NOVEL INFLAMMATORY RESPONSES OF INJURED ENDOTHELIUM

受损内皮的新炎症反应

• 批准号: 5214054
• 负责人: Thomas M McIntyre
• 金额: --
• 依托单位国家: 美国
• 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/5214054
• 关键词: adult respiratory distress syndrome; binding proteins; biological signal transduction; cell adhesion; cell cell interaction; cell migration; gene expression; heparin lyase; human tissue; immunoglobulins; inflammation; insect poison; interleukin 1; laboratory rabbit; laboratory rat; leukocyte activation /transformation; leukocyte adhesion molecules; mucopolysaccharides; neutrophil; protein purification; pulmonary edema; selectins; surface property; tumor necrosis factor alpha; vascular endothelium

Current evidence suggests that activation of the inflammatory cascade can culminate in ARDS. A complex interplay between activating molecules, responding inflammatory cells and vascular endothelial cells forms this inflammatory cascade. Mediators implicated in this response include the cytokines TNFalpha and Il-1, in addition to endotoxin or lipopolysaccharide itself. An essential component is the regulated interplay between activating molecules are currently being defined; the molecules and systems involved in neutrophil diapedesis on EC and extravasation through endothelial cell junctions are less well defined. Recent studies from our laboratory have identified a novel mechanism, or more likely mechanisms, that result in endothelial cell-dependent neutrophil adhesion, activation and migration across the monolayers. Our initial observations were made with the venom of Loxosceles and it now appears that these finding are also relevant to inflammatory cytokines (e.g. TNF, IL-1) that are key mediators of normal and pathologic inflammation. We find these inflammatory mediators induce the surface expression of E- selectin, but that on venom-treated cells this selectin has a markedly altered specificity and recognizes a different leukocyte counter receptor. We also find that cytokines and Loxosceles venom cause a redistribution of PECAM-1, a richly glycosylated (40%) member of the immunoglobulin superfamily of adhesion molecules, from its exclusive localization at endothelial cell intercellular junctions to the apical surface. PECAM-1 (CD31) is a glycosaminoglycan (GAG) binding protein and, as it is related to molecules like N-CAM, it may undergo Ca+2 dependent homotypic (self) association. Neutrophils and some T cells also express PECAM-1, where it is a transmembrane signaling molecule that activates cellular adhesion mechanisms. We find neutrophil and endothelial cell GAG are required for optimal adhesion to venom-treated endothelial cells, but not to cytokine-treated endothelial cells. However, we also find endothelial cell GAG are absolutely required for neutrophil activation and transmigration across cytokine-activated monolayers, showing that GAG receptors on neutrophils play an essential role in events after adhesion. The unanticipated role of GAG in these cellular interactions also implies a role for neutrophil heparinase in modulating these processes. These observations have the potential to provide novel insights, and thereby potentially new therapeutic interventions, into the underlying mechanisms that culminate in ARDS.

目前的证据表明，炎症级联的激活可以 最终导致ARDS。 活化分子之间复杂的相互作用， 反应性炎症细胞和血管内皮细胞形成此 炎症级联反应。 参与此回应的调解人包括 细胞因子 TNFα 和 Il-1，以及内毒素或 脂多糖本身。 一个重要组成部分是受监管的 目前正在定义激活分子之间的相互作用；这 参与 EC 和中性粒细胞血渗的分子和系统 通过内皮细胞连接的外渗尚不清楚。 我们实验室最近的研究发现了一种新的机制，或者 更可能的机制，导致内皮细胞依赖性 中性粒细胞在单层细胞上的粘附、激活和迁移。 我们的 最初的观察是用 Loxosceles 的毒液进行的，现在它 看来这些发现也与炎症细胞因子有关 （例如 TNF、IL-1）是正常和病理的关键介质 炎。 我们发现这些炎症介质诱导E-的表面表达 选择素，但在毒液处理的细胞上，该选择素具有显着的 改变特异性并识别不同的白细胞计数器 受体。 我们还发现细胞因子和 Loxosceles 毒液会导致 PECAM-1 的重新分布，PECAM-1 是一种富含糖基化 (40%) 的成员 粘附分子的免疫球蛋白超家族，来自其独有的 定位于内皮细胞细胞间连接处至顶端 表面。 PECAM-1 (CD31) 是一种糖胺聚糖 (GAG) 结合蛋白 并且，由于它与 N-CAM 等分子有关，因此可能会发生 Ca+2 依赖同型（自）关联。 中性粒细胞和一些 T 细胞 还表达 PECAM-1，它是一种跨膜信号分子 激活细胞粘附机制。 我们发现中性粒细胞和 内皮细胞 GAG 是与毒液处理的最佳粘附所必需的 内皮细胞，但不包括细胞因子处理的内皮细胞。 然而，我们还发现内皮细胞 GAG 对于 中性粒细胞激活和跨细胞因子激活的迁移 单层细胞，表明中性粒细胞上的 GAG 受体发挥着重要作用 在粘附后事件中的作用。 GAG 在这些方面发挥着意想不到的作用 细胞相互作用也意味着中性粒细胞肝素酶在 调节这些过程。 这些观察结果有可能 提供新颖的见解，从而提供潜在的新治疗方法 干预措施，深入了解导致 ARDS 的根本机制。