背景:肺纤维化(PF)是进行性和终末期的肺部疾病,这也是2019年冠状病毒病(COVID-19)幸存者最常见的后遗症。不幸的是,目前尚无治疗PF的方法。沙神麦冬汤(SMT),中药,已被用于治疗各种肺部疾病,这可能为PF提供潜在的治疗益处。
目的:研究SMT及其主要活性成分的抗纤维化作用及其治疗PF的潜在机制。
方法:首先,我们建立了基于UPLC-MS的定性和定量分析,用于SMT的质量控制。然后,在博来霉素(BLM)诱导的PF小鼠模型中研究了SMT的抗纤维化功效。网络药理学用于预测SMT治疗PF的机制和活性成分。在体外和体内进一步验证。
结果:SMT改善了体重减轻并减弱了羟脯氨酸,炎性细胞因子,BLM诱导的PF小鼠模型中的胶原沉积呈剂量依赖性。机械上,正如网络药理学分析所预测的那样,SMT及其活性化合物(山奈酚,槲皮素,和异鼠李素)调节丝裂原活化蛋白激酶(MAPK)信号通路,TGF-β/Smad信号通路,和YAP/TAZ信号通路,在PF小鼠和TGF-β诱导的A549细胞模型中进一步验证。此外,SMT平衡了PF小鼠模型外周血中CD4+T细胞增加和CD8+T细胞减少的比例。
结论:考虑到纤维化疾病的高死亡率和复杂的发病机制,我们的结果提供了新的证据,表明SMT通过调节MAPK来治疗肺纤维化,TGF-β/Smad,与YAP/TAZ信号通路同时存在。
BACKGROUND: Pulmonary fibrosis (PF) is progressive and terminal lung disease, which is also the most common sequelae of Corona Virus Disease 2019 (COVID-19) survivors. Unfortunately, there is currently no cure for PF. ShaShen-MaiDong decoction (SMT), a traditional Chinese medicine, has been employed in treating various lung diseases, which may offer potential therapeutic benefits for PF.
OBJECTIVE: To investigate the antifibrotic efficacy of SMT and its major active ingredients as well as the underlying mechanisms for treating PF.
METHODS: Fist, we build the UPLC-MS based qualitative and quantitative profiling for the quality control of SMT. Then, the antifibrotic efficacy of SMT was investigated in bleomycin (BLM)-induced PF mice model. Network pharmacology was used to predict the mechanism and active components of SMT for the treatment of PF, which was further verified in vitro and in vivo.
RESULTS: SMT improved the weight loss and attenuated hydroxyproline, inflammatory cytokines, and collagen deposition in BLM-induced PF mice model in a dose-dependent manner. Mechanistically, as predicted by network pharmacology analysis, SMT and its active compounds (kaempferol, quercetin, and isorhamnetin) regulated the mitogen-activated protein kinase (MAPK) signaling pathways, TGF-β/Smad signaling pathway, and YAP/TAZ signaling pathway, which was further verified in the PF mice and TGF-β-induced A549 cell model. Moreover, SMT balanced the proportions of increased CD4+ and decreased CD8+ T cells in the peripheral blood of PF mice model.
CONCLUSIONS: Considering the high mortality and complex pathogenesis of fibrotic diseases, our results provide novel evidence that SMT would be beneficial for pulmonary fibrosis therapy by modulating MAPK, TGF-β/Smad, and YAP/TAZ signaling pathways at same time.