【作者】 吕晓希；

【导师】 胡卓伟；

【作者基本信息】 北京协和医学院 ， 药理学， 2011， 博士

【摘要】 肺纤维化是一种慢性炎性肺疾病,其最主要组织病理学特征为间质性肺炎。肺纤维化的患病率随着年龄增长逐渐增加,其确诊五年后的生存率不到30%,且临床并无十分有效的治疗策略,目前使用的抗纤维化药物效果也差强人意。因此发现新型的抗肺纤维化药物迫在眉睫。在肺纤维化的发病过程中,机体免疫起着重要的调节作用。在重度肺纤维化期,肺部组织是以Th2型免疫反应为主的抑制性免疫微环境,伴有低度的Th1型刺激性免疫反应。此时的治疗策略应为打破这用Th2型免疫反应外加Treg参与介导的免疫抑制,同时保留部分Th1型免疫反应进行组织修复和免疫刺激。这也是为什么临床使用抗炎药物对抗纤维化效果不明显的原因。机体的过敏同样是由免疫反应和过敏细胞参与介导发生的,Th2型免疫反应此时也介导了过敏的产生,而Th1型免疫则不能引起过敏症状,起到一种保护作用。肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞活化都能介导免疫抑制或Th2型免疫反应,同时也与肺纤维化有着种种联系。因此我们认为应用一种安全有效的抗过敏药物能够逆转肺纤维化时的抑制性免疫微环境并达到抗纤维化效果。本文首先在综述中介绍了肺纤维化这种疾病的基本概况、发病机理、临床诊断原则、临床处置原则和目前用作抗纤维化治疗的药物以及正在进行临床试验的抗纤维化药物。还系统介绍了过敏性疾病与纤维化的联系,包括过敏性哮喘与纤维化,嗜酸性粒细胞、嗜碱性粒细胞、肥大细胞与纤维化的关系。实验选择的候选药物卢帕他定是2003年上市的第二代组胺H1受体抑制剂,并具有PAF受体抑制作用,其被证明可以抑制肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞脱颗粒,同时具有良好的抗炎作用。实验采用了博莱霉素所致小鼠肺纤维化模型和SiO2所致大鼠矽肺模型对卢帕他定的抗纤维化作用进行评价,并使用吡菲尼酮作为对照药物。此外我们还比较了卢帕他定与H1受体抑制剂氯雷他定和PAF受体抑制剂CV-3988的抗纤维化作用。实验结果显示,卢帕他定能提高博莱霉素所致肺纤维化小鼠生存率,降低肺部胶原沉积,减少上皮间充质转化的发生,逆转肺纤维化。同时证明其能有效控制肺部炎症,抑制炎性细胞和多种炎性细胞因子浸润,但同时保留Th1型细胞因子的表达。卢帕他定还可调节多种核因子的表达,达到打破免疫抑制的作用,此外还能将巨噬细胞M2极化方向逆转为M1极化方向。并且实验证明卢帕他定的抗纤维化效果优于氯雷他定和CV-3988。在大鼠矽肺模型上我们也取得了良好的卢帕他定抗纤维化终点。因此得出结论,卢帕他定是一种安全有效地,通过调节机体免疫反应抗纤维化的药物。这对临床治疗有着重要的提示意义。更多还原

【Abstract】 Pulmonary fibrosis is a chronic inflammatory lung disease that is characterized histopathologically by the presence of usual interstitial pneumonia. The prevalence rate of pulmonary fibrosis increased with age, and it has a Five-Year survival rate under 30% after diagnosis. There are no effective therapeutic strategies to this disease till now. The approach in the medical treatment of pulmonary fibrosis is merely adequate, so the discovery of anti-fibrosis drug is extremely urgent. The immune regulation plays an important role in the development of pulmonary fibrosis, and there is a Th2-dominant microenvironment in the advanced stage of this disease with limited Thl-type immune responses which has stimulant and protective effect. In our opinion the strategy to treat pulmonary fibrosis is breaking the immune suppress induced by Th2-type immune responses and more importantly is reserving moderate Thl-type immune responses. This theory also illustrated why the anti-inflammation drug has less effect on pulmonary fibrosis. Allergic diseases also were regulated by the immune response and allergic cells. It has been confirmed that Th2-type immune responses created by mast cell, eosinophil and basophil, can participate the development of allergy by inducing immune suppress, however, Thl-type immune responses can down regulate the immune suppress. Due to these phenomena and the allergic cells have closely associated with pulmonary fibrosis, we gave a hypothesis that using an anti-allergy drug can attenuate pulmonary fibrosis by regulation of the immune responses. In the first review, we summarize the general overview of pulmonary fibrosis include of pathogenesis, diagnosis principle, treatment and the medicine used to treat this disease in clinic as well as in clinical trials. In second review, we summarize the relationship between allergy and fibrosis include of asthma and fibrosis, the role of eosinophil, basophil and mast cell in pulmonary fibrosis. Based on previous theory, we chose Rupatadine as candidate drug to treat pulmonary fibrosis, it is a new generation dual inhibitor of H1 and PAF receptors used to treat allergies, which had been discovered by Uriach and launched in 2003 in Span. Previous pharmacology studies have shown that, Rupatadine can inhibit the degranulation of mast cells and the release of biochemical mediators from allergic cells. We used bleomycin-induced mice pulmonary fibrosis model and SiO2 induced silicosis model to test the hypothesis that Rupatadine may attenuate this chronic lung disease through its immune modulation property. Meanwhile, we compared the anti-fibrosis effects of Rupatadine with Histamine H1 receptor antagonist loratadine and PAF receptor antagonist CV-3988 at same dosage. Our results demonstrated that treatment with Rupatadine attenuated bleomycin-induced pulmonary fibrosis, reduced the mortality of fibrosis mouse, ameliorated the inflammatory responses, reversed the immunosuppressive Th2-dominant microenvironment, reserved a moderate Thl-type immune response in fibrosis mice and inhibited Epithelial-mesenchymal transition after bleomycin-instilled, in addition, rupatadine can reverse the M2 polarization to M1 after bleomycin injured. We found that single usage of Loratadine or CV-3988 had fewer effects of anti-inflammation and anti-fibrosis compared with rupatadine. We also demonstrated the anti-fibrosis effect of rupatadine on SiO2 induced silicosis model. So we have the conclusion that, rupatadine is a useful drug against pulmonary fibrosis with good safety. It can attenuate fibrosis through its immune regulation effect and this finding provides directive significance for clinical therapy.更多还原