Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease
Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease
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IL-33/ST2轴在香烟烟雾诱导的慢性阻塞性肺疾病气道重塑中的作用
DOI：
10.1136/thoraxjnl-2020-214712
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发表时间：
2021-08-01
期刊：
影响因子：
10
通讯作者：
Ying, Sun
中科院分区：
文献类型：
--
作者：
Huang, Qiong;Li, Chen Duo;Ying, Sun
目前对COPD气道重塑和阻塞的发病机制的认识不足，使有效的治疗和潜在的预防措施受到混淆。目的探讨IL-33/ST 2轴在香烟烟雾（CS）致气道重塑中的作用。方法采用C57 BL/6、BALB/c和IL-1 RL 1-/-小鼠，分别暴露于CS，建立COPD动物模型（空气暴露组5~8只，CS暴露组6~12只）。在小鼠中测量重塑的标志。在存在抗白细胞介素-33（抗IL-33）或hST 2抗体的情况下，测量香烟烟雾提取物（CSE）诱导的成纤维细胞体外增殖和蛋白质产生。分别在COPD患者和对照组的支气管肺泡灌洗液（BALF）（对照组=20，COPD=20）、血清（对照组=59，COPD=90）和肺组织切片（对照组=11，COPD=7）中测量IL-33和ST 2的表达以及其他重塑标志。结果暴露于CS的野生型小鼠在肺以及心脏、脾脏和肾脏中组织重塑标志的表达升高，而在IL-1 RL 1-/-小鼠中组织重塑标志的表达显著消除。与对照组相比，暴露于CSE的成纤维细胞表现出IL-33的早期细胞易位，伴随着增殖和蛋白质合成升高，所有这些都可通过阻断IL-33/ST 2信号传导而抑制。在COPD患者的BALF、血清和组织样本中，IL-33和ST 2的表达以及组织重塑的标志物显著且成比例地升高。结论暴露于CS可引起多器官的重构性改变。这些数据支持CS诱导的肺胶原沉积至少部分是CS诱导的IL-33移位和局部成纤维细胞释放的结果的假设。
Background Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD. Objective To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling. Methods C57BL/6, BALB/c and IL-1RL1 -/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls. Results Wild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1 -/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD. Conclusions Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.