大麻素WIN55,212-2通过调节氧化应激和STAT6磷酸化恢复支气管上皮
2025/10/11
摘要
背景：病毒感染和2型免疫应答导致气道上皮屏障功能障碍和炎症，从而促进哮喘的发生和发展。合成大麻素WIN55,212-2通过作用于不同的免疫系统细胞表现出抗炎特性。
目的：我们旨在研究WIN55,212-2在病毒感染或2型驱动的炎症背景下恢复哮喘支气管上皮屏障功能的能力。
方法：生成人气道上皮细胞的气液界面培养物和人气道上皮球体，以评估WIN55,212-2恢复由人鼻病毒A16（RV-A16）感染或2型炎症诱导的气道上皮屏障损伤的能力。采用RT-PCR、细胞因子定量、通透性测定、代谢研究、流式细胞术和Western blot技术评估WIN55,212～2对气道上皮的影响。我们在IL-13诱导的气道炎症小鼠模型中评估了研究结果的体内相关性。
结果：预防性和治疗性给予WIN55,212-2加速了RV-A16诱导的支气管上皮屏障损伤的恢复。WIN55,212-2在气液界面培养物、自组装支气管上皮球体和体内气道炎症及上皮功能障碍哮喘模型中抑制了IL-13诱导的2型哮喘特征的获得。机制上，WIN55,212-2损害了IL-13诱导的上皮细胞氧化应激，恢复了蛋白酪氨酸磷酸酶的活性，从而抑制了pSTAT6介导的信号通路和哮喘特征。
结论：大麻素WIN55,212-2在RV-A16感染或2型炎症期间通过调节氧化代谢和pSTAT6介导的信号通路相关机制表现出气道上皮屏障保护作用。
Cannabinoid WIN55,212-2 restores bronchial epithelium by regulating oxidative stress and STAT6 phosphorylation
Pérez-Diego M, Angelina A, Pat Y, Maldonado A, Sevilla-Ortega C, Martín-Cruz L, Yazici D, Rückert B, Sokolowska M, Martín-Fontecha M, Akdis M, Akdis CA, Palomares O
Abstract
BACKGROUND:Viral infections and type 2 immune responses perpetuate airway epithelial barrier dysfunction and inflammation, leading to the development and progression of asthma. The synthetic cannabinoid WIN55,212-2 displays anti-inflammatory properties by acting on different immune system cells.
OBJECTIVE:We sought to investigate the capacity of WIN55,212-2 to restore bronchial epithelial barrier function in asthma in the context of viral infections or type 2-driven inflammation.
METHODS:Air-liquid interface cultures of human bronchial epithelial cells and human bronchial epithelial spheroids were generated to assess the capacity of WIN55,212-2 to restore airway epithelial barrier damage induced by human rhinovirus A16 (RV-A16) infection or type 2 inflammation. RT-PCR, cytokine quantification, permeability assays, metabolic studies, flow cytometry, and Western blot techniques were employed to assess the effects of WIN55,212-2 on the airway epithelium. The in vivo relevance of our findings was evaluated in a murine model of IL-13-induced airway inflammation.
RESULTS: Prophylactic and therapeutic administration of WIN55,212-2 accelerated the recovery from RV-A16-induced bronchial epithelial barrier damage. WIN55,212-2 inhibited the acquisition of IL-13-induced type 2 asthma features in air-liquid interface cultures, self-assembled bronchial epithelial spheroids, and in vivo asthma model of airway inflammation and epithelial dysfunction. Mechanistically, WIN55,212-2 impaired IL-13-induced oxidative stress in epithelial cells, restoring the activity of protein tyrosine phosphatases, which in turn inhibited pSTAT6-mediated signaling pathways and asthma features.
CONCLUSION:The cannabinoid WIN55,212-2 displays airway epithelial barrier protective effects during RV-A16 infection or type 2 inflammation by mechanisms associated with the modulation of oxidative metabolism and pSTAT6-mediated signaling.
背景：病毒感染和2型免疫应答导致气道上皮屏障功能障碍和炎症，从而促进哮喘的发生和发展。合成大麻素WIN55,212-2通过作用于不同的免疫系统细胞表现出抗炎特性。
目的：我们旨在研究WIN55,212-2在病毒感染或2型驱动的炎症背景下恢复哮喘支气管上皮屏障功能的能力。
方法：生成人气道上皮细胞的气液界面培养物和人气道上皮球体，以评估WIN55,212-2恢复由人鼻病毒A16（RV-A16）感染或2型炎症诱导的气道上皮屏障损伤的能力。采用RT-PCR、细胞因子定量、通透性测定、代谢研究、流式细胞术和Western blot技术评估WIN55,212～2对气道上皮的影响。我们在IL-13诱导的气道炎症小鼠模型中评估了研究结果的体内相关性。
结果：预防性和治疗性给予WIN55,212-2加速了RV-A16诱导的支气管上皮屏障损伤的恢复。WIN55,212-2在气液界面培养物、自组装支气管上皮球体和体内气道炎症及上皮功能障碍哮喘模型中抑制了IL-13诱导的2型哮喘特征的获得。机制上，WIN55,212-2损害了IL-13诱导的上皮细胞氧化应激，恢复了蛋白酪氨酸磷酸酶的活性，从而抑制了pSTAT6介导的信号通路和哮喘特征。
结论：大麻素WIN55,212-2在RV-A16感染或2型炎症期间通过调节氧化代谢和pSTAT6介导的信号通路相关机制表现出气道上皮屏障保护作用。
（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）
（J Allergy Clin Immunol. 2025 Sep;156(3):651-667.DOI: 10.1016/j.jaci.2025.05.002.）
Cannabinoid WIN55,212-2 restores bronchial epithelium by regulating oxidative stress and STAT6 phosphorylation
Pérez-Diego M, Angelina A, Pat Y, Maldonado A, Sevilla-Ortega C, Martín-Cruz L, Yazici D, Rückert B, Sokolowska M, Martín-Fontecha M, Akdis M, Akdis CA, Palomares O
Abstract
BACKGROUND:Viral infections and type 2 immune responses perpetuate airway epithelial barrier dysfunction and inflammation, leading to the development and progression of asthma. The synthetic cannabinoid WIN55,212-2 displays anti-inflammatory properties by acting on different immune system cells.
OBJECTIVE:We sought to investigate the capacity of WIN55,212-2 to restore bronchial epithelial barrier function in asthma in the context of viral infections or type 2-driven inflammation.
METHODS:Air-liquid interface cultures of human bronchial epithelial cells and human bronchial epithelial spheroids were generated to assess the capacity of WIN55,212-2 to restore airway epithelial barrier damage induced by human rhinovirus A16 (RV-A16) infection or type 2 inflammation. RT-PCR, cytokine quantification, permeability assays, metabolic studies, flow cytometry, and Western blot techniques were employed to assess the effects of WIN55,212-2 on the airway epithelium. The in vivo relevance of our findings was evaluated in a murine model of IL-13-induced airway inflammation.
RESULTS: Prophylactic and therapeutic administration of WIN55,212-2 accelerated the recovery from RV-A16-induced bronchial epithelial barrier damage. WIN55,212-2 inhibited the acquisition of IL-13-induced type 2 asthma features in air-liquid interface cultures, self-assembled bronchial epithelial spheroids, and in vivo asthma model of airway inflammation and epithelial dysfunction. Mechanistically, WIN55,212-2 impaired IL-13-induced oxidative stress in epithelial cells, restoring the activity of protein tyrosine phosphatases, which in turn inhibited pSTAT6-mediated signaling pathways and asthma features.
CONCLUSION:The cannabinoid WIN55,212-2 displays airway epithelial barrier protective effects during RV-A16 infection or type 2 inflammation by mechanisms associated with the modulation of oxidative metabolism and pSTAT6-mediated signaling.
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