MECHANISMS OF INFLAMMATORY EDEMA

炎症性水肿的机制

• 批准号: 3345512
• 负责人: Douglas MICHAEL SHASBY
• 金额: $ 17.22万
• 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 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3345512
• 关键词: adenosine triphosphate; antioxidants; cell adhesion; edema; enzyme induction /repression; enzyme mechanism; epithelium; free fatty acids; inflammation; inositol phosphates; ion transport; lipid metabolism; lipid peroxides; membrane lipids; neutrophil; oxidizing agents; radiotracer; serum; spectrometry; swine; tissue /cell culture; vascular endothelium permeability; voltage /patch clamp

This application proposes to continue to investigate how polymorphonuclear leukocyte (PMN) derived inflammatory molecules (IM) alter endothelial (endo) and epithelial (epi) barriers. The goals of the original application were to determine some mechanisms for the reversible effects of oxidants on endo barriers. We have also extended our observations to epithelium and we have investigated two additional groups of PMN IM, neutrophil cationic proteins and chlorinated amines. These observations have led to 2 hypotheses. 1. PMN derived IM initiate phospholipase C hydrolysis of inositol phospholipids in endo and epi cells, and the products of the hydrolysis cause changes in the cells' cytoskeletons that contribute to changes in barrier function. 2. Cytolytic doses of PMN derived IM initiate phospholipase A hydrolysis of phospholipids, increase cell membrane ionic permeability and deplete cell energy stores. The depleted energy stores preclude maintenance of normal intracellular ionic concentrations in the face of increased membrane ionic permeability. The depleted energy stores also preclude reesterification of phospholipids with resultant increases in free fatty acids and lysophosdpholipids which further increase membrane ionic permeability. These events lead to progressive cell dysfunction and cessation of normal activities. We will use monolayers of cells cultured on permeable supports, assays of metabolic pathways in cultured cells, and patch clamping of cultured cells and synthetic lipid bilayers to answer the following questions relevant to the hypotheses. 1. Do PMN derived IM activate phospholipase C hydrolysis of inositol phospholipids in endo and epi cells? How is phospholipase C activated? 2. Do PMN derived IM deplete ATP in endo and epi cells? How is phospholipase C activated? 3. What are some of the effects of PMN derived IM on the cytoskeleton and endo and epi cells? 4. Does accumulation of free fatty acid and lysophospholipid contribute to cell dysfunction in endo and epi cells exposed to PMN derived IM? What is the role of ATP in this process? 5. Do PMN derived IM alter the ionic permeability of endo and epi cell membranes? Do the IM alter the permeability of a synthetic lipid bilayer. Answers to these questions will increase our knowledge of how inflammation alters endo and epi barriers.

该申请建议继续调查如何 多形核白细胞（PMN）衍生的炎症分子（IM） 改变内皮（Endo）和上皮（EPI）障碍。 目标 最初的应用是确定某些机制 氧化剂对内野屏障的可逆作用。 我们也扩展了 我们对上皮的观察结果，我们还研究了两个 PMN IM，中性粒细胞阳离子蛋白和氯化胺。 这些观察结果导致了2个假设。 1。PMN得出IM 启动内核中肌醇磷脂的磷脂酶C水解 和EPI细胞，水解产物导致了变化 细胞的细胞骨架会导致屏障功能的变化。 2。 PMN衍生的胞质剂量启动磷脂酶的水解 磷脂，增加细胞膜离子通透性和耗尽 细胞能量存储。 耗尽的能源存储排除了 面对增加的正常细胞内离子浓度 膜离子渗透性。 耗尽的能量储存也排除了 磷脂的重新酯化，导致游离脂肪的增加 酸和溶血液，进一步增加膜离子 渗透性。 这些事件导致进行性细胞功能障碍和 停止正常活动。 我们将使用在可渗透支撑物上培养的细胞单层，测定 培养细胞中的代谢途径和培养的贴片夹紧 细胞和合成脂质双层回答以下问题 与假设有关。 1。做PMN派生的IM激活 磷脂酶C的磷脂水解肌醇的磷脂和EPI中的磷脂磷脂 细胞？ 磷脂酶C如何激活？ 2。做PMN派生的IM耗尽 ATP在Endo和Epi细胞中？ 磷脂酶C如何激活？ 3。什么 PMN得出IM的某些影响对细胞骨架和endo的影响是否 和Epi细胞？ 4.自由脂肪酸的积累和 溶血磷脂有助于内部和EPI细胞的细胞功能障碍 暴露于PMN派生的IM？ ATP在此过程中的作用是什么？ 5。 PMN得出的IM改变了endo和Epi细胞的离子渗透性 膜？ 是否会改变合成脂质的渗透性 双层。 这些问题的答案将增加我们对如何的了解 炎症改变了Endo和Epi屏障。