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

Atish Gheware,Bhavana Prasher,Yash Parekh,Lipsa Panda,Bijay Ranjan Pattnaik,Dhwani Dholakia,Mitali Mukerji,Kiran Kumar Bokara,Vaibhav Jain,Ritu Rani,Sadasivam Kannan,Venkatesan Subramanian,M Ghalib Enayathullah,Anurag Agrawal

doi:10.1186/s12931-021-01698-9

Abstract

BackgroundCOVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models.MethodsIn this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication.ResultsOral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-β1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2.ConclusionOur results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.

Highlights

COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis
The interaction of the host and SARS-CoV2 is broadly described in three stages: first, asymptomatic state; second, a non-severe symptomatic state characterized by upper airway and conducting airway response; third, severe respiratory symptomatic state with the presence of hypoxia, acute respiratory distress syndrome (ARDS) and progression to sepsis [7]
As a follow-up, we evaluated Adhatoda Vasica (AV)’s usefulness in other severe lung pathologies, where hypoxia signalling is pertinent, and which are relevant to the clinical course of COVID19 namely lung injury, fibrosis, and thrombosis

Summary

Introduction

COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The induction of HIF-1α is Gheware et al Respir Res (2021) 22:99 considered to be pro-inflammatory It leads to transcriptional activation of essential genes implicated in airway remodelling and inflammation, such as vascular endothelial growth factor, transforming growth factor-beta 1 (TGF-β1), inducible nitric oxide synthase, interleukin -17 (IL-17), and IL-6 [3, 4]. It is not just a consequence of diseases, elevated tissue/cellular hypoxia actively participates in exaggerating the inflammatory response contributing to progressive lung damage/injury. Medicinal agents that possess immune-boosting and anti-hypoxic effects could hold a promise for a better therapeutic option to preclude the SARS-CoV2 infection and severity

Methods

Results

Discussion

Conclusion