基于抗原递呈活化肺巨噬细胞通路探讨温散酊治疗PAP作用机制

肺泡蛋白沉积症（PAP）属呼吸系统疑难罕见疾病，目前现代医学尚无有效药物和治疗方法维持患者的生活质量和提高生存率，探寻新的治疗方法和手段是目前急需解决的问题。申请人前期依据“肺主皮毛”和“经络背俞穴”的理论，自制温散酊结合经皮给药技术（TTS）治疗PAP，发现能够改善患者低氧状态，提高活动耐力，推测此治疗方案的疗效机制可能通过TTS给药系统使药物首先激活皮肤表面的树突状细胞，进而改善肺部巨噬细胞活性和表面活性物质肺泡内聚集，即通过朗格汉斯细胞参与抗原递呈激发肺的免疫反应，激活GM-CSF/PU.1/PPARg通路。本项目拟通过体内外细胞与动物实验模型，探讨温散酊通过TTS给药系统调节皮肤-肺的免疫反应，改善PAP发病及病变演化的作用机理，结合临床试验指标，运用免疫组学和基因组学技术阐释此治疗方案干预PAP的效应靶点及作用机制，发现并证实新的有效治疗PAP的方法，为日后临床应用提供实验依据。

Pulmonary alveolar proteinosis (PAP) is one of rare pulmonary diseases. Nowadays, there are no effective drugs and treatment methods in conventional medicine to maintain the quality of life and improve survival of PAP patients. According to Chinese Medicine theory of "lung dominating fur" and "beishu point of meridians ", the applicant has made Wensan tincture combined with TTS to treat PAP patients. It was found that the tincture could improve the patients' hypoxic state and activity endurance. Thus we speculate the underline mechanism of this novel treatment is that the drug first activate the dendritic cells on the skin through TTS administration system, so as to improve the lung macrophage function and reduce surfactant accumulation inside the alveoli. Our hypothesis is through Langerhans cells participating in antigen presentation to stimulate the immune response of the lung and activate the GM-CSF/Pu.1/PPARg pathway. We intend to explore the mechanism of Wensan tincture in regulating skin-lung immune response through in vivo and in vitro cell and animal experimental models, improving the pathogenesis and pathological progression of PAP. We will further explore the specific target and mechanism of this treatment scheme in intervening PAP using immunohistochemistry and genomics technology integrated with clinical biomarkers. We aim to find a novel and effective approach for PAP with experimental evidence for future clinical application.