Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on mouse models of acute allergic as well as severe asthma subtypes at physiological, histopathological, and molecular levels. Oral administration of AV extract attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice and alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC, and HIF-1α (hypoxia inducible factor-1alpha) in severe asthmatic mice. AV inhibits HIF-1α levels through restoration of expression of its negative regulator-PHD2 (prolyl hydroxylase domain-2). Alleviation of hypoxic response mediated by AV is further confirmed in the acute and severe asthma model. AV reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells - evident from bioenergetic profiles and morphological analysis of mitochondria. In silico docking of AV constituents reveal higher negative binding affinity for C and O- glycosides for HIF-1a, IL-6, Janus kinase 1/3, TNF-α and TGF- β -key players of hypoxia-inflammation. This study for the first time provides a molecular basis of action and effect of AV whole extract that is widely used in Ayurveda practice for diverse respiratory ailments. Further, through its effect on hypoxia-induced mitochondrial dysfunction, the study highlights its potential to treat severe steroid-resistant asthma.

中文翻译：

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Adhatoda Vasica挽救了低氧依赖性严重哮喘症状和线粒体功能障碍

严重哮喘是一种慢性气道疾病，对常规哮喘疗法的反应较差。越来越多的证据表明，低氧升高会增加患者和模型系统中哮喘炎症的严重性。在这项研究中，我们从生理，组织病理学和分子水平阐明了Adhatoda Vasica（AV）水提取物对急性过敏和重度哮喘亚型小鼠模型的治疗作用和机理基础。口服AV提取物可减轻急性过敏性哮喘小鼠气道阻力和炎症的增加，并减轻重度哮喘小鼠中类固醇（地塞米松）抗性的分子标记，如IL-17A，KC和HIF-1α（低氧诱导因子-1α） 。AV通过恢复其负调节因子PHD2（脯氨酰羟化酶域2）的表达来抑制HIF-1α的水平。在急性和重度哮喘模型中，进一步证实了由AV介导的低氧反应的减轻。AV可逆转人低氧诱导的人支气管上皮细胞中的线粒体功能障碍-从生物能谱和线粒体形态分析中可以明显看出。在计算机对接中，AV成分显示出C和O-苷对HIF-1a，IL-6，Janus激酶1/3，TNF-α和TGF-β的负结合亲和力更高，它们是缺氧炎症的关键参与者。这项研究首次为AV全提取物的作用和效果提供了分子基础，该提取物在阿育吠陀实践中广泛用于各种呼吸道疾病。此外，通过对缺氧引起的线粒体功能障碍的影响，