Jin Hualiang, Cai Cui, Li Bei, Jin Weizhong, Xia Junbo, Wang Limin, Ma Shenglin
Department of Respiratory Diseases, Affiliated Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
Department of Respiratory Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Pharmacol. 2019 Feb 27;10:161. doi: 10.3389/fphar.2019.00161. eCollection 2019.
Modified Si-Jun-Zi-Tang (MSJZT), a multi-herb formulation, is frequently used in traditional Chinese medicine for patients during the remission stage of asthma. However, the pharmacological basis underlying the effects of MSJZT on asthma has yet to be elucidated. This study aims at evaluating the anti-asthmatic effects of MSJZT and investigating its possible mechanism. A chronic murine model of asthma was established by sensitization and repeated challenge with ovalbumin (OVA) in female BALB/c mice, followed with oral administration of MSJZT during remission, and then mouse were re-challenged by OVA. The chemical profile of MSJZT was analyzed by high-performance liquid chromatography. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokine levels (IL-4, -5, -13, -17, and INF-γ), T regulatory (Treg) lymphocytes (Foxp3+CD4+CD25+), and T effector (Teff) lymphocytes (Foxp3-CD25+CD4+) in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling pathway were examined. MSJZT markedly suppressed airway hyper-responsiveness to aerosolized methacholine, and reduced levels of IL-4, IL-5, and IL-13 in the BALF. Histological studies showed that MSJZT significantly reduced inflammatory infiltration in lung tissues. The percentage and absolute number of Teff cells were suppressed to a remarkable level by MSJZT without affecting Treg cells. Furthermore, MSJZT effectively inhibited the mTORC1 activity, but exerted limited effects on mTORC2, as assessed by the phosphorylation of the mTORC1 and mTORC2 substrates, S6 ribosomal protein, p70 S6 kinase, mTOR S2481, and Akt, respectively. MSJZT attenuated chronic airway inflammation in a mouse model of asthma by inhibiting Teff cells, which occurred, at least in part, via modulation of the mTORC1 signaling pathway.
加味四君子汤（MSJZT）是一种多草药配方，在中医中常用于哮喘缓解期的患者。然而，MSJZT治疗哮喘作用的药理学基础尚未阐明。本研究旨在评估MSJZT的抗哮喘作用并探讨其可能的机制。通过用卵清蛋白（OVA）对雌性BALB/c小鼠进行致敏和反复激发建立慢性哮喘小鼠模型，在缓解期口服MSJZT，然后再次用OVA激发小鼠。采用高效液相色谱法分析MSJZT的化学特征。检测过敏性哮喘的特征，包括气道高反应性、组织病理学、细胞因子水平（IL-4、-5、-13、-17和INF-γ）、支气管肺泡灌洗液（BALF）中的调节性T（Treg）淋巴细胞（Foxp3+CD4+CD25+）和效应性T（Teff）淋巴细胞（Foxp3-CD25+CD4+），以及mTORC1/2信号通路的下游蛋白。MSJZT显著抑制对雾化乙酰甲胆碱的气道高反应性，并降低BALF中IL-4、IL-5和IL-13的水平。组织学研究表明，MSJZT显著减少肺组织中的炎症浸润。MSJZT将Teff细胞的百分比和绝对数量抑制到显著水平，而不影响Treg细胞。此外，通过分别检测mTORC1和mTORC2底物S6核糖体蛋白、p70 S6激酶、mTOR S2481和Akt的磷酸化来评估，MSJZT有效抑制mTORC1活性，但对mTORC2的作用有限。MSJZT通过抑制Teff细胞减轻哮喘小鼠模型中的慢性气道炎症，这至少部分是通过调节mTORC1信号通路实现的。
