Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: A review of immunomodulatory action
Anant Ramaswamy, Prabhat Bhargava, Pankaj Kumar Panda, Vikas Ostwal
Abstract
The novel coronavirus disease 2019 (COVID-19) is reported to cause acute respiratory distress syndrome (ARDS) in 20%–40% of the hospitalized patients. The pathophysiology of ARDS caused by a viral infection is still unknown; however, a histopathological hallmark of ARDS is diffuse alveolar damage due to excessive inflammation of the lung tissue from the inflammatory mediators released by the local epithelial and endothelial cells. ARDS is caused when there is an excessive inflammatory response compared to the anti-inflammatory response to the viral agent. It is often associated with multiorgan failure and increased chances of mortality. Epigenetic changes are known to cause rapid changes in the gene expression, thereby increasing hyperinflammatory/anti-inflammatory responses. Valproate (VPA), a histone deacetylase inhibitor, has been shown to inhibit the production of the nuclear factor-κB (NF-κB), tumor necrosis factor-alpha, and interleukin-6 in human cells stimulated with lipopolysaccharide. VPA has also been shown to block the migration of macrophages through the inhibition of pro-inflammatory cytokines. VPA can promote the differentiation of T cells toward Th2/M2 rather than Th1/M1, and it also stimulates the generation of the regulatory T cells (Treg), thereby reducing the percentage of CD8+ T lymphocytes. However, the anti-inflammatory action of VPA could decrease the cytokine expression and suppress the effector T cells, thereby delaying the viral clearance. This delayed clearance of the virus could be taken care of by the proposed direct antiviral activity of VPA.