期刊
RESPIROLOGY
卷 20, 期 5, 页码 730-738出版社
WILEY
DOI: 10.1111/resp.12546
关键词
asthma; fibrosis; IL-25; murine model; pathogenesis
资金
- National Natural Science Foundation of China [81102250, 81170039, 81270153, 81373177]
- Science and Technology Project of the Beijing Municipal Education Commission [KM201410025006]
- PhD Programs Foundation of Ministry of Education of China [20091107110006, 20101107110003]
- Key Projects in the National Science and Technology Pillar Program during the Twelfth Five-year Plan Period [2012BAI05B01, 2012BAI05B02, 2013BAI06B02]
- Capital Special Research Program for Health Development [Shou-Fa 2011-1004-01]
- DANA Foundation
- Asthma UK
- Friends of Guy's Hospital, London, UK
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- Medical Research Council [G1000758B, G1000758] Funding Source: researchfish
Background and objectiveInterleukin (IL)-25 has been implicated in the pathogenesis of human asthma by inducing a Th2 cytokine response, but its possible role in the development of airway remodelling is less clear. MethodsWe developed a murine surrogate of chronic airway inflammation induced by intranasal application of IL-25 alone. Comparison was with the classical' surrogate of ovalbumin (OVA) intranasal instillation into previously sensitized animals. Airway fibrotic biomarkers were analysed by immunohistochemistry and enzyme-linked immunosorbent assay. Additionally, proliferation assay and real-time polymerase chain reaction analysis were performed to assess IL-25's effects on primary human bronchial fibroblasts in vitro. ResultsIn Balb/c mice, intranasal instillation of IL-25 alone induced florid airway fibrosis, including increased lay down of extracellular matrix proteins such as collagen I, III, V and fibronectin, increased numbers of fibroblasts/myofibroblasts, a profibrotic imbalance in matrix metalloproteinase/tissue inhibitor of metalloproteinase production and increased expression of profibrotic mediators including connective tissue growth factor and transforming growth factor-1. These changes broadly reproduced those seen with classical intranasal OVA challenge in OVA-sensitized animals. Furthermore, IL-25 induced proliferation and expression of collagen I and III and smooth muscle -actin in primary human lung fibroblasts. ConclusionsWe conclude that chronic exposure of the airways to IL-25 alone is sufficient to cause functionally relevant airway remodelling, with the corollary that targeting of IL-25 may attenuate bronchial remodelling and fibrosis in human asthmatics. We developed a murine surrogate of chronic airway inflammation induced by intranasal application of interleukin 25 (IL-25) and found that IL-25 alone is sufficient to cause functionally relevant airway remodelling.
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