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. 2024 Oct;181(19):3700-3716.
doi: 10.1111/bph.16423. Epub 2024 Jun 9.

Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma

Ling Qin  1   2 , Ye Yao  1 , Weijie Wang  3 , Qingwu Qin  4 , Jingjing Liu  1 , Huijun Liu  3 , Lin Yuan  3 , Yunchang Yuan  5 , Xizi Du  3 , Bingrong Zhao  1 , Xinyu Wu  3 , Bei Qing  5 , Leng Huang  1 , Gang Wang  6 , Yang Xiang  3 , Xiangping Qu  3 , Xuewei Zhang  7 , Ming Yang  8 , Zhenkun Xia  5 , Chi Liu  1   2   3
Affiliations

Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma

Ling Qin et al. Br J Pharmacol. 2024 Oct.

Abstract

Background and purpose: Airway epithelial cells (AECs) regulate the activation of epithelial-mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure.

Experimental approach: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma.

Key results: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling.

Conclusion and implications: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.

Keywords: airway epithelial cell; airway remodelling; cathepsin K; epithelial–mesenchymal trophic unit.

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