RC#3: Fibroblast Activation and Abnormal Matrix Remodelling

基本信息

批准号：
8046480
负责人：
Dean Paul Jones
金额：
$ 28.2万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8046480
关键词：
Acetylcysteine Acute Lung Injury Acute respiratory infection Address Affect Alcohol Phenotype Alcohol abuse Alcohols Alveolar Angiotensin II Animals Attention Biology Bronchoalveolar Lavage Fluid Bungarotoxins Cells Cholinergic Receptors Chronic Collagen Complex Couples Cysteine Cystine Data Deposition Disulfides Ethanol Event Exposure to Extracellular Matrix Extracellular Matrix Degradation Factor V Fibroblasts Fibronectins Funding Generations Glycoproteins Human Immune In Vitro Intervention Knockout Mice Laboratories Ligands Liquid substance Lung Lung diseases Matrix Metalloproteinases Mediating Myofibroblast Neurons Nicotinic Receptors Nuclear Hormone Receptors Oxidation-Reduction Oxidative Stress PPAR gamma Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Predisposition Process Production RNA Splicing Rattus Recruitment Activity Regulatory Pathway Relative (related person)Reporting Rodent Rodent Model Role Signal Pathway Signal Transduction Stromal Cells Structure of parenchyma of lung Sulfhydryl Compounds Testing Tissues Transforming Growth Factors Variant alcohol effect alcohol exposure design extracellular gene induction in vivo inhibiting antibody inhibitor/antagonist injury and repair lung injury member novel oxidant stress oxidation problem drinker receptor repaired response small molecule stromelysin 2 therapeutic target transdifferentiation

项目摘要

Members of the Emory Alcohol and Lung Biology Center unveiled a strong association between ethanol abuse and susceptibility to acute lung injury. We hypothesized that one mechanism by which ethanol promotes acute lung injury relates to the activation of tissue remodeling characterized by both increased expression and degradation of lung extracellular matrices. We set out to investigate this during the prior funding period and showed that chronic exposure to ethanol in rodents leads to the activation in lung of matrix metalloproteinases and increased collagen fragmentation, increased expression of Transforming Growth Factor-pi (TGFp), and increased expression of fibronectin, a matrix glycoprotein implicated in injury and repair. We also showed evidence of activation of lung tissue remodeling in otherwise 'healthy' alcoholics. More importantly, these studies unveiled the lung fibroblast as a target for ethanol. Thus, we now propose to explore the mechanisms by which ethanol affects fibroblast functions, the signaling pathways triggered, and the potential role of extracellular matrices as modulators of these events. Interestingly, we found that ethanol-induced oxidative stress via oxidation of thiol disulfide couples activates non-neuronal nicotinic acetylcholine receptors (nAChRs) and triggers TGF|31/Smad3 signaling followed by the induction of genes involved in control of matrix expression and myofibroblast transdifferentiation. We also found that this pathway results in the deposition of fibronectin-rich matrices that help sustain the 'alcoholic phenotype', whereas peroxisome proliferator activated receptors-gamma (PPARy) downregulate these responses. These novel observations led us to postulate that in lung fibroblasts, ethanol-induced oxidative stress triggers redox signaling via nAChRs that leads to TGFp1/Smad3 signaling. In turn, TGFp1/Smad3 signaling promotes alterations in fibroblast phenotype and the production of fibronectin-rich extracellular matrices that render the lung susceptible to fibroproliferation in the setting of acute lung injury. These events are counterbalanced by PPARy. This hypothesis will be tested in aims designed to: 1) Identify the nAChRs responsible for mediating the effects of ethanol in lung fibroblasts. 2) Examine the role of TGFp1/Smad3 signaling in ethanol-induced susceptibility to acute lung injury. 3) Explore the mechanisms by which fibroblast-derived fibronectin-rich matrices contribute to the ethanol-induced effects. 4) Determine the role of PPARy in downregulating ethanol-induced fibroblast activation and matrix expression, and examine how manipulation of this pathway in vivo affects ethanolrelated consequences. Lav summary: This project will examine how chronic exposure to alcohol activates lung fibroblasts and promotes acute lung injury.

埃默里酒精与肺生物学中心的成员揭示了乙醇之间的密切联系滥用和对急性肺损伤的易感性。我们假设乙醇的一种机制促进急性肺损伤与组织重塑的激活有关，其特征是增加肺细胞外基质的表达和降解。我们在之前的时间里就开始对此进行调查资助期间，并表明啮齿类动物长期接触乙醇会导致肺部激活基质金属蛋白酶和胶原蛋白碎片增加，转化蛋白表达增加生长因子-pi (TGFp) 和纤连蛋白（一种与损伤有关的基质糖蛋白）表达增加和修复。我们还显示了在其他“健康”中肺组织重塑激活的证据酗酒者。更重要的是，这些研究揭示了肺成纤维细胞作为乙醇的靶标。因此，我们现在提议探索乙醇影响成纤维细胞功能的机制，信号传导触发的途径，以及细胞外基质作为这些事件调节剂的潜在作用。有趣的是，我们发现乙醇通过二硫化硫醇对的氧化诱导氧化应激激活非神经元烟碱乙酰胆碱受体 (nAChR) 并触发 TGF|31/Smad3 信号传导随后诱导参与控制基质表达和肌成纤维细胞的基因转分化。我们还发现该途径导致富含纤连蛋白的基质沉积有助于维持“酒精表型”，而过氧化物酶体增殖物激活受体-γ (PPARy) 下调这些反应。这些新颖的观察结果使我们推测，在肺中成纤维细胞中，乙醇诱导的氧化应激通过 nAChR 触发氧化还原信号传导，从而导致 TGFp1/Smad3 信号传导。反过来，TGFp1/Smad3 信号传导促进成纤维细胞表型和富含纤连蛋白的细胞外基质的产生，使肺部容易发生纤维增殖在急性肺损伤的情况下。这些事件由 PPARy 抵消。这个假设将是测试目的旨在：1) 识别负责介导乙醇对肺部影响的 nAChR 成纤维细胞。 2) 检查TGFp1/Smad3信号传导在乙醇诱导的急性肺易感性中的作用受伤。 3) 探索成纤维细胞衍生的富含纤连蛋白的基质促进纤维化的机制乙醇引起的影响。 4) 确定PPARy在下调乙醇诱导的成纤维细胞中的作用激活和基质表达，并检查体内该途径的操纵如何影响乙醇相关结果。 Lav 摘要：该项目将研究长期接触酒精如何激活肺成纤维细胞并促进急性肺损伤。