EFFECT OF IL-1 AND TNF ON ELASTIN PRODUCTION IN COPD

IL-1 和 TNF 对 COPD 患者弹性蛋白产生的影响

• 批准号: 6285814
• 负责人: Ronald Howard Goldstein
• 金额: $ 36.12万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6285814
• 关键词: alveolar macrophages; biological signal transduction; cellular pathology; chronic obstructive pulmonary disease; elastin; emphysema; enhancer binding protein; gel mobility shift assay; genetic promoter element; genetic transcription; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; immunoregulation; in situ hybridization; inflammation; interleukin 1; laboratory mouse; mitogen activated protein kinase; molecular pathology; nuclear runoff assay; protein biosynthesis; protein kinase C; receptor expression; tumor necrosis factor alpha; western blottings

DESCRIPTION (adapted from the applicants' abstract) Emphysema is defined as an abnormal enlargement of the respiratory spaces with destruction of the alveolar wall. Loss of elastic recoil of the lung and loss of alveolar attachments to small airways cause irreversible airway obstruction. Epidemiological evident suggest that the disease develops because of complex interactions between inflammatory events, alveolar structures and repair processes. Accumulating evidence suggest that repair processes involving elastin resynthesis by myofibroblasts limit alveolar damage and perhaps restore alveolar units. This proposal will focus on the inflammatory processes that hinder the repair of the alveolar matrix following injury. The investigators' preliminary data reveal that interleukin1 (IL-1) and tumor necrosis factor-(TNF-) down-regulate elastin mRNA and subsequently reduce the accumulation of elastin in the extracellular matrix by lung fibroblasts in culture. These mediators are present in the alveolar space following lung injury and thus may impair elastin production in the alveolar wall. IL-1 decreases the rate of transcription of the elastin gene by more than 80 percent as determined by nuclear run-on assays. Transient transfection experiments indicate that IL-1 and TNF- function through cis- acting elements in the proximal elastin promoter. Electrophoretic gel shift assays utilizing nuclear proteins isolated implicate C/EBP- proteins and an unidentified zinc finger type protein in mediating this down-regulation. Mice deficient in TNF- receptors (double receptor knockout) sustained less injury following intratracheal elastase administration as assessed by measurements of tissue density. The investigators will determine the molecular mechanisms whereby these effector substances regulate elastin transcription. The investigators will investigate the signaling pathway utilized by IL-1 and TNF- to decrease elastin transcription. The investigators postulate that this down-regulation of elastin production limits lung repair in vivo. The investigators will test their hypothesis using wild-type and IL-1 and TNF- receptor knockout mice treated with intratracheal pancreatic elastase administration or exposure to cigarette smoke. These studies will provide new insights into the pathogenesis of emphysema and suggest new treatment options.

描述（改编自申请人的摘要） 肺气肿被定义为呼吸空间异常扩大 肺泡壁的破坏。 肺弹性回缩力丧失和丧失 小气道的肺泡附着导致不可逆气道 梗阻。 流行病学证据表明该病已发展 由于炎症事件之间复杂的相互作用，肺泡 结构和修复过程。 越来越多的证据表明修复 涉及肌成纤维细胞重新合成弹性蛋白的过程限制了肺泡 损伤并可能恢复肺泡单位。 该提案将重点关注 阻碍肺泡基质修复的炎症过程 受伤。 研究人员的初步数据显示，白细胞介素1 (IL-1) 肿瘤坏死因子 (TNF) 下调弹性蛋白 mRNA，随后 通过肺减少细胞外基质中弹性蛋白的积累 培养中的成纤维细胞。 这些介质存在于肺泡腔中 肺损伤后，因此可能会损害肺泡中弹性蛋白的产生 墙。 IL-1 使弹性蛋白基因的转录率降低更多 根据核连续分析测定，超过 80%。 瞬态 转染实验表明 IL-1 和 TNF- 通过顺式发挥作用 近端弹性蛋白启动子中的作用元件。 电泳凝胶位移 利用分离的核蛋白进行的测定涉及 C/EBP-蛋白和 未鉴定的锌指型蛋白介导了这种下调。 小鼠 TNF-受体缺陷（双受体敲除）受到的伤害较小 通过测量评估气管内弹性蛋白酶给药后 组织密度。 研究人员将确定分子机制 这些效应物质借此调节弹性蛋白转录。 这 研究人员将研究 IL-1 和 TNF- 使用的信号通路 减少弹性蛋白转录。 调查人员推测，这 弹性蛋白产生的下调限制了体内肺的修复。 这 研究人员将使用野生型、IL-1 和 TNF- 来检验他们的假设 受体敲除小鼠气管内胰腺弹性蛋白酶治疗 给药或接触香烟烟雾。 这些研究将提供新的 深入了解肺气肿的发病机制并提出新的治疗方案。