MECHANISMS OF INFLAMMATORY EDEMA

炎症性水肿的机制

• 批准号: 2217263
• 负责人: Douglas MICHAEL SHASBY
• 金额: $ 22.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217263
• 关键词: animal tissue; antioxidants; biological signal transduction; bradykinin; cell morphology; cytoskeleton; dystrophin; edema; electron spin resonance spectroscopy; enzyme activity; histamine; human fetus tissue; inflammation; myosin light chain kinase; myosins; neutrophil; phosphorylation; stimulant /agonist; thrombin; tissue /cell culture; vascular endothelium

The research program outlined in this application is designed to extend our prior observations on the pathogenesis of inflammatory edema. It is built around the observations that inflammatory edema, whether caused by histamine, bradykinin or activated neutrophils, is invariably associated with the retraction of adjacent endothelial cells. In the past we have identified neutrophil derived mediators that activate signal transduction pathways that cause retraction of endothelial cells. Histamine and bradykinin activate these same pathways and also cause cell retraction. We have recently found that these pathways lead to phosphorylation of the light chain of myosin (MLC), and phosphorylation of the light chain is necessary for cell retraction in response to histamine or when cell attachment to substrate is interrupted by chelating extracellular calcium. In the proposed experiments we will determine if histamine, bradykinin, and thrombin increase centripetal tension in endothelial cells, and if they do, if the increase in tension is dependent on phosphorylation of MLC. We will also determine if histamine, bradykinin or thrombin cause endothelial cells to release from substrate and cell-cell attachments, and if they do, if this is occurs in the absence of an increase in centripetal tension. We have new preliminary data that are consistent with a paradigm in which agonists such as histamine and bradykinin release endothelial cells from attachments without increasing centripetal tension. In our recent experiments we have also observed that the magnitude and duration of MLC phosphorylation in response to histamine and bradykinin are very limited. These same experiments identify a potentially important role for phosphatases in the control of light chain phosphorylation. We will extend these observations to more precisely determine the role of phosphatases in controlling the extent of MLC phosphorylation in endothelium. We expect these investigations to increase our understanding of how inflammatory edema occurs; and to direct our future investigations into understanding how cell attachments can be regulated and whether some edemagenic agonists may directly alter the activity of endothelial phosphatases.

本应用程序中概述的研究计划旨在扩展 我们先前关于炎症性水肿发病机理的观察。这是 围绕炎症性水肿的观察，无论是由 组胺，心动激肽或活化的嗜中性粒细胞总是相关的 随着相邻内皮细胞的缩回。过去，我们有 鉴定出激活信号转导的中性粒细胞衍生的介体 导致内皮细胞缩回的途径。组胺和 心动激肽激活这些相同的途径并引起细胞回缩。我们 最近发现这些途径导致 肌球蛋白（MLC）的轻链和轻链的磷酸化为 响应组胺或细胞时细胞回缩所需的必需 粘膜外钙的附着在底物上的附着会中断。 在提出的实验中，我们将确定组胺是Bradykinin是否 凝血酶增加内皮细胞中的中心张力，以及 他们确实如此，如果张力的增加取决于 MLC。我们还将确定组胺，心动激肽或凝血酶是否原因 内皮细胞从底物和细胞附着件中释放，以及 如果这样做，如果发生这种情况，则会发生centripetal的增加 紧张。我们有新的初步数据，这些数据与范式一致 其中组胺和心动激素等激动剂释放内皮 附着的细胞而不会增加中心张力。在我们的 最近的实验我们还观察到幅度和持续时间 响应组胺和心动激素的MLC磷酸化非常非常 有限的。这些相同的实验确定了潜在的重要作用 光链磷酸化控制中的磷酸酶。我们将扩展 这些观察结果更精确地决定了磷酸酶在 控制内皮中MLC磷酸化的程度。我们期望 这些调查以增加我们对炎症的理解 出现水肿；并将我们未来的调查指导到理解 如何调节细胞附件以及是否某些杂志激动剂 可能直接改变内皮磷酸酶的活性。