Therapeutic Potential of Refanalin in Pulmonary Fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种毁灭性疾病，5年生存率低于50%。虽然类固醇和其他免疫抑制剂是IPF的标准治疗方法，但这些药物已被证明是不充分的，并且有不良副作用。最近的研究发现肝细胞生长因子（HGF）是一种抗纤维化药物，在几种动物模型中可以防止肝和肺纤维化。观察到HGF特异性地刺激支气管上皮细胞的生长而不诱导成纤维细胞复制，这表明基于HGF的疗法在治疗肺纤维化方面可能更有效。为了克服蛋白质治疗的缺点和费用，我们通过噬菌体展示和分子建模技术的新颖结合，合理设计了一种模拟HGF活性的小分子。在体外，我们的主要HGF模拟物reanalin激活HGF受体c-Met，并诱导其生物学功能，包括激活内皮细胞和支气管上皮细胞增殖，抑制胶原mRNA合成和肝纤维化。最近的研究表明，在体外，reanalin通过诱导细胞表面纤溶蛋白生成来增加纤溶电位，并在体内降低博莱霉素诱导的肺纤维化中胶原含量。定量组织学评估显示，与药物治疗组相比，reanalin治疗的肺切片间质纤维化、肺泡凋亡和损伤组织减少。在拟开展的研究中，我们将通过肺纤维化动物模型进一步评估雷伐纳林对肺的保护作用，探索其诱导抗纤维化通路的潜在机制，以及其减少肺纤维化的纤溶潜力。我们的研究目标是开发一种新的治疗策略来抑制组织纤维化的进展。这些研究有望为雷伐那林作为一种治疗肺纤维化的新方法的可行性和有效性提供基础的临床前信息。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival. While steroids and other immunosuppressive agents serve as the standard treatment for IPF, these agents have proved inadequate and have adverse side effects. Recent studies have identified hepatocyte growth factor (HGF) as an antifibrogenic agent that protects against liver and lung fibrosis in several animal models. The observation that HGF specifically stimulates growth of bronchial epithelial cells without inducing fibroblast replication suggests that HGF-based therapies could be more effective in the treatment of pulmonary fibrosis. In order to overcome the shortcomings and expense of protein therapy, we have developed a small molecule mimetic of HGF activity that was rationally designed through a novel combination of phage display and molecular modeling technology. In vitro, our lead HGF mimetic, Refanalin, activates the HGF receptor, c-Met, and induces its biological functions including activation of endothelial and bronchial epithelial cell proliferation, and inhibition of collagen mRNA synthesis and liver fibrosis in vivo. Recent studies suggest that Refanalin increases fibrinolytic potential by inducing cell surface plasmin generation in vitro, and decreases collagen content in bleomycin-induced pulmonary fibrosis in vivo. Quantitative histological evaluation demonstrated that Refanalin-treated lung sections have reduced interstitial fibrosis, alveolar apoptosis, and damaged tissue compared with the vehicle-treated group. In the proposed studies, we will further evaluate the protective effects of Refanalin on lung from pulmonary fibrosis animal models and explore the potential mechanisms involved in inducing anti fibrotic pathways, and the fibrinolytic potential in reducing lung fibrosis. The goal of our research is to develop a novel therapeutic strategy to inhibit the progression of tissue fibrosis. These studies promise to provide fundamental, preclinical information about the feasibility and efficacy of Refanalin as a new therapeutic approach for the treatment of pulmonary fibrosis.