Adhatoda vasica rescues the hypoxia-dependent severe asthma symptoms and mitochondrial dysfunction

Abstract

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.

Adhatoda Vasica attenuates inflammatory and hypoxic responses in preclinical mouse models: potential for repurposing in COVID-19-like conditions

“…We have recently shown that AV alleviates the severe airway inflammation in steroid-nonresponsive asthmatic features by inhibition of HIF-1α (key transcription factor in hypoxia) via its negative regulator, PHD2. AV thereby modulates hypoxic response, which forms the basis for its diverse therapeutic effects including amelioration of mitochondrial dysfunction [16]. In this study we examined anti-hypoxic effects of AV in other hypoxia-inflammation prevalent conditions such as lung injury, fibrosis, and thrombosis.…”

“…For transcriptomic study, BALB/c mice were divided into Vehicle (distil water, oral, two times a day, n = 4) and Adhatoda Vasica (AV) extract group. AV group was further subdivided according to its dose: AV-D2 (Adhatoda Vasica extract 130 mg/kg, dissolved in distilled water, oral, two times a day, n = 5) and AV-D4 (Adhatoda Vasica extract 260 mg/kg, dissolved in distilled water, oral, two times a day, n = 5) as described previously [16]. Distil water or AV (130 mg/kg or 260 mg/kg) treatment was given to mice by oral gavage for four consecutive days, as represented in the Fig.…”

“…Bronchoalveolar lavage fluid (BAL) was collected by instilling 1 ml PBS into the tracheotomised airway and recovered BAL fluids were processed to get total leukocyte count, as described previously [16,20]. For lung Fig.…”

“…S2, S3, and S4. In addition, AV's flavonoids are also shown to have a higher binding affinity for proteins involved in hypoxia and inflammation [16]. We also compared docking analysis of AV (Table 1) with known antivirals, JAK inhibitors and hydroxychloroquine (HCQ) against SARS-CoV2 and host target proteins (Table 2, Additional file 1: Table S3).…”

“…We have recently shown an extract of Adhatoda Vasica (AV); an ayurvedic medicine that possesses robust antihypoxic properties and can reduce severe airway inflammation induced by an augmented hypoxic response in treatment-resistant asthmatic mice [16]. The anti-HIF-1α effect of AV also restores the cellular hypoxia-mediated loss of mitochondrial morphofunction in vitro [16]. As a follow-up, we evaluated AV's usefulness in other severe lung pathologies, where hypoxia signalling is pertinent, and which are relevant to the clinical course of COVID-19 namely lung injury, fibrosis, and thrombosis.…”