Huang Qiong, Li Chen Duo, Yang Yi Ran, Qin Xiao Feng, Wang Jing Jing, Zhang Xin, Du Xiao Nan, Yang Xia, Wang Ying, Li Lun, Mu Mi, Lv Zhe, Cui Ye, Huang Kewu, Corrigan Chris J, Wang Wei, Ying Sun
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Laboratory Animal Sciences, Capital Medical University, Beijing, China.
Thorax. 2021 Feb 15. doi: 10.1136/thoraxjnl-2020-214712.
Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.
To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.
C57BL/6, BALB/c and mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=58, CS-exposed=612). 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.
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 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.
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.
目前对慢性阻塞性肺疾病（COPD）气道重塑和阻塞发病机制的无知，使有效治疗和潜在预防措施受到困扰。
探讨白细胞介素-33（IL-33）/ST2轴在香烟烟雾（CS）暴露诱导的气道重塑中的作用。
将暴露于CS的C57BL/6、BALB/c和 小鼠用于建立COPD动物模型（空气暴露组=58只，CS暴露组=612只）。检测小鼠的重塑特征。测量香烟烟雾提取物（CSE）在抗白细胞介素-33（抗IL-33）或人ST2抗体存在下体外诱导成纤维细胞增殖和蛋白质产生的情况。分别检测慢性阻塞性肺疾病患者和对照组支气管肺泡灌洗液（BALF）（对照组=20例，COPD组=20例）、血清（对照组=59例，COPD组=90例）和肺组织切片（对照组=11例，COPD组=7例）中IL-33和ST2的表达以及其他重塑特征。
暴露于CS的野生型小鼠肺部以及心脏、脾脏和肾脏中组织重塑特征的表达升高，而在 小鼠中这些特征明显减轻。与对照组相比，暴露于CSE的成纤维细胞表现出IL-33早期细胞易位，伴有增殖和蛋白质合成增加，所有这些均可被IL-33/ST2信号通路阻断所抑制。COPD患者的BALF、血清和组织样本中IL-33和ST2的表达以及组织重塑特征均显著且成比例升高。
暴露于CS会诱导多个器官发生重塑变化。数据支持以下假设：CS诱导的肺胶原沉积至少部分是CS诱导的IL-33从局部成纤维细胞易位和释放的结果。
