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Original research
Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease
  1. Qiong Huang1,
  2. Chen Duo Li1,
  3. Yi Ran Yang1,
  4. Xiao Feng Qin1,
  5. Jing Jing Wang2,
  6. Xin Zhang1,
  7. Xiao Nan Du1,
  8. Xia Yang3,
  9. Ying Wang4,
  10. Lun Li5,
  11. Mi Mu6,
  12. Zhe Lv1,
  13. Ye Cui1,
  14. Kewu Huang4,
  15. Chris J Corrigan7,
  16. Wei Wang1,
  17. Sun Ying1
  1. 1Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
  2. 2Department of Laboratory Animal Sciences, Capital Medical University, Beijing, China
  3. 3Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
  4. 4Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
  5. 5Department of Respiratory Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  6. 6Department of Respiratory Medicine, the Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
  7. 7Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, UK
  1. Correspondence to Dr Sun Ying, School of Basic Medical Sciences, Department of Immunology, Capital Medical University, Beijing 100069, China; ying.sun{at}


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.

  • COPD àü mechanisms
  • COPD pathology
  • cytokine biology

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  • Contributors QH participated in the design of the study, data acquisition, statistical analysis and drafting of the manuscript. CDL, YRY, XFQ, XZ and XND participated in acquisition of the data. JJW bred the IL-1RL1-/- mice. XY, YW, LL, MM and KH participated in collecting clinic samples from healthy controls and patients with COPD. ZL and YC participated in the design of the study. CJC, WW and SY participated in the design of the study, reviewed and edited the manuscript. All authors read and approved the final manuscript.

  • Funding We acknowledge financial support from the National Natural Science Foundation of China (81770049, 81700026, 81971510, 81974050, 82090013), the Natural Science Foundation of Beijing Municipality (7192023) and the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (IDHT20190510).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was monitored and approved by the Institutional Animal Care and Use Committee of the Capital Medical University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data used to support the findings of the current study are available from the corresponding authors upon request. Corresponding author, Professor Sun YingE-mail:; Phone (Office): (+86)10-83911743.

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