MODULATION OF PMN ADHERENCE BY ENDOTHELIAL CELLS

内皮细胞对 PMN 粘附的调节

• 批准号: 3346504
• 负责人: Sharon Irene Smith Rounds
• 金额: $ 15.19万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3346504
• 关键词: adenine nucleotides; adenosine; calcium flux; cell adhesion; cell adhesion molecules; cytokine; human tissue; inflammation; neutrophil; pulmonary edema; radiotracer; receptor binding; respiratory pharmacology; tissue /cell culture; tumor necrosis factor alpha; tumor necrosis factor beta; vascular endothelium permeability

The overall objective of this renewal application remains elucidation of the pathogenesis of acute lung injury resulting in increased permeability pulmonary edema. The focus is on study of the interaction of neutrophils (PMN's) with vascular endothelial cells, with emphasis on changes in potential mechanisms protective against PMN-induced endothelial cell injury. The central hypothesis of the proposal is that endothelial cell injury is due to loss of balance between protective mechanisms, which normally prevent PMN-induced injury, and factors which exacerbate PMN- induced injury. A potential protective mechanism is production by endothelial cells of adenosine. The potentially injurious effect to be studied is the effect on PMN adherence to endothelium of extracellular adenine nucleotides, released with vascular injury. We will compare the effects of adenosine and adenine nucleotides on isolated PMN adherence to cultured endothelium and the mechanisms of these effects, including mediation by receptors, changes in cell surface adherence proteins, effects on cation fluxes, and effects of uptake or metabolism of these ligands. In order to assess whether agents or conditions which alter PMN adherence also change endothelial cell adenosine metabolism, we will study the effects of the inflammatory cytokine, tumor necrosis factor-alpha (TNFalpha) on endothelial cell production and metabolism of adenosine and adenine nucleotides. The studies outlined in this proposal will determine how TNFalpha alters adenosine and adenine nucleotide production by endothelium and whether changes in these correlate with PMN adherence. We will determine the mechanism responsible for changes in adenosine and adenine nucleotide production and metabolism by investigating effects of TNFalpha on adenosine uptake, rapid transport, release, and ectonucleotidase activity. We will compare intracellular metabolism of adenosine into purines and nucleotides after stimulation of endothelial cells with TNFalpha. Because of the potential therapeutic importance of extracellular adenosine as protection against PMN-induced endothelial cell injury, we will ascertain whether pharmacologic agents which alter adenosine uptake or metabolism, also change PMN adherence to endothelium in response to TNFalpha. These studies will determine the effects of TNFalpha on endothelial cell adenosine and adenine nucleotide production and metabolism and will assess the biologic effects of adenosine and adenine nucleotides on PMN adherence to endothelium, a crucial early step in PMN-induced vascular injury.

此更新应用的总体目标仍然阐明 急性肺损伤的发病机理导致渗透率提高 肺水肿。 重点是研究中性粒细胞的相互作用 （PMN）带有血管内皮细胞，重点是变化 潜在的机制保护PMN诱导的内皮细胞 受伤。 该提案的中心假设是内皮细胞 伤害是由于保护机制之间失去平衡的原因，而保护机制 通常可以防止PMN诱导的损伤，以及加剧PMN-的因素 诱发受伤。 潜在的保护机制是由 腺苷的内皮细胞。 潜在的有害影响是 研究的是对细胞外内皮的PMN依从性的影响 腺嘌呤核苷酸，释放出血管损伤。 我们将比较 腺苷和腺嘌呤核苷酸对分离的PMN遵守的影响 培养的内皮和这些作用的机制，包括 受体介导，细胞表面粘附蛋白的变化，影响 在阳离子通量以及这些配体摄取或代谢的影响上。 在 为了评估改变PMN依从性的代理或条件 改变内皮细胞腺苷代谢，我们将研究 炎性细胞因子，肿瘤坏死因子-Alpha（TNFALPHA） 腺苷和腺嘌呤的内皮细胞产生和代谢 核苷酸。 该提案中概述的研究将决定 tnfalpha改变内皮的腺苷和腺嘌呤核苷酸的产生 这些变化是否与PMN依从性相关。 我们将 确定负责腺苷和腺嘌呤变化的机制 通过研究TNFALPHA的作用，核苷酸的产生和代谢 在腺苷的摄取，快速运输，释放和邻核核苷酸酶上 活动。 我们将将腺苷的细胞内代谢进行比较 刺激内皮细胞后的嘌呤和核苷酸 tnfalpha。 由于细胞外潜在的治疗重要性 腺苷作为防止PMN诱导的内皮细胞损伤的保护，我们 将确定会改变腺苷摄取的药理学剂还是 代谢，也改变了对内皮的PMN依从性。 tnfalpha。 这些研究将确定tnfalpha对 内皮细胞腺苷和腺嘌呤核苷酸的产生和代谢 并将评估腺苷和腺嘌呤核苷酸的生物学作用 关于PMN遵守内皮，这是PMN引起的至关重要的早期步骤 血管损伤。