Adhatoda Vasica rescues the hypoxia dependent severe asthma symptoms and mitochondrial dysfunction

Abstract

Severe asthma is chronic airway disease, exhibit poor response to conventional asthma therapies.Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patient and model systems. In this study, we elucidate the therapeutic effect and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on acute allergic as well as severe asthma subtypes, at physiological, histopathological and molecular levels using mouse models.We observed, oral administration of AV extract not only attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice but also alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC and HIF-1 (hypoxia inducible factor-1alpha) in severe asthmatic mice. The reversal of pathophysiological features after AV treatment is associated with inhibition of elevated HIF-1 levels by restoring the expression of its negative regulator-PHD2 (prolyl hydroxylase domain-2). This was further confirmed in acute and severe asthma model developed by augmented hypoxic response. Further, AV treatment reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells -evident from bioenergetic profiles and morphological analysis of mitochondria. Involvement of hypoxia and mitochondrial dysfunction in asthma severity is being increasingly realised. Extract of AV although widely used in Ayurveda practice for the treatment of diverse respiratory ailments, including asthma, its molecular basis of action and effect on severe asthma subtype is still unclear. This study, demonstrates therapeutic mechanism of Adhatoda Vasica through hypoxia-induced mitochondrial dysfunction and highlights its potential in the treatment of severe steroid-resistant asthma. Significance StatementSevere asthma is a global health concern found to be unresponsive to current treatment modalities involving corticosteroids. Recent findings suggest that elevated hypoxia has a critical role in severity of asthma. Here, we report therapeutic treatment with aqueous extract of Adhatoda Vasica (AV), an ayurvedic medicine, is effective in attenuation of severe steroid-insensitive asthmatic features in mice. The observed anti-asthmatic effects of AV was through inhibition of hypoxic response, both in vivo and in vitro. AV also reverses mitochondrial dysfunction, a key consequence associated with hypoxia, and asthma. This study not only highlights the translational potential of AV for the treatment of severe asthma but also provides opportunities for its usage in other disease conditions where hypoxia is pertinent. 250,000 annual deaths, asthma significantly contributes to the global health burden (3). Initially, it was considered to be primarily an allergic, eosinophilic Th2 biased disease with involvement of its cytokines (IL-4, IL-5 and IL-13) in the inflammatory cascade leading to allergic exacerbations (4).However, there are non-Th2 asthma patho-phenotypes, where cells like Th17, Th1 and their respective cytokines play a ...

Adhatoda Vasica: a potential ayurvedic intervention against COVID-19 associated impaired immune response and hypoxia-inflammation phenotype

“…However, none of the studies have so far studied the effect of AV on molecular markers of asthma/in ammation phenotype in its aqueous extract form prescribed in Ayurveda. For the rst time, we have shown that the anti-asthmatic effect of AV is not only limited to acute asthmatic features but it also alleviates the severe airway in ammation in steroid-nonresponsive asthmatic mice [14]. We show that the AV extract causes inhibition of HIF-1α (key transcription factor in hypoxia) by increasing the expression of its negative regulator, PHD2, thereby modulates hypoxic response, which forms the basis for its diverse therapeutic effects [14].…”

“…For the rst time, we have shown that the anti-asthmatic effect of AV is not only limited to acute asthmatic features but it also alleviates the severe airway in ammation in steroid-nonresponsive asthmatic mice [14]. We show that the AV extract causes inhibition of HIF-1α (key transcription factor in hypoxia) by increasing the expression of its negative regulator, PHD2, thereby modulates hypoxic response, which forms the basis for its diverse therapeutic effects [14]. Further, AV treatment to lung epithelial cells has also been shown to reduce hypoxia's downstream impact such as mitochondrial dysfunction [14].…”

“…We show that the AV extract causes inhibition of HIF-1α (key transcription factor in hypoxia) by increasing the expression of its negative regulator, PHD2, thereby modulates hypoxic response, which forms the basis for its diverse therapeutic effects [14]. Further, AV treatment to lung epithelial cells has also been shown to reduce hypoxia's downstream impact such as mitochondrial dysfunction [14]. In this study we examined anti-hypoxic effects of AV in other hypoxia-in ammation prevalent conditions.…”

“…For transcriptomic research (n = 4-5), BALB/c mice divided into Vehicle (distil water, oral) and Adhatoda Vasica (AV) extract group. AV group is further subdivided into two according to its dose: AV-D2 (Adhatoda Vasica extract 130 mg/kg, dissolved in distilled water, oral) and AV-D4 (Adhatoda Vasica extract 260 mg/kg, dissolved in distilled water, oral) as described previously [14]. Distil water or AV ( 130mg/kg or 260mg/kg) treatment was given to mice by oral gavage for consecutive four days as represented in the gure.…”

“…We have recently shown an extract of Adhatoda Vasica (AV); an ayurvedic medicine possesses robust anti-hypoxic properties and can reduce severe airway in ammation induced by an augmented hypoxic response in treatment-resistant asthmatic mice [14]. The anti-HIF-1α effect of AV also restores the cellular hypoxia-mediated loss of mitochondrial morphofunction in vitro [14]. As a follow-up we evaluated AV's usefulness in other severe lung pathologies, where hypoxia signalling is pertinent.…”