Eicosanoids and Lung Function

类二十烷酸和肺功能

• 批准号: 6106636
• 负责人: Darryl C Zeldin
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106636
• 关键词: clinical research; fibroblasts; gene induction /repression; growth factor receptors; human subject; interleukin 1; lung disorder; platelet derived growth factor; prostaglandin E; protein isoforms; protein structure function; tissue /cell culture

We are investigating the role of eicosanoids in regulating expression of the platelet-derived growth factor receptor (PDGF-R ) in cultured human lung fibroblasts. We have shown that early passage human lung fibroblast isolates constitutively express PDGF-R and avidly proliferate in response to PDGF-AA, which only binds PDGF-R . Importantly, the cyclooxygenase-derived eicosanoid PGE2 markedly attenuates constitutive PDGF-R activity and PDGF-stimulated 3H-thymidine incorporation in the cultured cells. The effects of PGE2 occur at concentrations as low as 50 nM, are dose-dependent, and occur maximally 24 hours following PGE2 addition. Identical results were obtained with several different primary human lung mesenchymal cell lines established in our laboratory from histologically normal lung tissue suggesting that the observed phenomena were not cell line-specific. These findings are particularly important given the known effects of PGE2 on mesenchymal cell proliferation and in light of the recent findings that fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize PGE2. Current efforts are focused on delineating the signaling mechanisms whereby PGE2 may modulate PDGF-R expression on lung fibroblasts in vitro. In a related clinical study, we are investigating the role of PDGF receptors in the pathogenesis of fibroproliferative lung disease that develops in patients with cancer receiving high-dose chemotherapy. We are collecting bronchoalveolar lavage fluid and transbronchial biopsy specimens from patients before and after chemotherapy in order to study differences in PDGF receptor expression, regulation and function. Preliminary results suggest that post-chemotherapy BAL fluid stimulates thymidine incorporation in cultured human lung fibroblasts and that this proliferative effect is blocked by inhibitory antibodies to PDGF. This data is consistent with a role of the PDGF/PDGF-receptor pathway in the pathogenesis of the disease. We hope that this clinical study will provide insight into basic cellular, molecular, and biochemical mechanisms responsible for initiating and perpetuating the fibroproliferative response in patients exposed to environmental lung toxins, and will set the stage for a second study aimed at novel therapeutic and preventative strategies for fibroproliferative lung disease.

我们正在研究类二十烷酸的作用 调节血小板衍生生长因子受体的表达 (PDGF-R) 存在于培养的人肺成纤维细胞中。我们已经证明 早期传代人肺成纤维细胞分离株组成型表达 PDGF-R 并响应 PDGF-AA 迅速增殖， 只结合 PDGF-R 。重要的是，环氧合酶衍生的 类二十烷酸 PGE2 显着减弱 PDGF-R 的组成型活性 和 PDGF 刺激的 3H-胸苷掺入培养物中 细胞。 PGE2 的作用发生在浓度低至 50 nM 的情况下， 具有剂量依赖性，并且最多在 PGE2 后 24 小时内发生 添加。用几种不同的方法得到了相同的结果 我们的原代人肺间充质细胞系 实验室从组织学正常肺组织中提取的结果表明 观察到的现象不具有细胞系特异性。这些发现是 考虑到 PGE2 对人体的已知影响，这一点尤为重要。 间充质细胞增殖并根据最近的发现 从特发性肺病患者身上分离出的成纤维细胞 纤维化导致合成 PGE2 的能力下降。当前的 努力的重点是描绘信号机制 PGE2 可能调节肺中 PDGF-R 的表达 体外成纤维细胞。在一项相关的临床研究中，我们正在调查 PDGF受体在纤维增殖性疾病发病机制中的作用 接受癌症治疗的患者出现肺部疾病 高剂量化疗。我们正在收集支气管肺泡灌洗液 患者术前和术后的液体和经支气管活检标本 化疗后以研究PDGF受体的差异 表达、调节和功能。初步结果表明 化疗后 BAL 液刺激胸苷掺入 培养的人肺成纤维细胞，这种增殖作用是 被 PDGF 抑制性抗体阻断。这个数据是一致的 PDGF/PDGF 受体途径在 该疾病的发病机制。我们希望这项临床研究能够 提供对基本细胞、分子和生化的深入了解 负责启动和延续这一机制的机制 暴露于环境的患者的纤维增殖反应 肺毒素，并将为第二项旨在新颖的研究奠定基础 纤维增生性肺的治疗和预防策略 疾病。