- Title
- Airway Epithelial ITGB4 Deficiency Induces Airway Remodeling in a Mouse Model
- Creator
- Yuan, Lin; Liu, Huijun; Xiang, Yang; Qu, Xiangping; Qin, Xiaoqun; Yang, Ming; Liu, Chi; Du, Xizi; Yao, Ye; Qin, Ling; Xia, Zhenkun; Zhou, Kai; Wu, Xinyu; Yuan, Yunchang; Qing, Bei
- Relation
- Journal of Allergy and Clinical Immunology Vol. 151, Issue 2, p. 431-446.e16
- Publisher Link
- http://dx.doi.org/10.1016/j.jaci.2022.09.032
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2023
- Description
- Background: Airway epithelial cells (AECs) with impaired barrier function contribute to airway remodeling through the activation of epithelial-mesenchymal trophic units (EMTUs). Although the decreased expression of ITGB4 in AECs is implicated in the pathogenesis of asthma, how ITGB4 deficiency impacts airway remodeling remains obscure. Objective: This study aims to determine the effect of epithelial ITGB4 deficiency on the barrier function of AECs, asthma susceptibility, airway remodeling, and EMTU activation. Methods: AEC-specific ITGB4 conditional knockout mice (ITGB4−/−) were generated and an asthma model was employed by the sensitization and challenge of house dust mite (HDM). EMTU activation-related growth factors were examined in ITGB4-silenced primary human bronchial epithelial cells of healthy subjects after HDM stimulation. Dexamethasone, the inhibitors of JNK phosphorylation or FGF2 were administered for the identification of the molecular mechanisms of airway remodeling in HDM-exposed ITGB4−/− mice. Results: ITGB4 deficiency in AECs enhanced asthma susceptibility and airway remodeling by disrupting airway epithelial barrier function. Aggravated airway remodeling in HDM-exposed ITGB4−/− mice was induced through the enhanced activation of EMTU mediated by Src homology domain 2–containing protein tyrosine phosphatase 2/c-Jun N-terminal kinase/Jun N-terminal kinase–dependent transcription factor/FGF2 (SHP2/JNK/c-Jun/FGF2) signaling pathway, which was partially independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling and EMTU activation in HDM-exposed ITGB4−/− mice. Conclusions: Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model of asthma through enhanced EMTU activation that is regulated by the SHP2/JNK/c-Jun/FGF2 pathway.
- Subject
- Integrin β4; airway epithelium; asthma; airway remodeling; epithelial-mesenchymal trophic unit; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1480977
- Identifier
- uon:50606
- Identifier
- ISSN:0091-6749
- Language
- eng
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