Eicosanoids and Lung Function

我们正在调查二十烷类化合物在 调节血小板衍生生长因子受体的表达 (PDGF-R)在培养的人肺成纤维细胞中表达。我们已经证明了 早期传代人肺成纤维细胞分离株组成性表达 PDGF-R，并在PDGF-AA刺激下大量增殖 只与PDGF-R结合。重要的是，环氧合酶衍生 二十烷类前列腺素E_2显著减弱结构性PDGF-R活性 和PDGF刺激的~3H-胸腺嘧啶核苷掺入 细胞。PGE2的作用发生在低至50 nM的浓度下， 是剂量依赖的，最多发生在PGE2之后的24小时 加法。用几种不同的方法得到了相同的结果 原代培养人肺间充质细胞系的建立 实验室从组织学上正常的肺组织中提取的数据表明 观察到的现象不是细胞系特有的。这些发现是 尤其重要的是，鉴于PGE2对 间充质细胞的增殖和根据最近的发现 从特发性肺病患者体内分离的成纤维细胞 纤维化降低了合成PGE2的能力。当前 努力的重点是描述信号机制 前列腺素E_2可调节肺组织中PDGF-R的表达 体外培养成纤维细胞。在相关的临床研究中，我们正在调查 PDGF受体在纤维增生性疾病发病机制中的作用 癌症患者在接受治疗后发生的肺部疾病 大剂量化疗。我们正在收集支气管肺泡灌洗液 术前和术后患者的体液和经支气管镜活检标本 化疗后血小板衍生生长因子受体变化的研究 表达、调节和功能。初步结果表明， 化疗后BAL液对小鼠胸腺嘧啶核苷掺入的影响 培养的人肺成纤维细胞，这种增殖效应 被PDGF的抑制性抗体阻断。这个数据是一致的 与PDGF/PDGF受体通路在血管内皮细胞生长中的作用 疾病的发病机制。我们希望这项临床研究将 深入了解基本的细胞、分子和生物化学 负责启动和保持 暴露于环境中的患者的纤维增殖反应 肺毒素，并将为第二次研究奠定基础，旨在 纤维增生性肺的治疗和预防策略 疾病。

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.