EFFECTS OF TRANSFORMING GROWTH FACTOR-BETA ON ELASTIN

吸烟引起的慢性炎症可能导致 通过促进弹性蛋白降解，以及通过 影响受损弹性蛋白的修复。 慢性病的影响 修复过程中的炎症可能部分由转化介导， 生长因子-β（TGF-β）。 肺巨噬细胞可能在 在调节TGF-β在肺纤维化中的作用中的作用， 分泌这种生长因子并激活TGF-β， 由其他细胞产生。 初步研究表明，TGF-β 在培养的细胞中，原弹性蛋白（TE）的产量增加了2倍。 新生和成年大鼠肺成纤维细胞。 这一增长反映在 弹性蛋白mRNA的稳态水平也有类似的升高。的 TGF-β限制新生血管的蛋白水解降解的能力 将通过表征TGF-β的作用来检查合成的TE 对大鼠肺产生蛋白酶和蛋白酶抑制剂的影响 成纤维细胞 TGF-β介导的弹性蛋白基因表达的改变 将进一步通过翻译分离的多聚A-RNA来表征， 体外，通过检测弹性蛋白基因的转录速率， 分离的细胞核，并通过分析弹性蛋白mRNA的稳定性。 初步实验表明，正常人和仓鼠的肺泡 巨噬细胞和正常仓鼠间质巨噬细胞分泌TGF-β。 肺泡和间质TGF-β的产生和分泌 将检查肺巨噬细胞以确定是否 炎症 与吸烟或气管内滴入碳有关 颗粒进入仓鼠可能会增加分泌和生物活性 TGF-β大鼠肺成纤维细胞产生和分泌TGF-β的研究 也将进行检查，因为初步数据表明，TGF-β可能 通过自分泌机制影响这些细胞产生弹性蛋白。 共培养的肺成纤维细胞和巨噬细胞之间的相互作用将 分析以确定这些相互作用是否可以促进 激活这些细胞分泌的TGF-β， 说明负责促进这一工作的机制的特点。 的作用 将详细研究该过程中纤溶酶的产生。 更好的 了解TGF-β在弹性蛋白合成中的潜在作用 在肺结核，可能最终有助于发展 可以促进肺气肿患者弹性蛋白修复的治疗方法， 人类的肺

Chronic inflammation produced by cigarette smoking may contribute to the development of emphysema by promoting elastin degradation, and also by influencing the repair of damaged elastin. The influence of chronic inflammation on the repair process may in part be mediated by transforming growth factor-beta (TGF-Beta). Pulmonary macrophages may play a central role in modulating the effects of TGF-Beta in the pulmonary interstitium by secreting this growth factor and activating TGF-Beta which has been produced by other cells. Preliminary studies have shown that TGF-Beta elicits a 2-fold increase in tropoelastin (TE) production by cultured neonatal and adult rat lung fibroblasts. This increase is reflected by a similar elevation in the steady-state levels of elastin mRNA. The capability of TGF-Beta to limit the proteolytic degradation of newly synthesized TE will be examined by characterizing the effects of TGF-Beta on the production of proteinases and proteinase inhibitors by rat lung fibroblasts. Alterations in elastin gene expression mediated by TGF-Beta will be further characterized by translation of isolated poly A-RNA in vitro, by examining the rate of transcription of the elastin gene using isolated nuclei, and by analyzing the stability of elastin mRNA. Preliminary experiments have shown that normal human and hamster alveolar macrophages and normal hamster interstitial macrophages secrete TGF-beta. The production and secretion of TGF-Beta by alveolar and interstitial pulmonary macrophages will be examined to determine whether inflammation associated with cigarette smoking or intratracheal instillation of carbon particles into hamsters may increase the secretion and biologic activity of TGF-Beta. The production and secretion of TGF-Beta by rat lung fibroblasts will also be examined as preliminary data suggest that TGF-Beta may influence elastin production by these cells through an autocrine mechanism. Interactions between co-cultured pulmonary fibroblasts and macrophages will be analyzed to determine whether these interactions may promote the activation of TGF-Beta that has been secreted by these cells and to characterize the mechanisms responsible for this promotion. The role of plasmin generation in this process will be examined in detail. A better understanding of the potential role of TGF-Beta in the synthesis of elastin in the pulmonary interstitium, may ultimately contribute to the development of therapies that could promote the repair of elastin in emphysematous human lungs.