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

描述（改编自申请人的摘要） 肺气肿的定义是呼吸空间的异常扩大， 肺泡壁的破坏。 肺弹性回缩丧失和 肺泡附着在小气道上， 梗阻 流行病学证据表明， 由于炎症事件、肺泡 结构和修复过程。 越来越多的证据表明 肌成纤维细胞再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。 本提案将侧重于 炎症过程阻碍了肺泡基质的修复， 损伤 研究人员的初步数据显示，白细胞介素1（IL-1） 和肿瘤坏死因子-（TNF-α）下调弹性蛋白mRNA， 减少肺组织细胞外基质中弹性蛋白的积聚 培养的成纤维细胞。 这些介质存在于肺泡腔中 因此可能损害肺泡中弹性蛋白的产生 墙 IL-1降低弹性蛋白基因的转录速率， 超过80%，这是由核试验确定的。 瞬态 转染实验表明IL-1和TNF-α通过顺式- 近端弹性蛋白启动子中的作用元件。 电泳凝胶位移 利用分离的核蛋白的测定涉及C/EBP-蛋白， 未鉴定的锌指型蛋白介导这种下调。 小鼠 缺乏TNF受体（双受体敲除）的损伤较小 在腹膜内给予弹性蛋白酶后， 组织密度 研究人员将确定分子机制 由此这些效应物质调节弹性蛋白转录。 的 研究人员将研究IL-1和TNF-α所利用的信号通路， 来降低弹性蛋白的转录 研究人员推测， 弹性蛋白产生的下调限制了体内肺修复。 的 研究人员将使用野生型和IL-1和TNF-α来检验他们的假设。 用胰弹性蛋白酶治疗的受体敲除小鼠 给药或暴露于香烟烟雾。 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。

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.