Therapeutic Potential of Refanalin in Pulmonary Fibrosis

Refanalin 在肺纤维化中的治疗潜力

• 批准号: 6833326
• 负责人: LATHA PAKA
• 金额: $ 17.53万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2005-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833326
• 关键词: biomimetics; biotechnology; dosage; drug design /synthesis /production; drug screening /evaluation; hepatocyte growth factor; histology; idiopathic pulmonary fibrosis; intravenous administration; laboratory mouse; nonhuman therapy evaluation; oral administration; phage display; respiratory disorder chemotherapy; respiratory function; small molecule; statistics /biometry; tissue /cell culture; western blottings

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.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种毁灭性疾病，五年生存率小于50％。尽管类固醇和其他免疫抑制剂是IPF的标准治疗方法，但这些药物已证明不足，并且具有不利的副作用。最近的研究已将肝细胞生长因子（HGF）确定为一种抗纤维化剂，可在几种动物模型中预防肝脏和肺纤维化。 HGF在不诱导成纤维细胞复制的情况下特异性刺激支气管上皮细胞的生长的观察结果表明，基于HGF的疗法可能在治疗肺纤维化方面更有效。为了克服蛋白质治疗的缺点和费用，我们开发了一种小分子模拟于HGF活性，该分子是通过噬菌体显示和分子建模技术的新型组合合理设计的。在体外，我们的铅HGF模拟物，黄油素，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，并抑制胶原mRNA MRNA合成和体内肝纤维化。最近的研究表明，红质蛋白通过在体外诱导细胞表面纤溶酶产生，并降低体内博来霉素诱导的肺纤维化中的胶原蛋白含量来增加纤维蛋白水解潜力。定量组织学评估表明，与媒介物处理的组相比，经过重藻蛋白治疗的肺切片减少了间质纤维化，肺泡凋亡和组织受损的组织。在拟议的研究中，我们将进一步评估肺纤维化动物模型对肺中肺的保护作用，并探索诱导抗纤维化途径的潜在机制，以及减少肺纤维化中的纤维蛋白水解潜力。我们研究的目的是制定一种新型的治疗策略来抑制组织纤维化的发展。这些研究承诺，将提供有关黄褐素作为治疗肺纤维化治疗的新治疗方法的基本临床前信息。