PULMONARY FIBROSIS IN PDGF TRANSGENIC MICE

间质性肺疾病的特征是炎症和纤维化 这可能是由有毒物质，如灰尘，颗粒，药物，或 传染源无论起始药物是什么，肺纤维化 吸入有毒物质的共同特点，其中包括 炎症，间质细胞增殖，以及 细胞外基质我们一直在研究 石棉诱导的肺纤维化，一种模型纤维化剂。等 材料上调了肺中的多种基因，但这些基因 肺纤维化的关键启动介质尚未被 鉴定我们已经研究了血小板衍生生长因子（PDGF）作为一种 肺纤维化的候选介质。PDGF是最有效的 间充质细胞有丝分裂原已知，也被牵连作为一个 细胞外基质分泌诱导剂。我们发现， 实验室啮齿类动物肺中PDGF的含量在 吸入致纤维化剂量的温石棉。一个特别 高水平的石棉诱导的PDGF表达被发现在上皮细胞中 细胞我们提出了一个模型，其中纤维增生反应引起 通过吸入致纤维化剂，由从纤维化剂释放的PDGF驱动。 覆盖上皮细胞。 这里要检验的中心假设是 上皮来源的PDGF是间质性肺损伤的关键介质， 纤维化 这一假设将在转基因小鼠中进行测试， 过表达PDGF亚基基因或显性阴性PDGF突变体， 肺上皮特异性表面活性蛋白C（SPC）基因启动子。 SPC启动子将用于过表达编码PDGF A的基因， 和PDGF B基因单独和组合，以评估 PDGF同种型在缺乏免疫调节剂的情况下引发肺纤维化 纤维化剂这些转基因小鼠将接触石棉， 检测PDGF过度表达和石棉诱导的 肺损伤还将产生表达一种新基因的转基因小鼠。 显性阴性形式的PDGF，以确定是否干扰 上皮来源的PDGF功能防止石棉诱导的肺损伤。 拟议的实验将允许确定哪些特征 肺纤维化可以由PDGF引发，并且需要其他治疗。 触发事件。PDGF作为纤维化关键介质的鉴定 将有助于建立这个因素作为治疗的目标， 间质性肺病的干预。

Interstitial lung diseases are characterized by inflammation and fibrosis that can be caused by toxic agents such as dusts, particles, drugs, or infectious agents. Regardless of the initiating agent, pulmonary fibrosis induced by inhaled toxicants shares common features, which include inflammation, proliferation of interstitial cells, and deposition of extracellular matrix. We have been studying the molecular mechanisms of pulmonary fibrosis induced by asbestos, a model fibrogenic agent. Such materials upregulate a variety of genes in lung, but the genes that are the key, initiating mediators of pulmonary fibrosis have not been identified. We have studied platelet-derived growth factor (PDGF) as a candidate mediator of pulmonary fibrosis. PDGF is the most potent mesenchymal cell mitogen known, and has also been implicated as an inducer of extracellular matrix secretion. We have found that the levels of PDGF in the lungs of laboratory rodents increase dramatically after inhalation of a fibrogenic dose of chrysotile asbestos. A particularly high level of asbestos-induced PDGF expression is found in epithelial cells. We propose a model in which the fibroproliferative response caused by inhalation of a fibrogenic agent is driven by PDGF released from the overlying epithelial cells. The central hypothesis to be tested here is that epithelial-derived PDGF is a key mediator of interstitial pulmonary fibrosis. The hypothesis will be tested in transgenic mice that overexpress PDGF subunit genes or a dominant-negative PDGF mutant from the lung epithelial-specific surfactant protein C (SPC) gene promoter. The SPC promoter will be used to overexpress genes encoding the PDGF A and PDGF B genes singly and in combination to assess the potential of PDGF isoforms to initiate pulmonary fibrosis in the absence of a fibrogenic agent. These transgenic mice will be exposed to asbestos to examine the combined effect of PDGF overexpression and asbestos-induced lung injury. Transgenic mice will also be generated that express a dominant-negative form of PDGF to determine whether interference with epithelial-derived PDGF function prevents asbestos-induced lung injury. The proposed experiments will allow a determination of which features of pulmonary fibrosis can be initiated by PDGF and which require other triggering events. Identification of PDGF as a key mediator of fibrosis would serve to establish this factor as a target for therapeutic intervention in interstitial lung disease.