Glucocorticoids: Therapeutic relevanceJuly 11, 2020
Viral infections, including COVID-19, show increased inflammatory cells, arterial dilation, increased blood flow and other substantial changes. Glucocorticoids, including dexamethasone, are used to reduce inflammation from both direct and indirect mechanisms. Therapeutically, the capability of glucocorticoids to suppress inflammation in diseases such as asthma can become the most potent therapy for viral infections.
The clinical efficacy of these synthetic steroids comes from their ability to mimic natural bodily steroids. Several bodily insults such as infections, pain, inflammation and mental stress can lead to the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Due to these stimuli, the hypothalamus gets activated and releases corticotropin-releasing hormone (CRH). CRH acts on anterior pituitary, inducing the synthesis and the release of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to release glucocorticoids like cortisol. Cortisol, once in the blood, reaches target organs and elicits numerous metabolic effects, including immunological suppression. Thus, while glucocorticoids have strong anti-inflammatory power, their clinical usefulness as drugs is limited by HPA insufficiency. It is also understood that the metabolic effects of glucocorticoids include an increased transcription of genes such as tyrosine aminotransferase (TAT) and phosphoenolpyruvate carboxykinase (PEPCK) and negative regulation of inflammatory genes.
It is known that the effects of glucocorticoids on cells are mediated via glucocorticoid receptor (GR). Three important molecules — HSP90, calreticulin and immunophilin p59 — form an inactive complex with ligand-free GR. The entry of glucocorticoids into cells upon binding of a ligand to the ligand-binding domain of GR changes the conformation and translocates GR to the nucleus, thus helping to regulate gene expression via binding to glucocorticoid response elements in DNA. Many inflammatory genes that are repressed by glucocorticoids are transcriptionally regulated by genes such as nuclear factor- κB(NF- κB) and AP-1. GR does not need to bind to DNA directly to regulate certain inflammatory genes but can interact with transcriptional activators such as the ones mentioned above to cause indirect repression or transrepression called “tethering GRE”. The leading belief is that the majority of anti-inflammatory effects of glucocorticoids are driven by the inhibition of transcription (transrepression) and metabolic effects are derived from positive transcriptional effect (transactivation). This aspect further leads to research on the specialisation of “dissociating” steroids. Several deletion studies have identified mutant variations which have transrepression and transactivation as separate functions. Initial studies of dissociated steroid RU24858 showed anti-inflammatory properties in-vivo with reduced side effects.
A favourable electrical force from epithelial cells drive chloride ion (Cl- ) efflux at the basolateral membrane where K+ channel plays an important role in basal and agonist-stimulated Cl- transport. This transport plays an important role in inflammation and fluid accumulation. Dexamethasone acts on lung epithelial cells to augment anti-inflammatory activity and enhance the treatment of airway hypertension by rapidly inhibiting transepithelial chloride ion secretion via targeting three types of K+ channels through Ca2+ activated secretion via KCNN4 (KCa3.1) channels and cAMP-activated secretion via KCNQ1 (Kv7.1) and KATP (Kir6.1,6.2) channels. As the functioning of these channels are necessary for maintaining the electrical driving force for electrolyte secretion, the anti-secretory response to dexamethasone could have implications for the development and use of new pharmacological tools in the treatment of lung disease typified by hypersecretion and viscous mucous, as seen in COVID-19 infections. The antisecretory response can be expected to be additive to anti-inflammatory responses and can be of additional therapeutic value in the treatment of airway infections by glucocorticoids. Caution, of course, needs to be taken in assigning a physiological role or therapeutic value for results from immortalised airway cell lines. However, several research publications have attested to the anti-secretory effects of dexamethasone in primary cultures of human bronchial cells, potentially indicating therapeutic relevance to COVID-19 therapy.
The author is a medical scientist and former director of SGRF, Bangalore