气道上皮过度表达的 cathepsin K 可通过激活哮喘的上皮-间质营养单位诱导气道重塑
2024/07/30
摘要
背景：气道上皮细胞（AECs）通过分泌信号介质，在气道重塑过程中调节上皮-间充质营养单位（EMTUs）的活化。然而，气道重塑的主要触发因素和内在发病机制仍不清楚。
方法：通过RNA测序和信号通路分析，筛选并验证了气道上皮细胞中与气道重塑相关的不同表达基因。然后，在体外和体内鉴定了气道上皮细胞中组织蛋白酶K（CTSK）的增加对气道重塑和EMTU激活的影响，并在EMTU模型中阐明了其分子机制。在不同严重程度的哮喘队列中分析了CTSK作为气道重塑的有效生物标记物的潜力。最后，对哮喘患者气道重塑的潜在治疗干预施用了CTSK抑制剂。
结果：在屋尘螨（HDM）诱导的哮喘模型中，气道上皮细胞中CTSK的表达随着气道重塑的发展而显著增加。气道上皮细胞分泌的CTSK增加通过激活PAR2介导的通路诱导EMTUs活化。阻断 CTSK可抑制EMTU的活化并缓解气道重塑，是气道重塑的有效干预靶点。
结论：气道上皮细胞中CTSK表达的增加通过EMTU激活参与了哮喘气道重塑的发展，而EMTU激活部分是通过PAR2介导的信号通路。CTSK是气道重塑的潜在生物标志物，也可能是哮喘患者气道重塑的有效干预目标。
Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma.
L. Qin, Y. Yao, W. Wang, Q. Qin, J. Liu, H. Liu, et al.
Abstract
BACKGROUND: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.
METHODS: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.
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.
CONCLUSIONS: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.
背景：气道上皮细胞（AECs）通过分泌信号介质，在气道重塑过程中调节上皮-间充质营养单位（EMTUs）的活化。然而，气道重塑的主要触发因素和内在发病机制仍不清楚。
方法：通过RNA测序和信号通路分析，筛选并验证了气道上皮细胞中与气道重塑相关的不同表达基因。然后，在体外和体内鉴定了气道上皮细胞中组织蛋白酶K（CTSK）的增加对气道重塑和EMTU激活的影响，并在EMTU模型中阐明了其分子机制。在不同严重程度的哮喘队列中分析了CTSK作为气道重塑的有效生物标记物的潜力。最后，对哮喘患者气道重塑的潜在治疗干预施用了CTSK抑制剂。
结果：在屋尘螨（HDM）诱导的哮喘模型中，气道上皮细胞中CTSK的表达随着气道重塑的发展而显著增加。气道上皮细胞分泌的CTSK增加通过激活PAR2介导的通路诱导EMTUs活化。阻断 CTSK可抑制EMTU的活化并缓解气道重塑，是气道重塑的有效干预靶点。
结论：气道上皮细胞中CTSK表达的增加通过EMTU激活参与了哮喘气道重塑的发展，而EMTU激活部分是通过PAR2介导的信号通路。CTSK是气道重塑的潜在生物标志物，也可能是哮喘患者气道重塑的有效干预目标。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Br J Pharmacol. 2024 Jun 9. doi: 10.1111/bph.16423.）
（Br J Pharmacol. 2024 Jun 9. doi: 10.1111/bph.16423.）
Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma.
L. Qin, Y. Yao, W. Wang, Q. Qin, J. Liu, H. Liu, et al.
Abstract
BACKGROUND: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.
METHODS: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.
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.
CONCLUSIONS: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.
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高盐饮食对人类和小鼠哮喘的影响：对特定T细胞特征和微生物组的影响
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