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: The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19.

Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often characterized by a hyperactive immune response, known as a cytokine storm. Dexamethasone anti-inflammatory properties make it a potent tool in modulating this exaggerated immune response.

Lung inflammation may lead to excessive fluid accumulation in the airways which can reduce gas exchange and mucociliary clearance. Pulmonary oedema and flooding of the airways are hallmarks of severe COVID-19 lung disease. The volume of airway surface liquid is determined by a delicate balance of salt and water secretion and absorption across the airway epithelium. In addition to its anti-inflammatory actions, dexamethasone modulates the activity of ion channels which regulate electrolyte and water transport across the airway epithelium. The observations of dexamethasone activation of sodium ion absorption via ENaC Na channels and inhibition of chloride ion secretion via CFTR Cl- channels to decrease airway surface liquid volume indicate a novel therapeutic action of the glucocorticoid to reverse airway flooding.

This brief review delves into the early non-genomic and late genomic signaling mechanisms of dexamethasone regulation of ion channels and airway surface liquid dynamics, shedding light on the molecular mechanisms underpinning the action of the glucocorticoid in managing COVID-19.

Graphical abstract: Dexamethasone reduces airway secretion by modulating the activity of ion channels which stimulate water flux out of the airways to reduce pulmonary edema in COVID-19.

* Patients receiving dexamethasone in severe COVID-19 show marked reduction in morbidity and mortality.

* Airway flooding is a hallmark of severe acute respiratory distress in COVID-19.

* Dexamethasone regulates ion channels which modulate the volume of airway surface liquid.

* Dexamethasone stimulation of NaCl and water absorption may reduce alveolar flooding in COVID-19.

(C) 2024Elsevier, Inc.