Mechanisms and control of epithelial to mesenchymal transition in chronic asthma

慢性持续性哮喘与持续的气道炎症和气道重塑有关。 气道炎症和重塑之间的关系仍然不确定;但 有证据表明皮质类固醇治疗不能阻止气道重塑的发展。因此， 一个主要的推动力，了解气道重塑的发病机制，在一个更基本的水平。之一 气道重塑的关键成分是肌成纤维细胞的产生。肌成纤维细胞有助于 包括I型和III型胶原蛋白在内的基质蛋白沉积增强， 收缩器关于哮喘中肌成纤维细胞的起源知之甚少。三 气道肌成纤维细胞的潜在来源是常驻肺成纤维细胞的活化，骨的募集， 骨髓成纤维细胞干细胞分化为成纤维细胞和气道的转化或转分化 上皮细胞转化为肌成纤维细胞。对其他器官，特别是肾脏的研究表明， 间充质转化（EMT）是损伤或创伤后肌成纤维细胞的主要来源。我们 假设慢性哮喘气道上皮细胞建立了一个局部环境， 上皮细胞转化为肌成纤维细胞，这是气道重塑的重要组成部分。一个 这一假说的一个重要推论是，改变局部环境可以促进成肌纤维细胞向上皮细胞转化 转型，从而改善重塑。 为了验证这一假设，我们提出了以下具体目标：1：评估潜在的机制 研究气道上皮细胞的上皮-间充质转化（EMT）; 2）分析上皮-间充质转化的调控机制， 探讨上皮细胞与间质细胞的关系 慢性哮喘患者的气道转换和气道重塑。 这些研究将直接解决气道可能经历的基本机制， 慢性哮喘期间的重塑。因为上皮细胞向间质细胞转化的途径 受当前和未来药物的调节，定义了治疗过程中的分子步骤。 过渡将为今后限制重塑的努力提供指导。最后，开发生物标志物， 重塑将显着增强监测这些治疗工作的能力。

Chronic persistent asthma has been linked to both ongoing airway inflammation and airway remodeling. The relationship between airway inflammation and remodeling has remained uncertain; but there is evidence that corticosteroid therapy does not prevent the development of airway remodeling. Thus, there is a major impetus to understand the pathogenesis of airway remodeling at a more fundamental level. One of the critical components of airway remodeling is the generation of myofibroblasts. Myofibroblasts contribute both to the enhanced deposition of matrix protein including types I and III collagens as well as to the contractile apparatus. Relatively little is known about the origin of myofibroblasts involved in asthma. Three potential sources of airway myofibroblasts are activation of resident lung fibroblasts, recruitment of bone marrow fibroblast stem cells that differentiate into fibroblasts and transition or transdifferentiation of airway epithelial cell into myofibroblasts. Studies in other organs, particularly the kidney, have shown that epithelial to mesenchymal transition (EMT) is a major source of myofibroblasts following injury or trauma. Our hypothesis is that airway epithelial cells in chronic asthma establish a local milieu that promotes transition of epithelial cells to myofibroblasts, and that this represents a significant component of airway remodeling. An important corollary of this hypothesis is that changing the local milieu can promote myofiblast to epithelial transition, and thereby improve remodeling. To test this hypothesis, we propose the following specific aims: 1: Assess the mechanisms underlying epithelial-mesenchymal transition (EMT) in airway epithelial cells; 2) Analyze the regulation of epithelialmesenchymal transition in airway epithelial cells; and 3) Explore the relationship between epithelialmesenchymal transition and in vivo airway remodeling in patients with chronic asthma. These studies will directly address a fundamental mechanism by which the airway may undergo remodeling during chronic asthma. Because the pathways leading to epithelial to mesenchymal transition are subject to regulation by current and future medications, defining the molecular steps in the process of transition will provide guidance for future efforts to limit remodeling. Finally, development of a biomarker for remodeling will significantly enhance the ability to monitor these therapeutic efforts.