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和通过 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在一定程度上是通过转化 生长因子-β(TGF-β)。肺巨噬细胞可能发挥中枢作用 大鼠肺间质中转化生长因子-β的调节作用 分泌这种生长因子并激活转化生长因子-β 由其他细胞产生。初步研究表明，转化生长因子-β 使原弹性蛋白(TE)的产量增加2倍 新生和成年大鼠肺成纤维细胞。这一增长反映在一个 弹性蛋白mRNA的稳态水平也有类似的升高。这个 转化生长因子-β限制新生细胞蛋白降解的能力 合成的TE将通过表征转化生长因子-β的作用进行检测 大鼠肺产生蛋白水解酶及其抑制剂的研究 成纤维细胞。转化生长因子-β对弹性蛋白基因表达的影响 将进一步表征分离的聚A-RNA在 体外，通过检测弹性蛋白基因的转录速度 分离细胞核，并对弹性蛋白mRNA的稳定性进行分析。 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转化生长因子-β。 肺泡和间质产生和分泌转化生长因子-β 将检查肺巨噬细胞以确定是否存在炎症 与吸烟或气管内滴注碳有关 进入仓鼠体内的颗粒可能会增加细胞的分泌和生物活性 转化生长因子-β。大鼠肺成纤维细胞产生和分泌转化生长因子-β 也将进行检查，因为初步数据表明，转化生长因子-β可能 通过自分泌机制影响这些细胞的弹性蛋白生产。 共培养的肺成纤维细胞与巨噬细胞的相互作用 进行分析，以确定这些交互作用是否会促进 激活这些细胞分泌的转化生长因子-β，并 描述负责这一提升的机制。的作用 在这一过程中纤溶酶的产生将被详细研究。更好的 理解转化生长因子-β在弹性蛋白合成中的潜在作用 在肺间质中，可能最终有助于发育 可促进肺气肿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.