Shao Rui, Wang Fu-Jiang, Lyu Ming, Yang Jian, Zhang Peng, Zhu Yan
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Research and Development Center of Tianjin University of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
Front Pharmacol. 2019 Apr 24;10:412. doi: 10.3389/fphar.2019.00412. eCollection 2019.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options. It also leads to progressive respiratory failure, which subsequently affects the heart functionality, a pathological heart-lung interaction increasingly noticed and defined as pulmonary-heart disease (PHD). Traditional Chinese medicine (TCM) theory for treating "phlegm-stasis cementation syndrome" may suggest a possibility of treating PHD complication with Chinese medicine prescriptions previously used for cardiovascular diseases. Here, we evaluate the efficacies of two compound Chinese medicine prescriptions, Danlou prescription (DLP) and Danhong prescription (DHP), which share a common herbal component, Salvia miltiorrhiza (Danshen), on pulmonary fibrosis. Severity grades of Bleomycin (BLM)-induced pulmonary fibrosis were assessed by micro-Computerized Tomography (μCT) in accordance with the clinical evaluation standard. Lung pathological changes and collagen deposition were investigated by histopathology. Myofibroblast differentiation was assessed by immunohistochemistry of α-SMA and TGF-β receptor type II expression . Network pharmacology analysis of the drug-target interaction in IPF progression for DLP or DHP was performed using Ingenuity Pathways Analysis (IPA) system. We show that a non-invasive μCT effectively monitor and quantify BLM-induced pulmonary fibrosis and its treatment efficacy by Chinese medicine prescription in rodents. In addition, although both containing Salvia miltiorrhiza, DLP but not DHP mitigates BLM-induced lung fibrosis by inhibiting the TGF-β signaling-activated myofibroblast differentiation and α-SMA expression in a mouse model. Core analysis by IPA revealed that DLP ingredients regulated not only pulmonary fibrosis related inflammatory genes but also genes associated with myofibroblast activation and collagen deposition. This study suggests that a clinically efficacious cardiovascular Chinese herbal medicine (DLP) can be successfully repurposed to treat a lung disease in pulmonary fibrosis guided by TCM theory. Our comparative study between DLP and DHP demonstrated a critical requirement of suppressing both pro-inflammatory and pro-fibrotic pathways for the treatment of pulmonary fibrosis, supporting that a multi-component prescription capable of "removing both phlegm and blood stasis" will better achieve co-protection of heart and lung in PHD.
特发性肺纤维化(IPF)是一种治疗选择有限的毁灭性肺部疾病。它还会导致进行性呼吸衰竭,进而影响心脏功能,这种病理上的心肺相互作用越来越受到关注,并被定义为肺心病(PHD)。中医治疗“痰瘀胶结证”的理论可能提示,用先前用于心血管疾病的中药方剂治疗PHD并发症具有一定可能性。在此,我们评估了两种复方中药方剂——丹蒌方(DLP)和丹红方(DHP)对肺纤维化的疗效,这两种方剂都含有共同的草药成分丹参。根据临床评估标准,通过微型计算机断层扫描(μCT)评估博来霉素(BLM)诱导的肺纤维化的严重程度分级。通过组织病理学研究肺部病理变化和胶原沉积。通过α - SMA免疫组织化学和II型转化生长因子-β受体表达评估肌成纤维细胞分化。使用 Ingenuity Pathways Analysis(IPA)系统对DLP或DHP在IPF进展中的药物 - 靶点相互作用进行网络药理学分析。我们发现,一种非侵入性的μCT能够有效监测和量化BLM诱导的肺纤维化及其在啮齿动物中中药方剂的治疗效果。此外,虽然DLP和DHP都含有丹参,但在小鼠模型中,DLP而非DHP通过抑制转化生长因子-β信号激活的肌成纤维细胞分化和α - SMA表达减轻了BLM诱导的肺纤维化。IPA的核心分析表明,DLP成分不仅调节与肺纤维化相关的炎症基因,还调节与肌成纤维细胞活化和胶原沉积相关的基因。这项研究表明,一种临床有效的心血管中药(DLP)可以在中医理论指导下成功地重新用于治疗肺纤维化中的肺部疾病。我们对DLP和DHP的比较研究表明,抑制促炎和促纤维化途径对于治疗肺纤维化至关重要,支持了一种能够“祛痰化瘀”的多成分方剂将更好地实现对PHD中心脏和肺部的共同保护。