MODULATION OF COLLAGEN SYNTHESIS IN LUNG FIBROBLASTS

博莱霉素是一种糖肽，用于治疗各种癌症。一 博莱霉素治疗的毒性之一是肺纤维化，它是主要的 并限制这种抗肿瘤药物的毒性。该计划的目的是 建议的研究是确定博莱霉素诱导的机制(S) 肺组织胶原合成增加，胶原沉积增加。这项建议 包含转化生长因子-β(转化生长因子-β)和 白介素1在博莱霉素诱导的肺损伤反应中的作用 I型前胶原mRNAs和I型前胶原合成增加。这些 博莱霉素、转化生长因子-β和IL-1均能增加胶原参数。 博莱霉素处理的大鼠肺成纤维细胞将被检测I型 前胶原合成和数量，I型前胶原mRNA转录， IL-1mRNAs和转化生长因子-βmRNAs、生长因子mRNAs的合成和降解。 我们已经证明了转化生长因子-βmRNA和转化生长因子-βmRNA的合成 在博莱霉素处理的大鼠肺成纤维细胞中增加。要评估 在活体情况下，我们将测定I型前胶原的合成和 数量，I型前胶原mRNA转录，细胞数量 转化生长因子-βmRNA、IL-1mRNAs及其生长的合成和降解 对照组和对照组肺成纤维细胞中因子mRNAs的表达 博莱霉素组大鼠。我们将确定转化生长因子-β的直接影响 和IL-1对I型前胶原合成和数量、细胞水平的影响 I型前胶原mRNAs、mRNA的合成和降解。我们将使用DNA 缺失构建以确定特定的DNA序列(S) I型前胶原基因5‘侧翼区可能是 博莱霉素、转化生长因子-β和IL-1对前胶原基因的调节作用 表情。拟议的研究将定义一个分子基础 博莱霉素性肺纤维化及其可能的机制 肺纤维化致病因子。这些研究还将建立一个 博莱霉素性肺纤维化的相互关系 胶原合成与生长因子IL-1、TGF-4的关系。

Bleomycin is a glycopeptide which is used to treat various carcinomas. One of the toxicities of bleomycin therapy is lung fibrosis which is the major and limiting toxicity of this antineoplastic drug. The purpose of the proposed studies is to determine the mechanism(s) of bleomycin induced increased collagen synthesis and collagen deposition in lung. This proposal encompasses the role of transforming growth factor beta (TGF-beta) and interleukin-1 (IL-1) in mediating the bleomycin-induced response of lung to increased type I procollagen mRNAs and type I procollagen synthesis. These collagen parameters are both increased by bleomycin, TGF-beta and IL-1. Bleomycin-treated rat lung fibroblasts will be assayed for type I procollagen synthesis and amount, type I procollagen mRNA transcription, IL-1 mRNAs and TGF-beta MRNA, growth factor mRNA synthesis and degradation. We have already demonstrated that TGF-beta mRNA and TGF-beta MRNA synthesis are increased in rat lung fibroblasts treated with bleomycin. To assess the in vivo situation we will determine type I procollagen synthesis and amount, type I procollagen MRNA transcription, the cellular amounts of TGF-beta mRNA, IL-1 mRNAs and the synthesis and degradation of these growth factor mRNAs in fibroblasts isolated from lung of control and bleomycin-treated rats. We will determine the direct effects of TGF-beta and IL-1 on type I procollagen synthesis and amount, the cellular levels of type I procollagen mRNAs, MRNA synthesis and degradation. We will use DNA deletion constructs to determine the specific DNA sequence(s) in the 5'flanking region of the type I procollagen gene which possibly are required for bleomycin, TGF-beta and IL-1 regulation of procollagen gene expression. The proposed studies will define a molecular basis for bleomycin-induced lung fibrosis and possibly a mechanism for other fibrogenic agents of lung. These studies will also establish an interrelationship between bleomycin-induced lung fibrosis, increased collagen synthesis and the growth factors, IL-1 and TGF-4.