Gao Fei, Liu Xing, Shen Ziying, Jia Xiaohui, He Han, Gao Jing, Wu Jianhong, Jiang Chunhong, Zhou Hu, Wang Yiping
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, China.
Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, China.
Front Physiol. 2018 Aug 17;9:939. doi: 10.3389/fphys.2018.00939. eCollection 2018.
Andrographolide sulfonate (Andro-S), a sulfonation derivative of andrographolide, is known to be effective in treating inflammation-related diseases, while the underlying mechanisms and global protein alterations in response to Andro-S remain unknown. This study aimed to investigate the pharmacological effects and potential targets of Andro-S in a murine model of acute lung injury (ALI). ALI was induced by aerosolized lipopolysaccharide (LPS) exposure before treatment with Andro-S. Inflammatory state of each treatment group was determined by histological analysis and quantification of inflammatory markers. Differentially expressed proteins in lung tissues were identified by an iTRAQ-based quantitative proteomic approach and further confirmed by immunohistochemistry analysis. Administration of Andro-S alleviated LPS-induced histological changes in the lung and reduced the expression of inflammatory markers in serum, bronchoalveolar fluid and lung tissues. Proteomic analysis identified 31 differentially expressed proteins from a total of 2,234 quantified proteins in the lung. According to bioinformatics analysis, neutrophil elastase (ELANE), cathepsin G (CTSG) and myeloperoxidase (MPO), three neutrophil-derived proteases related to immune system process and defense responses to fungi were chosen as potential targets of Andro-S. Further immunohistochemistry analysis confirmed the inhibitory effects of Andro-S on LPS-induced ELANE, CTSG and MPO up-regulation. These results indicate that Andro-S suppressed the severity of LPS-induced ALI, possibly by attenuating the expression of and neutrophil-derived proteases.
穿心莲内酯磺化物（Andro-S）是穿心莲内酯的磺化衍生物，已知其在治疗炎症相关疾病方面有效，但其潜在机制以及对Andro-S应答时的整体蛋白质变化仍不清楚。本研究旨在探讨Andro-S在急性肺损伤（ALI）小鼠模型中的药理作用和潜在靶点。在用Andro-S治疗前，通过雾化暴露脂多糖（LPS）诱导ALI。通过组织学分析和炎症标志物定量来确定每个治疗组的炎症状态。通过基于iTRAQ的定量蛋白质组学方法鉴定肺组织中差异表达的蛋白质，并通过免疫组织化学分析进一步确认。给予Andro-S可减轻LPS诱导的肺组织学变化，并降低血清、支气管肺泡灌洗液和肺组织中炎症标志物的表达。蛋白质组学分析从肺中总共2234种定量蛋白质中鉴定出31种差异表达的蛋白质。根据生物信息学分析，选择与免疫系统过程和对真菌的防御反应相关的三种中性粒细胞衍生蛋白酶，即中性粒细胞弹性蛋白酶（ELANE）、组织蛋白酶G（CTSG）和髓过氧化物酶（MPO）作为Andro-S的潜在靶点。进一步的免疫组织化学分析证实了Andro-S对LPS诱导的ELANE、CTSG和MPO上调的抑制作用。这些结果表明，Andro-S可能通过减弱中性粒细胞衍生蛋白酶的表达来抑制LPS诱导的ALI的严重程度。
