - disease rate Normal tissue morphology Organ Oxidative Stress Pathologic Phagocytosis Phase Populations at Risk Process Production Proteins Quality of life Recovery Regulation Resistance Resolution Risk Role Signal Pathway Signal Transduction Signaling Molecule Survivors Testing Therapeutic Therapeutic Intervention Tight Junctions Tissues Transforming Growth Factor beta Up-Regulation alcohol effect alcohol exposure alveolar epithelium cell injury cell motility cell type chronic alcohol ingestion cytokine design equilibration disorder exosome extracellular vesicles insight intercellular communication lung injury lung repair mortality novel prevent preventive intervention problem drinker repaired reparative process response restoration tissue injury tissue repair wound

项目摘要

Project Summary Tissue disrepair following injury leads to organ dysfunction and increases morbidity and mortality of those who survive the initial insult. In the lung, the disrepair process is associated with excessive collagen deposition along with failure of both re-epithelialization and epithelial cell tight junction formation. Tissue disrepair is associated with dysregulation of TGFβ signaling in a variety of pulmonary diseases including the acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Our laboratory utilizes experimental models of chronic alcohol ingestion and bleomycin- induced lung injury to assess the molecular mechanisms of lung repair and identify novel preventative and therapeutic interventions. We have previously shown that alcohol induces excessive and persistent TGFβ expression in the lung. Additionally, we demonstrated that in the lung of chronic alcohol-exposed animals, TGFβ is a critical molecule driving many cellular anomalies by increasing airway oxidative stress, decreasing alveolar macrophages phagocytosis, and priming the lung for fibroproliferative disrepair following acute injury. Our preliminary data show that alcohol-exposed lung fibroblasts interfere with epithelial cell barrier formation likely through induction of epithelial-mesenchymal transition (EMT). Additionally, inhibition of TGFβ signaling attenuates the effect of alcohol-exposed fibroblasts on epithelial cells. Interestingly, we also showed that fibroblasts influence epithelial cells indirectly via fibroblast-derived exosomes rather than direct secretion of cytokines or growth factors. Furthermore, we showed that alcohol disturbs the balance of pro- and anti-fibrotic microRNA (miR) expression. Specifically, alcohol increases pro-fibrotic miR-21 and attenuates anti-fibrotic miRNA-1946a in lung fibroblasts. These data lead us to hypothesize that alcohol exposure disrupts alveolar epithelial cell tight junction formation and barrier function following injury through an imbalance of miR-21 and miR-1946a in exosomes secreted by lung fibroblasts. The experimental approaches are designed to test this hypothesis, and these studies are expected to provide a firm scientific basis for the underlying mechanism(s) by which alcohol interferes with normal repair following lung injury. The results from this proposal will set the basis for future studies to investigate potential therapeutic strategies to prevent or mitigate tissue injury and disrepair in the at-risk population (i.e., alcoholic individuals).

项目摘要受伤后的组织失修会导致器官功能障碍，并增加那些幸免于难的人。在肺中，失修过程与过量的胶原蛋白有关沉积以及重新上皮化和上皮细胞紧密结的失败。组织失修与多种肺部疾病中的TGFβ信号传导失调有关急性呼吸窘迫综合征（ARDS），慢性阻塞性肺疾病（COPD）和间质肺部病（ILD）。我们的实验室利用了慢性酒精摄入和博来霉素的实验模型诱导肺损伤以评估肺修复的分子机制，并确定新颖的预防性和治疗干预措施。我们以前已经表明，酒精会诱导过度和持续的TGFβ 在肺中的表达。此外，我们证明了在慢性酒精暴露动物的肺中 TGFβ是通过增加气道氧化应激来驱动许多细胞异常的关键分子肺泡巨噬细胞吞噬作用，并在急性损伤后启动肺部纤维增生性失修。我们的初步数据表明，酒精暴露的肺成纤维细胞干扰上皮细胞屏障的形成可能通过诱导上皮 - 间质转变（EMT）。另外，抑制TGFβ信号传导衰减酒精暴露的成纤维细胞对上皮细胞的影响。有趣的是，我们还表明成纤维细胞通过成纤维细胞衍生的外泌体间接影响上皮细胞，而不是直接分泌细胞因子或生长因子。此外，我们表明酒精会扰乱促纤维和抗纤维化的平衡 microRNA（mir）表达。具体而言，酒精会增加促纤维化miR-21并减弱抗纤维化 miRNA-1946a在肺成纤维细胞中。这些数据使我们假设酒精暴露会破坏肺泡通过miR-21的不平衡和由肺成纤维细胞分泌的外泌体中的miR-1946a。实验方法旨在测试假设，预计这些研究将为基本机制提供牢固的科学基础。肺损伤后酒精会干扰正常修复。该提案的结果将设定未来研究的基础，以调查预防或减轻组织损伤和减轻组织损伤的潜在治疗策略处于高危人群（即酒精个体）中的失修。