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间隙的异常增大 肺泡壁的破坏。肺的弹性后坐力损失和损失 肺泡附着在小气道上导致不可逆的呼吸道 障碍物。流行病学证据表明，这种疾病是由 由于炎症事件之间的复杂相互作用，肺泡 结构和维修流程。越来越多的证据表明，修复 肌成纤维细胞参与弹性蛋白再合成的过程限制肺泡 损害肺泡单位，也许还能恢复。这项提案将重点放在 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) 和肿瘤坏死因子(TNF-)下调弹性蛋白mRNA，从而 减少肺组织弹性蛋白在细胞外基质中的积聚 培养中的成纤维细胞。这些中介物存在于牙槽间隙。 在肺损伤后，从而可能损害肺泡内弹性蛋白的产生 墙。IL-1使弹性蛋白基因的转录速度降低更多 超过80%是通过核运行分析确定的。瞬变 转染实验表明，IL-1和肿瘤坏死因子-1通过顺式作用发挥作用。 近端弹性蛋白启动子中的作用元件。凝胶电泳法 利用分离的核蛋白进行分析涉及C/EBP-蛋白和AN 未知的锌指型蛋白参与了这一下调过程。老鼠 缺乏肿瘤坏死因子受体(双受体敲除)的人受到的伤害较小 在气管内应用弹性蛋白酶后，通过测量以下指标来评估 组织密度。研究人员将确定分子机制 通过这些效应物质调节弹性蛋白的转录。这个 研究人员将研究IL-1和TNF-1所利用的信号通路 以减少弹性蛋白的转录。调查人员推测，这一点 弹性蛋白产生的下调限制了体内的肺修复。这个 研究人员将使用野生型和IL-1和TNF-1来验证他们的假设。 气管内胰腺弹性蛋白酶治疗受体敲除小鼠 吸入或暴露在香烟烟雾中。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.