依赖氧化还原的ATF3抑制通过MKP-1/p38 MAPK信号通路损害哮喘中的类固醇敏感性
2025/11/28
摘要
慢性氧化应激（OS）是导致哮喘患者激素抵抗（SI）的关键因素，其中p38丝裂原活化蛋白激酶（p38 MAPK）的过度激活起着核心作用。尽管丝裂原活化蛋白激酶磷酸酶-1（MKP-1）的下调与这一过程有关，但对氧化还原敏感的上游调节因子仍知之甚少。本研究旨在利用卵清蛋白-臭氧（OVA-臭氧）小鼠哮喘模型，阐明激活转录因子3（ATF3）在慢性氧化应激诱导的激素抵抗中的作用。慢性（8周）臭氧暴露导致活性氧（ROS）持续积累，并显著降低肺组织中ATF3和MKP-1的表达，这与急性条件下的上调情况形成对比。通过慢性臭氧暴露联合反复OVA刺激，成功建立了激素抵抗性哮喘模型，在该模型中，地塞米松（DEX）对肺部炎症和肺功能的抑制作用明显减弱。使用抗氧化剂治疗或增强ATF3基因表达，均可恢复慢性OVA-臭氧哮喘模型的激素敏感性，同时伴有ATF3和MKP-1表达升高以及p38 MAPK磷酸化受到抑制。此外，ATF3基因敲除小鼠建立的过敏性哮喘模型的激素敏感性降低，而补充ATF3基因可部分恢复DEX的抑制作用。特别地，在体外实验中，ATF3基因可反式激活MKP-1启动子，上调MKP-1表达并抑制p38 MAPK磷酸化。综上所述，我们的研究发现ATF3是一种氧化还原敏感的转录调节因子，它通过MKP-1/p38 MAPK轴关键地控制哮喘患者的激素反应性。在慢性氧化应激条件下，ATF3表达下调导致激素抵抗，而通过N-乙酰半胱氨酸（NAC）进行药物干预或通过过表达进行基因干预来恢复ATF3表达，可通过调节该信号通路恢复激素敏感性。这些结果揭示了激素抵抗背后一种新的氧化还原依赖性机制，并强调ATF3是恢复难治性哮喘激素疗效的一个有前景的治疗靶点。
慢性氧化应激（OS）是导致哮喘患者激素抵抗（SI）的关键因素，其中p38丝裂原活化蛋白激酶（p38 MAPK）的过度激活起着核心作用。尽管丝裂原活化蛋白激酶磷酸酶-1（MKP-1）的下调与这一过程有关，但对氧化还原敏感的上游调节因子仍知之甚少。本研究旨在利用卵清蛋白-臭氧（OVA-臭氧）小鼠哮喘模型，阐明激活转录因子3（ATF3）在慢性氧化应激诱导的激素抵抗中的作用。慢性（8周）臭氧暴露导致活性氧（ROS）持续积累，并显著降低肺组织中ATF3和MKP-1的表达，这与急性条件下的上调情况形成对比。通过慢性臭氧暴露联合反复OVA刺激，成功建立了激素抵抗性哮喘模型，在该模型中，地塞米松（DEX）对肺部炎症和肺功能的抑制作用明显减弱。使用抗氧化剂治疗或增强ATF3基因表达，均可恢复慢性OVA-臭氧哮喘模型的激素敏感性，同时伴有ATF3和MKP-1表达升高以及p38 MAPK磷酸化受到抑制。此外，ATF3基因敲除小鼠建立的过敏性哮喘模型的激素敏感性降低，而补充ATF3基因可部分恢复DEX的抑制作用。特别地，在体外实验中，ATF3基因可反式激活MKP-1启动子，上调MKP-1表达并抑制p38 MAPK磷酸化。综上所述，我们的研究发现ATF3是一种氧化还原敏感的转录调节因子，它通过MKP-1/p38 MAPK轴关键地控制哮喘患者的激素反应性。在慢性氧化应激条件下，ATF3表达下调导致激素抵抗，而通过N-乙酰半胱氨酸（NAC）进行药物干预或通过过表达进行基因干预来恢复ATF3表达，可通过调节该信号通路恢复激素敏感性。这些结果揭示了激素抵抗背后一种新的氧化还原依赖性机制，并强调ATF3是恢复难治性哮喘激素疗效的一个有前景的治疗靶点。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（Free Radic Biol Med. 2025 Nov 10:243:1-15. doi: 10.1016/j.freeradbiomed.2025.11.011. ）
Redox-dependent suppression of ATF3 impairs steroid sensitivity in asthma through MKP-1/p38 MAPK signaling
Jinxiu Li, Lei Zhao, Yali Qiu, Jiawei Liao, Xue Tian, Jianwei Gao, Min Zhang, Aihua Bao
Abstract
Chronic oxidative stress (OS) is a critical contributor to steroid insensitivity (SI) in asthma, in which p38 mitogen-activated protein kinase (p38 MAPK) overactivation playing a central role. Although mitogen-activated protein kinase phosphatase-1 (MKP-1) downregulation has been implicated in this process, the redox-sensitive upstream regulators remain poorly understood. This study aimed to elucidate the role of activating transcription factor 3 (ATF3) in chronic OS-induced SI using an ovalbumin-ozone (OVA-ozone) murine asthma model. Chronic (8-week) ozone exposure led to sustained ROS accumulation and significantly reduced ATF3 and MKP-1 expression in lung tissue, contrasting with the upregulation observed under acute conditions. A steroid-insensitive asthma model was successfully established through chronic ozone exposure combined with repeated OVA stimulations, in which the inhibitory effects of Dexamethasone (DEX) on the pulmonary inflammation and lung function were substantially blunted. Treatment with antioxidant or gene augmentation of ATF3 can both restored the steroids insensitivity of this chronic OVA-ozone asthma model, accompanied by elevated ATF3 and MKP-1 expression and suppressed p38 MAPK phosphorylation. Furthermore, steroid sensitivity of allergic asthma model established with ATF3 knockout mice was blunted, while genetic supplementation of ATF3 gene can partly restore the inhibitory effects of DEX. Particularly, in vitro, ATF3 gene was shown to transactivate the MKP-1 promoter, upregulate MKP-1 expression and suppress p38 MAPK phosphorylation. Collectively, our findings identify ATF3 as a redox-sensitive transcriptional regulator that critically controls steroid responsiveness in asthma through the MKP-1/p38 MAPK axis. Under chronic OS, ATF3 downregulation drives SI, while its restoration-pharmacologically via NAC or genetically via overexpression-reinstates steroid sensitivity by modulating this pathway. These results reveal a novel redox-dependent mechanism underlying SI and highlight ATF3 as a promising therapeutic target for restoring steroid efficacy in refractory asthma.
Jinxiu Li, Lei Zhao, Yali Qiu, Jiawei Liao, Xue Tian, Jianwei Gao, Min Zhang, Aihua Bao
Abstract
Chronic oxidative stress (OS) is a critical contributor to steroid insensitivity (SI) in asthma, in which p38 mitogen-activated protein kinase (p38 MAPK) overactivation playing a central role. Although mitogen-activated protein kinase phosphatase-1 (MKP-1) downregulation has been implicated in this process, the redox-sensitive upstream regulators remain poorly understood. This study aimed to elucidate the role of activating transcription factor 3 (ATF3) in chronic OS-induced SI using an ovalbumin-ozone (OVA-ozone) murine asthma model. Chronic (8-week) ozone exposure led to sustained ROS accumulation and significantly reduced ATF3 and MKP-1 expression in lung tissue, contrasting with the upregulation observed under acute conditions. A steroid-insensitive asthma model was successfully established through chronic ozone exposure combined with repeated OVA stimulations, in which the inhibitory effects of Dexamethasone (DEX) on the pulmonary inflammation and lung function were substantially blunted. Treatment with antioxidant or gene augmentation of ATF3 can both restored the steroids insensitivity of this chronic OVA-ozone asthma model, accompanied by elevated ATF3 and MKP-1 expression and suppressed p38 MAPK phosphorylation. Furthermore, steroid sensitivity of allergic asthma model established with ATF3 knockout mice was blunted, while genetic supplementation of ATF3 gene can partly restore the inhibitory effects of DEX. Particularly, in vitro, ATF3 gene was shown to transactivate the MKP-1 promoter, upregulate MKP-1 expression and suppress p38 MAPK phosphorylation. Collectively, our findings identify ATF3 as a redox-sensitive transcriptional regulator that critically controls steroid responsiveness in asthma through the MKP-1/p38 MAPK axis. Under chronic OS, ATF3 downregulation drives SI, while its restoration-pharmacologically via NAC or genetically via overexpression-reinstates steroid sensitivity by modulating this pathway. These results reveal a novel redox-dependent mechanism underlying SI and highlight ATF3 as a promising therapeutic target for restoring steroid efficacy in refractory asthma.
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