Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China.
Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China; Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai, China.
Phytomedicine. 2023 Mar;111:154646. doi: 10.1016/j.phymed.2023.154646. Epub 2023 Jan 6.
Obese asthma is one of the important asthma phenotypes that have received wide attention in recent years. Excessive oxidative stress and different inflammatory endotypes may be important reasons for the complex symptoms, frequent aggravation, and resistance to traditional treatments of obese asthma. Apigenin (API), is a flavonoid natural small molecule compound with good anti-inflammatory and antioxidant activity in various diseases and proved to have the potential efficacy to combat obese asthma.
In vivo, this study fed C57BL/6 J mice with high-fat diets(HFD)for 12 weeks and then stimulated them with OVA for 6 weeks to establish a model of chronic obese asthma, while different doses of oral API or dexamethasone were used for therapeutic interventions. In vitro, this study used HDM to stimulate human bronchial cells (HBEs) to establish the model and intervened with API or Selonsertib (SEL).
This study clarified that OVAinduced a type of mixed granulocytic asthma with elevated neutrophils and eosinophils in obese male mice fed with long-term HFD, which also exhibited mixed TH17/TH1/TH2 inflammation. Apigenin effectively suppressed this complex inflammation and acted as a regulator of immune homeostasis. Meanwhile, apigenin reduced AHR, inflammatory cell infiltration, airway epithelial cell apoptosis, airway collagen deposition, and lung oxidative stress via the ROS-ASK1-MAPK pathway in an obese asthma mouse model. In vitro, this study found that apigenin altered the binding status of TRAF6 to ASK1, inhibited ASK1 phosphorylation, and protected against ubiquitin-dependent degradation of ASK1, suggesting that ROS-activated ASK1 may be an important target for apigenin to exert anti-inflammatory and anti-apoptotic effects. To further verify the intervention mechanism, this study clarified that apigenin improved cell viability and mitochondrial function and inhibited apoptosis by interfering with the ROS-ASK1-MAPK pathway.
This study demonstrates for the first time the therapeutic effect of apigenin in chronic obese asthma and further clarifies its potential therapeutic targets. In addition, this study clarifies the specificity of chronic obese asthma and provides new options for its treatment.
肥胖型哮喘是近年来受到广泛关注的重要哮喘表型之一。过度的氧化应激和不同的炎症内型可能是肥胖型哮喘症状复杂、频繁加重和对传统治疗抵抗的重要原因。芹菜素（API）是一种具有良好抗炎和抗氧化活性的黄酮类天然小分子化合物，已被证明在多种疾病中有潜在的疗效，可对抗肥胖型哮喘。
在体内，本研究用高脂肪饮食（HFD）喂养 C57BL/6J 小鼠 12 周，然后用 OVA 刺激 6 周，建立慢性肥胖型哮喘模型，同时用不同剂量的 API 或地塞米松进行治疗干预。在体外，本研究用 HDM 刺激人支气管细胞（HBE）建立模型，并干预 API 或 Selonsertib（SEL）。
本研究表明，OVA 诱导长期 HFD 喂养的肥胖雄性小鼠产生一种混合粒细胞性哮喘，伴有中性粒细胞和嗜酸性粒细胞升高，同时也表现出混合 TH17/TH1/TH2 炎症。芹菜素能有效抑制这种复杂的炎症，并作为免疫稳态的调节剂。同时，芹菜素通过 ROS-ASK1-MAPK 通路降低肥胖型哮喘小鼠模型的 AHR、炎症细胞浸润、气道上皮细胞凋亡、气道胶原沉积和肺氧化应激。在体外，本研究发现，芹菜素改变了 TRAF6 与 ASK1 的结合状态，抑制了 ASK1 的磷酸化，并防止了 ASK1 的泛素依赖性降解，提示 ROS 激活的 ASK1 可能是芹菜素发挥抗炎和抗凋亡作用的重要靶点。为了进一步验证干预机制，本研究阐明，芹菜素通过干扰 ROS-ASK1-MAPK 通路改善细胞活力和线粒体功能，抑制细胞凋亡。
本研究首次证明了芹菜素在慢性肥胖型哮喘中的治疗效果，并进一步阐明了其潜在的治疗靶点。此外，本研究阐明了慢性肥胖型哮喘的特异性，为其治疗提供了新的选择。
