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.

埃默里酒精和肺生物学中心的成员推出了乙醇之间的牢固关联滥用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，其特征是两者都增加肺细胞外基质的表达和降解。我们着手在先前进行调查资金期间，表明啮齿动物中长期暴露于乙醇会导致肺的激活基质金属蛋白酶和增加胶原蛋白的碎片化，转化的表达增加生长因子-PI（TGFP），以及纤连蛋白的表达增加，纤连蛋白是与损伤有关的基质糖蛋白和维修。我们还展示了在其他“健康”中激活肺组织重塑的证据酗酒者。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，我们现在建议探索乙醇影响成纤维细胞功能的机制，信号传导途径触发，细胞外矩阵作为这些事件的调节剂的潜在作用。有趣的是，我们发现乙醇诱导的氧化应激是通过氧化二硫化物夫妇的氧化激活非神经元烟碱乙酰胆碱受体（NACHRS）和触发TGF | 31/SMAD3信号传导然后诱导与基质表达和肌纤维细胞控制有关的基因转变。我们还发现，该途径导致纤连蛋白富含矩阵的沉积这有助于维持“酒精表型”，而过氧化物酶体增殖物激活受体伽玛（PPARY）下调这些响应。这些新颖的观察结果使我们假设在肺中成纤维细胞，乙醇诱导的氧化应激通过NACHR触发氧化还原信号传导，导致 TGFP1/SMAD3信号传导。反过来，TGFP1/SMAD3信号促进成纤维细胞表型的改变富含纤连蛋白的细胞外基质的产生，使肺部容易受到纤维化的影响在急性肺损伤的情况下。这些事件被PPARY平衡。这个假设将是在旨在：1）识别负责介导乙醇在肺中介导的NACHR的目标中进行了测试成纤维细胞。 2）检查TGFP1/SMAD3信号在乙醇引起的急性肺的敏感性中的作用受伤。 3）探讨成纤维细胞衍生的纤维蛋白含量富含矩阵的机制乙醇引起的作用。 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，并检查该途径在体内的操纵如何影响乙醇相关结果。 LAV摘要：该项目将研究长期暴露于酒精的活动肺成纤维细胞并促进急性肺损伤。