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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).

项目摘要损伤后的组织修复会导致器官功能障碍，并增加疾病的发病率和死亡率那些在最初的侮辱中幸存下来的人。在肺部，失修过程与过多的胶原蛋白有关。随着再上皮化和上皮细胞紧密连接形成的失败而沉积。组织在多种肺部疾病中，修复丧失与转化生长因子β信号的失调有关，包括急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺疾病(COPD)和间质肺部疾病(ILD)。本实验室采用慢性酒精摄入和博莱霉素的实验模型。诱导肺损伤以评估肺修复的分子机制并确定新的预防和治疗方法治疗性干预。我们先前已经证明，酒精会诱导过量且持久的转化生长因子β。在肺中的表达。此外，我们还证明，在慢性酒精暴露的动物的肺中，转化生长因子β是一种关键分子，通过增加呼吸道氧化应激，减少肺泡巨噬细胞吞噬，并为急性损伤后肺纤维增殖性破坏做好准备。我们的初步数据显示，酒精暴露的肺成纤维细胞干扰上皮细胞屏障的形成可能是通过诱导上皮-间充质转化(EMT)。此外，对转化生长因子β信号的抑制减轻酒精暴露的成纤维细胞对上皮细胞的影响。有趣的是，我们还展示了成纤维细胞通过成纤维细胞来源的外切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，我们还发现酒精破坏了促肝纤维化和抗肝纤维化的平衡。 MicroRNA(MiR)的表达。具体地说，酒精增加了促纤维化的miR-21，减弱了抗纤维化的作用肺成纤维细胞中的miRNA-1946a。这些数据让我们假设酒精暴露会扰乱肺泡通过miR-21和miR-21失衡实现损伤后上皮细胞紧密连接的形成和屏障功能肺成纤维细胞分泌的外切体中的MIR-1946a。实验方法就是为了测试这一点而设计的假说，这些研究有望为潜在机制提供坚实的科学基础(S) 酒精会干扰肺损伤后的正常修复。这项提案的结果将设定为未来研究潜在的治疗策略奠定基础，以预防或减轻组织损伤和高危人群(即酗酒者)年久失修。