线粒体脂肪酸氧化酶CPT1A缺陷导致重度哮喘气道上皮屏障功能障碍
2026/07/31
摘要
背景：线粒体脂肪酸经肉碱棕榈酰转移酶1A（CPT1A）氧化可生成ATP。本研究考察CPT1A在调控哮喘气道上皮细胞通透性及线粒体代谢稳态中的作用。
方法：将健康对照者和重度哮喘（SA）患者的原代鼻上皮细胞（NECs）进行气-液界面（ALI）培养，并分别给予CPT1A小干扰RNA（siRNA）、CPT1A过表达慢病毒或左旋肉碱（LCA）处理。测定跨上皮电阻（TEER）和异硫氰酸荧光素（FITC）-葡聚糖转运。同时研究健康者和SA患者的支气管活检标本，以及屋尘螨（HDM）诱导的哮喘小鼠模型。
结果：在ALI培养的NECs以及SA患者支气管活检来源的支气管上皮细胞（BECs）中，CPT1A表达均低于健康对照。在健康NECs中敲低CPT1A可降低Occludin和E-cadherin表达，并损害上皮屏障完整性（EBI）；而在SA-NECs中采用CPT1A过表达慢病毒或LCA上调CPT1A，可增加上述屏障蛋白表达并改善EBI。在健康BECs中敲低CPT1A可增加线粒体活性氧（mtROS）释放，伴有线粒体结构破坏以及ERK1/2-NF-κB信号通路激活。HDM暴露使上述改变进一步加重；但在CPT1A敲低并暴露于HDM的条件下，N-乙酰半胱氨酸和MitoTempo可降低p-ERK1/2及p-P65活化，并减轻EBI受损。在小鼠模型中，气道上皮CPT1A蛋白表达降低，与气道高反应性和炎症减轻以及Occludin和ZO-1表达降低相关；LCA可部分逆转这些效应，并恢复线粒体完整性和EBI。
结论：CPT1A通过恢复哮喘气道上皮细胞的线粒体功能来维持上皮屏障功能。恢复重度哮喘患者气道上皮中缺失的CPT1A，可能成为一种新的治疗策略。
Deficiency of Mitochondrial Fatty Acid Enzyme, CPT1A, Underlies Airway Epithelial Barrier Dysfunction in Severe Asthma
Muyun Wang, Haiyang Hu, Kun Wang, Di Wu, Ximing Liao, Jing Gao, Tian Li, Wujian Xu, Shaoyong Gao, Qiang Li, Pankaj Kumar Bhavsar, Wei Gao, Kian Fan Chung
Abstract
BACKGROUND:Mitochondrial fatty acid oxidation through carnitine palmitoyltransferase-1A (CPT1A) leads to ATP generation. We examined its role in regulating permeability and mitochondrial metabolic homeostasis of airway epithelial cells in asthma.
METHODS:Primary nasal epithelial cells (NECs) from healthy controls and severe asthma (SA) patients in air-liquid interface (ALI) were exposed to CPT1A siRNA/CPT1A overexpression lentiviral/L-carnitine (LCA). Epithelial TEER and FITC-dextran transport were measured. Bronchial biopsies from healthy and SA subjects and house dust mite (HDM) asthma mouse model were also studied.
RESULTS:In NECs-ALI and in bronchial epithelial cells (BECs) from bronchial biopsies of SA, CPT1A expression was reduced compared to healthy controls. Knock-down of CPT1A in healthy NECs reduced expression of Occludin and E-cadherin and impaired epithelial barrier integrity (EBI), while upregulation of CPT1A with CPT1A overexpression lentiviral/LCA in SA-NECs increased the barrier proteins with improved EBI. CPT1A knockdown in healthy BECs increased release of mtROS, with mitochondrial disruption and activation of ERK1/2-NF-κB signaling pathway. These were aggravated with HDM exposure but N-acetyl-cysteine and MitoTempo reduced p-ERK1/2 and p-P65 activation, as well as EBI with CPT1A knockdown and HDM. In the mouse model, there was decreased airway epithelial CPT1A protein expression, associated with reduced airway hyperreactivity and inflammation, and in Occludin and ZO-1 expression, effects partly reversed by LCA, with restoration of mitochondrial integrity and EBI.
CONCLUSION:CPT1A maintains epithelial barrier function through restoration of mitochondrial function in asthmatic airway epithelial cells. Restoration of deficient epithelial CPT1A of SA may represent a new treatment approach.
背景：线粒体脂肪酸经肉碱棕榈酰转移酶1A（CPT1A）氧化可生成ATP。本研究考察CPT1A在调控哮喘气道上皮细胞通透性及线粒体代谢稳态中的作用。
方法：将健康对照者和重度哮喘（SA）患者的原代鼻上皮细胞（NECs）进行气-液界面（ALI）培养，并分别给予CPT1A小干扰RNA（siRNA）、CPT1A过表达慢病毒或左旋肉碱（LCA）处理。测定跨上皮电阻（TEER）和异硫氰酸荧光素（FITC）-葡聚糖转运。同时研究健康者和SA患者的支气管活检标本，以及屋尘螨（HDM）诱导的哮喘小鼠模型。
结果：在ALI培养的NECs以及SA患者支气管活检来源的支气管上皮细胞（BECs）中，CPT1A表达均低于健康对照。在健康NECs中敲低CPT1A可降低Occludin和E-cadherin表达，并损害上皮屏障完整性（EBI）；而在SA-NECs中采用CPT1A过表达慢病毒或LCA上调CPT1A，可增加上述屏障蛋白表达并改善EBI。在健康BECs中敲低CPT1A可增加线粒体活性氧（mtROS）释放，伴有线粒体结构破坏以及ERK1/2-NF-κB信号通路激活。HDM暴露使上述改变进一步加重；但在CPT1A敲低并暴露于HDM的条件下，N-乙酰半胱氨酸和MitoTempo可降低p-ERK1/2及p-P65活化，并减轻EBI受损。在小鼠模型中，气道上皮CPT1A蛋白表达降低，与气道高反应性和炎症减轻以及Occludin和ZO-1表达降低相关；LCA可部分逆转这些效应，并恢复线粒体完整性和EBI。
结论：CPT1A通过恢复哮喘气道上皮细胞的线粒体功能来维持上皮屏障功能。恢复重度哮喘患者气道上皮中缺失的CPT1A，可能成为一种新的治疗策略。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Allergy. 2026 Jul; DOI: https://doi.org/10.1111/all.70428）
（Allergy. 2026 Jul; DOI: https://doi.org/10.1111/all.70428）
Deficiency of Mitochondrial Fatty Acid Enzyme, CPT1A, Underlies Airway Epithelial Barrier Dysfunction in Severe Asthma
Muyun Wang, Haiyang Hu, Kun Wang, Di Wu, Ximing Liao, Jing Gao, Tian Li, Wujian Xu, Shaoyong Gao, Qiang Li, Pankaj Kumar Bhavsar, Wei Gao, Kian Fan Chung
Abstract
BACKGROUND:Mitochondrial fatty acid oxidation through carnitine palmitoyltransferase-1A (CPT1A) leads to ATP generation. We examined its role in regulating permeability and mitochondrial metabolic homeostasis of airway epithelial cells in asthma.
METHODS:Primary nasal epithelial cells (NECs) from healthy controls and severe asthma (SA) patients in air-liquid interface (ALI) were exposed to CPT1A siRNA/CPT1A overexpression lentiviral/L-carnitine (LCA). Epithelial TEER and FITC-dextran transport were measured. Bronchial biopsies from healthy and SA subjects and house dust mite (HDM) asthma mouse model were also studied.
RESULTS:In NECs-ALI and in bronchial epithelial cells (BECs) from bronchial biopsies of SA, CPT1A expression was reduced compared to healthy controls. Knock-down of CPT1A in healthy NECs reduced expression of Occludin and E-cadherin and impaired epithelial barrier integrity (EBI), while upregulation of CPT1A with CPT1A overexpression lentiviral/LCA in SA-NECs increased the barrier proteins with improved EBI. CPT1A knockdown in healthy BECs increased release of mtROS, with mitochondrial disruption and activation of ERK1/2-NF-κB signaling pathway. These were aggravated with HDM exposure but N-acetyl-cysteine and MitoTempo reduced p-ERK1/2 and p-P65 activation, as well as EBI with CPT1A knockdown and HDM. In the mouse model, there was decreased airway epithelial CPT1A protein expression, associated with reduced airway hyperreactivity and inflammation, and in Occludin and ZO-1 expression, effects partly reversed by LCA, with restoration of mitochondrial integrity and EBI.
CONCLUSION:CPT1A maintains epithelial barrier function through restoration of mitochondrial function in asthmatic airway epithelial cells. Restoration of deficient epithelial CPT1A of SA may represent a new treatment approach.
上一篇：
维生素A和D对成人及儿童哮喘患者肺功能和表观遗传调控的影响
下一篇：
2型细胞因子生物标志物高表达和低表达的重度哮喘患者气道转录组
