中性粒细胞胞外诱捕网的阻断可改善甲苯二异氰酸酯诱导的激素抵抗性哮喘。
Blockade of neutrophil extracellular traps ameliorates toluene diisocyanate-induced steroid-resistant asthma.
作者信息
Peng Xianru, Li Yuemao, Zhao Wenqu, Yang Shuluan, Huang Junwen, Chen Ying, Wang Yanhong, Gong Zhaoqian, Chen Xin, Yu Changhui, Cai Shaoxi, Zhao Haijin
机构信息
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
出版信息
Int Immunopharmacol. 2023 Apr;117:109719. doi: 10.1016/j.intimp.2023.109719. Epub 2023 Feb 22.
BACKGROUND AND PURPOSE
Toluene diisocyanate (TDI)-induced asthma is characterized by mixed inflammation dominated by neutrophils, and is refractory to steroid treatment. Neutrophil extracellular traps (NETs) play an important role in severe asthma, but their role in TDI-induced asthma models is unclear. This study focused on the role and mechanism of NETs in steroid-resistant TDI-induced asthma.
METHODS
Induced sputum was collected from 85 asthmatic patients and 25 healthy controls to detect eDNA. A murine TDI-induced asthma model was prepared, and asthmatic mice were given dexamethasone or DNase I. In vitro, the human bronchial epithelial cell line HBE was stimulated with NETs or TDI-human serum albumin (TDI-HSA).
RESULTS
Asthma patients had higher sputum eDNA compared to healthy subjects. In asthma patients, eDNA was positively correlated with sputum neutrophils, and negatively correlated with FEV1%predicted. Airway inflammation, airway reactivity, Th2 cytokine levels in lymph supernatant, and levels of NETs were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by DNase I, but not by dexamethasone. Inhibition of NETs improved interleukin (IL)-8 and MKP1 mRNA expression, and reduced phosphorylation of GR-S226 induced by TDI. Inhibition of NETs improved airway epithelial barrier disruption, as well as p38 and ERK signaling pathways in TDI-induced asthmatic mice. In vitro, NETs promoted the expression of IL-8 mRNA in HBE cells, and reduced the expression of MKP1. IL-8 elevation induced by NETs was suppressed by a p38 inhibitor or ERK inhibitor, but not by dexamethasone. Pretreatment with RAGE inhibitor reduced NETs induced p38/ERK phosphorylation and IL-8 levels in HBE cells.
CONCLUSION
Our data suggest that targeting NETs might effectively improved TDI-induced airway inflammation and airway epithelial barrier function. This may potentially be a treatment for patients with steroid-resistance asthma.
背景与目的
甲苯二异氰酸酯（TDI）诱发的哮喘以中性粒细胞为主导的混合性炎症为特征，且对类固醇治疗具有抗性。中性粒细胞胞外陷阱（NETs）在重度哮喘中起重要作用，但其在TDI诱发的哮喘模型中的作用尚不清楚。本研究聚焦于NETs在类固醇抵抗性TDI诱发哮喘中的作用及机制。
方法
收集85例哮喘患者和25例健康对照者的诱导痰以检测细胞外DNA（eDNA）。制备小鼠TDI诱发的哮喘模型，给哮喘小鼠给予地塞米松或脱氧核糖核酸酶I（DNase I）。在体外，用人支气管上皮细胞系HBE用NETs或TDI-人血清白蛋白（TDI-HSA）刺激。
结果
与健康受试者相比，哮喘患者的痰液eDNA更高。在哮喘患者中，eDNA与痰液中性粒细胞呈正相关，与预测的第一秒用力呼气容积（FEV1）百分比呈负相关。TDI诱发的哮喘小鼠气道炎症、气道反应性、淋巴细胞上清液中Th2细胞因子水平及NETs水平显著升高。这些升高被DNase I抑制，但未被地塞米松抑制。抑制NETs可改善白细胞介素（IL）-8和丝裂原活化蛋白激酶磷酸酶1（MKP1）mRNA表达，并减少TDI诱导的糖皮质激素受体（GR）丝氨酸226（GR-S226）磷酸化。抑制NETs可改善TDI诱发的哮喘小鼠气道上皮屏障破坏以及p38和细胞外信号调节激酶（ERK）信号通路。在体外，NETs促进HBE细胞中IL-8 mRNA表达，并降低MKP1表达。NETs诱导的IL-8升高被p38抑制剂或ERK抑制剂抑制，但未被地塞米松抑制。用晚期糖基化终末产物受体（RAGE）抑制剂预处理可降低NETs诱导的HBE细胞中p38/ERK磷酸化和IL-8水平。
结论
我们的数据表明，靶向NETs可能有效改善TDI诱发的气道炎症和气道上皮屏障功能。这可能是类固醇抵抗性哮喘患者的一种潜在治疗方法。
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