CELLULAR AND MOLECULAR MECHANISMS OF AIRWAY INFLAMMATION

这项申请是为了继续正常的多学科研究 呼吸道细胞和阐明细胞和分子机制 与呼吸道炎症有关。纳德尔博士、巴斯鲍姆博士、考伊博士和 麦克唐纳多年来一直在这一PPG上密切合作，他们 将使用他们的不同技能来研究呼吸道炎症过程 使用细胞生物学、分子、形态和生理学方法。 研究人员将检查表面上皮细胞的影响， 内皮细胞、腺体和炎性细胞及其相互作用 都参与了炎症反应，这些因素影响着 这些反应的质量和规模、急性反应的后果 炎症，以及减少呼吸道炎症的新策略。一 计划项目的组成部分将定义蜂窝机制， 血浆渗漏发生在炎症部位，目的是桥接 血管内皮细胞渗漏机制的体外研究差距 并在体内测量炎症介质对 血管通透性。因为任何单一的机制都不可能解释 呼吸道中所有类型的血管渗漏，模型系统 急性炎症(神经源性炎症)和更长时间 炎症(晚期过敏反应)将进行比较。因素 可增加或减少内皮细胞对 炎症介质也将被研究。第二个组件将 阐述呼吸道上皮对炎症的作用。因为 呼吸道上皮存在于与外部的交界处。 环境，它的理想位置是信号刺激物是 吸入，如香烟烟雾、污染物、病毒和细菌；这些 细胞位于战略位置，以对吸入的刺激物做出反应。 中性粒细胞产物与炎症反应和呼吸道有关 上皮细胞(包括其他细胞)产生一种细胞因子--白介素8(IL-8) 这是一种强有力的化学诱导剂。目的是为了阐明这些角色 IL-8在对外来刺激物的炎症反应中的作用这些细胞 负责IL_8和改变这些反应的因素将是 探索过了。在人类和狗身上研究IL-8的工具正在开发中 发展起来的。对人体组织的研究将包括永久性的人体呼吸道 来自移植供者的上皮细胞系、肺组织和细胞以及 收件人。狗的呼吸道将在体内和体外进行研究，使用 在这个实验室开发的分子工具。的第三个组件 计划项目将研究腺体的分子机制 肥大。控制扩散、迁移和 将探索腺细胞的分化，重点放在生长上。 参与腺体生长的因子和生长因子受体。 本地生产的蛋白酶在降解和降解过程中的作用 生长的粘膜腺体对细胞外基质的穿透将 也被定义为。第四部分考察了桅杆的贡献。 细胞蛋白水解酶对呼吸道组织的反应。化学、组织学和 我们将利用生理学方法来探讨桅杆的作用。 细胞丝氨酸和金属蛋白酶与呼吸道炎症。特别是， 这些研究将考察肥大细胞蛋白水解酶在 炎性呼吸道组织生长和重塑。此外， 蛋白水解酶与血管的相互作用及其在血管中的作用 将研究调节血管通透性的蛋白水解酶。最后， 一种新发现的蛋白的结构、细胞表达和功能 肥大细胞蛋白水解酶、dMCP-3的测定。此计划项目团队 有着悠久的合作研究和使用 研究呼吸道炎症的多学科策略。其目的是 是使制定更有效的战略成为可能 防止或减轻血浆外渗，粘膜增厚， 粘液产生，以及与哮喘相关的气流阻塞， 支气管炎、囊性纤维化等呼吸道炎症性疾病。

This application is to continue multidisciplinary studies of normal airway cells and to elucidate cellular and molecular mechanisms associated with airway inflammation. Drs. Nadel, Basbaum, Caughey, and McDonald have collaborated closely in this PPG for many years, and they will use their diverse skills to study airway inflammatory processes using cell biological, molecular, morphologic and physiologic approaches. The investigators will examine effects in surface epithelial, endothelial, gland, and inflammatory cells and their interactions that are involved in inflammatory responses, factors that influence the quality and magnitude of these responses, consequences of acute inflammation, and novel strategies for reducing airway inflammation. One component of the Program Project will define cellular mechanisms by which plasma leakage occurs at sites of inflammation, with the goal of bridging the gap between in vitro studies of the mechanisms of endothelial leakage and in vivo measurements of the effects of inflammatory mediators on vascular permeability. Because no single mechanism is likely to explain all types of vascular leakage in the respiratory tract, model systems of acute inflammation (neurogenic inflammation) and more prolonged inflammation (late phase allergic response) will be compared. Factors that can increase or decrease the response of endothelial cells to inflammatory mediators will also be studied. A second component will address the contribution of airway epithelium to inflammation. Because the airway epithelium exists at the interface with the external environment, it is ideally positioned to signal irritants that are inhaled, such cigarette smoke, pollutants, viruses and bacteria; these cells are strategically located to respond to inhaled irritants. Neutrophil products are implicated in inflammatory responses, and airway epithelial cells (among others) produce a cytokine, interleukin-8 (IL-8) that is a potent chemoattractant. The purpose is to elucidate the roles of IL-8 in inflammatory responses to foreign irritants. The cells responsible for IL_8 and factors that modify these responses will be explored. Tools for studying IL-8 in humans and dogs are being developed. Studies of human tissues will include permanent human airway epithelial cell lines, lung tissues and cells from transplant donors and recipients. Dog airways will be studied in vivo and in vitro, using molecular tools developed in this laboratory. A third component of the Program Project will examine molecular mechanisms responsible for gland hypertrophy. Mechanisms controlling proliferation, migration, and differentiation of gland cells will be explored with a focus on growth factors and growth factor receptors that participate in gland growth. The action of locally produced proteases in the degradation and penetration of the extracellular matrix by growing mucosal glands will also be defined. The fourth component examines the contributions of mast cell proteases to airway tissue responses. Chemical, histological, and physiological approaches will be utilized to explore the roles of mast cell serine and metalloproteases in airway inflammation. In particular, the studies will examine the participation of mast cell proteases in inflammatory airway tissue growth and remodeling. Furthermore, the interactions of the proteases with blood vessels and the role of the proteases in modulating vascular permeability will be examined. Finally, the structure, cellular expression and functions of a newly discovered mast cell protease, dMCP-3 will be determined. This Program Project team has a long tradition of collaborative research and the use of multidisciplinary strategies for studying airway inflammation. The aim is to make it possible to develop more effective strategies for preventing or reducing the plasma extravasation, mucosal thickening, mucus production, and airflow obstruction associated with asthma, bronchitis, cystic fibrosis and other inflammatory airway diseases.