IL -1 and TNF alpha in the development of COPD

肺气肿是一种呼吸间隙的异常扩大，并伴有肺泡壁的破坏。越来越多的证据表明，由间质性肺成纤维细胞重新合成弹性蛋白的修复过程限制了肺泡损伤，并可能恢复肺泡单位。本研究将聚焦于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)受体缺乏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在弹性蛋白酶损伤后下调弹性蛋白mRNA，诱导肺泡壁细胞凋亡，导致肺泡破裂和肺泡空间扩大。初步数据表明，这些介质通过位于近端弹性蛋白启动子的顺式作用元件减少弹性蛋白转录。电泳凝胶移位实验利用从未经处理和il -1 β处理的成纤维细胞分离的核蛋白，涉及NF-kappaB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。第二个目标将描述这些效应物质下调肺成纤维细胞中tropoelastin mRNA的信号转导途径。第三个目标将进一步研究弹性损伤对缺乏tnf - α受体和1型（p80） il -1 β受体的小鼠的影响。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.