IL -1 and TNF alpha in the development of COPD

肺气肿是一种伴随肺泡壁破坏的呼吸腔异常扩大。越来越多的证据表明，修复过程涉及弹性蛋白再合成的肺间质成纤维细胞限制肺泡损伤，并可能恢复肺泡单位。该提案将重点关注损伤后阻碍肺泡基质修复的炎症过程。我们的初步数据显示，白细胞介素1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）受体缺陷的小鼠比野生型小鼠更能抵抗弹性蛋白酶损伤。我们推测，IL-1 β和TNF-α下调弹性蛋白酶损伤后的弹性蛋白mRNA，并诱导肺泡壁细胞凋亡，导致肺泡破裂和肺泡腔扩大。初步数据表明，这些介质的功能，以减少弹性蛋白转录通过顺式作用元件位于近端弹性蛋白启动子。电泳凝胶位移分析利用从未经处理和IL-1 β处理的成纤维细胞分离的核蛋白，涉及NF-κ B和C/EBP-β蛋白。在这个提议中，我们的第一个目标是确定IL-1 β和TNF-α下调弹性蛋白转录的机制。第二个目标将表征这些效应物质用于下调肺成纤维细胞中弹性蛋白原mRNA的信号转导途径。第三个目标将进一步检查弹性蛋白溶解损伤对TNF-α受体和1型（p80）IL-1 β受体缺陷小鼠的影响。我们还将使用Caspace-11缺陷小鼠来阐明凋亡在这一过程中的作用。这些研究将为COPD的发病机制提供新的见解，并提出新的治疗方案。

Emphysema is an abnormal enlargement of the respiratory spaces with destruction of the alveolar wall. Accumulating evidence suggests that repair processes involving elastin re-synthesis by interstitial lung fibroblasts limits 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. Our preliminary data reveal that mice deficient in the interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) receptors are more resistant to elastase injury than are wild type mice. We postulate that IL-1beta and TNF- alpha down-regulate elastin mRNA following elastase injury and induce apoptosis in the alveolar wall resulting in alveolar rupture and airspace enlargement. Preliminary data indicate that these mediators function to decrease elastin transcription via cis-acting elements located in the proximal elastin promoter. Electrophoretic gel shift assays utilizing nuclear proteins isolated from untreated and IL-1beta treated fibroblasts implicated NF-kappaB and C/EBP-beta proteins. In this proposal, our first aim will determine the mechanism whereby IL-1beta and TNF- alpha down-regulate elastin transcription. The second aim will characterize the signal transduction pathway utilized by these effector substances to down-regulate tropoelastin mRNA in lung fibroblasts The third aim will further examine the effect of elastolytic injury on mice deficient in the TNF-alpha receptors and type 1 (p80) IL-1beta receptors. We will also use caspace-11 deficient mice to clarify the role of apoptosis in this process. These studies will provide new insights into the pathogenesis of COPD and suggest new treatment options.