A study published in "The Journal of Immunotoxicology" indicated that nicotine or GTS-21 (low molecular weight compounds that lead to activation of cholinergic anti-inflammatory reflex) might represent a promising approach for attenuating dysregulated inflammation in people suffering from severe COVID-19.

Myalgia, coughing, acute inflammatory lung injury, shortness of breath, and fever are the commonly reported mild-to-moderate symptoms in COVID-19 people. On the other hand, respiratory failure and acute respiratory distress syndrome (ARDS) occur in people with severe COVID-19. To some extent, the cytokine-storm syndrome (a dysregulated hyperinflammatory response due to elevated levels of circulating cytokines) mediates ARDS.

There are FDA-approved agents (like dexamethasone or other corticosteroids and interleukin-6 inhibitors, including siltuximab, tocilizumab, and sarilumab) that alleviate dysregulated inflammatory responses occurring in coronavirus-infected people, But, the effectiveness of these therapies have demonstrated inconsistency.

By minimizing extracellular levels of high mobility group box-1 (HMGB1) in circulation and airways, compounds that lead to activation of vagus nerve-mediated cholinergic anti-inflammatory reflex (like GTS-21) reduce inflammatory lung injury/ARDS.

HMGB1 might be a crucial mediator of "cytokine-storm syndrome." In coronavirus-infected individuals, raised plasma levels of HMGB1 have been noted. A substantial negative correlation exists between clinical outcomes and plasma levels of HMGB1. Nicotine is capable of activating the cholinergic anti-inflammatory reflex, that mitigates the up-regulation and excessive production of pro-inflammatory cytokines/chemokines. This, in turn, attenuates inflammatory lung injury elicited by SARS-CoV-2 infection.