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）是一种破坏性疾病，5年生存率低于50%。虽然类固醇和其他免疫抑制剂作为IPF的标准治疗，但这些药物已被证明是不够的，并具有不良副作用。最近的研究已经确定肝细胞生长因子（HGF）作为一种抗纤维化剂，在几种动物模型中保护肝脏和肺纤维化。HGF特异性刺激支气管上皮细胞生长而不诱导成纤维细胞复制的观察结果表明，基于HGF的疗法在治疗肺纤维化中可能更有效。为了克服蛋白质治疗的缺点和费用，我们开发了一种通过噬菌体展示和分子模拟技术的新组合来合理设计的HGF活性的小分子模拟物。在体外，我们的主要HGF模拟物Refanalin激活HGF受体c-Met，并诱导其生物学功能，包括激活内皮和支气管上皮细胞增殖，抑制胶原mRNA合成和体内肝纤维化。最近的研究表明，Refanalin在体外通过诱导细胞表面纤溶酶的产生来增加纤溶潜力，并在体内降低博莱霉素诱导的肺纤维化中的胶原含量。定量组织学评价表明，与溶剂处理组相比，Refanalin处理的肺切片具有减少的间质纤维化、肺泡凋亡和受损组织。本研究将进一步评价Refanalin对肺纤维化动物模型的肺保护作用，探讨Refanalin诱导抗纤维化途径的可能机制，以及其在减轻肺纤维化中的纤溶作用。我们研究的目标是开发一种新的治疗策略来抑制组织纤维化的进展。这些研究有望提供有关Refanalin作为治疗肺纤维化的新治疗方法的可行性和有效性的基本临床前信息。