Liao Wupeng, Lim Albert Y H, Tan W S Daniel, Abisheganaden John, Wong W S Fred
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore.
Br J Pharmacol. 2020 Aug;177(16):3662-3673. doi: 10.1111/bph.15080. Epub 2020 Jun 1.
Corticosteroid resistance poses a major barrier to an effective anti-inflammatory therapy for chronic obstructive pulmonary disease (COPD). The present study aimed to investigate potential corticosteroid re-sensitization actions of andrographolide, a bioactive molecule from the herb Andrographis paniculata, in COPD models, particularly in peripheral blood mononuclear cells (PBMCs) from COPD patients.
Corticosteroid sensitivity in PBMCs collected from COPD patients, or in human monocytic U937 cells exposed to cigarette smoke extract (CSE), was determined by measuring LPS-induced IL-8 production, in the presence and absence of andrographolide. The mechanisms of corticosteroid re-sensitization action of andrographolide were evaluated in a mouse cigarette smoke (CS)-induced acute lung injury model.
Impaired inhibition of IL-8 production by dexamethasone was detected in PBMCs from COPD patients and in CSE-exposed U937 cells, together with reduced levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and histone deacetylase-2 (HDAC2). In both PBMCs and CSE-exposed U937 cells, andrographolide restored dexamethasone inhibition of IL-8 production, accompanied by the up-regulation of Nrf2 and HDAC2 levels. In the U937 cells, andrographolide was able to block CSE-induced Akt and reduce the level of c-Jun. Besides, andrographolide also augmented dexamethasone actions on lowering total and neutrophil counts, cytokine levels, and oxidative damage markers in bronchoalveolar lavage fluid from CS-exposed mice.
We report here for the first time a novel corticosteroid re-sensitization property of andrographolide in human PBMCs and provide mechanistic evidence to support clinical evaluation of andrographolide in reversing steroid resistance in COPD.
皮质类固醇抵抗是慢性阻塞性肺疾病（COPD）有效抗炎治疗的主要障碍。本研究旨在探讨穿心莲内酯（一种来自穿心莲的生物活性分子）在COPD模型中，特别是在COPD患者外周血单核细胞（PBMC）中的潜在皮质类固醇再敏化作用。
通过测量脂多糖（LPS）诱导的白细胞介素-8（IL-8）产生，在有或没有穿心莲内酯的情况下，测定从COPD患者收集的PBMC或暴露于香烟烟雾提取物（CSE）的人单核细胞U937细胞中的皮质类固醇敏感性。在小鼠香烟烟雾（CS）诱导的急性肺损伤模型中评估穿心莲内酯的皮质类固醇再敏化作用机制。
在COPD患者的PBMC和暴露于CSE的U937细胞中检测到地塞米松对IL-8产生的抑制作用受损，同时核因子红细胞2相关因子2（Nrf2）和组蛋白脱乙酰酶-2（HDAC2）水平降低。在PBMC和暴露于CSE的U937细胞中，穿心莲内酯恢复了地塞米松对IL-8产生的抑制作用，同时伴随着Nrf2和HDAC2水平的上调。在U937细胞中，穿心莲内酯能够阻断CSE诱导的Akt并降低c-Jun水平。此外，穿心莲内酯还增强了地塞米松对降低CS暴露小鼠支气管肺泡灌洗液中总细胞数和中性粒细胞计数、细胞因子水平以及氧化损伤标志物的作用。
我们首次报道了穿心莲内酯在人PBMC中的一种新的皮质类固醇再敏化特性，并提供了机制证据来支持穿心莲内酯在逆转COPD中类固醇抵抗方面的临床评估。
