SSRIs: Applications in inflammatory lung disease and implications for COVID-19

Abstract

Selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID-19. SSRIs exert anti-inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF-κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL-6, IL-8, TNF-α, and IL-1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID-19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID-19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti-inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID-19-associated inflammatory lung disease.

Keywords: ARDS; COVID-19; NF-κB; lung inflammation; selective serotonin reuptake inhibitor.

FIGURE 1

Mechanism of SSRI modulation in pulmonary inflammatory disease. Infectious and inflammatory insults stimulate NF‐κB translocation and cytokine release in alveolar macrophages and epithelial cells. These cytokines recruit neutrophils to the lung, leading to tissue damage and apoptosis. In acute inflammatory disease, M1 macrophages stimulate platelet activation and endothelial injury, and activated platelets recruit neutrophils and promote NET formation, mediating further tissue damage. In chronic disease, T cells lead to direct and indirect tissue damage and promote remodeling associated with decreased pulmonary function. SSRIs reduce pulmonary inflammation in each of these pathways by inhibiting NF‐κB activity, (2) downstream cytokine release, and (3) cellular activity by impairing serotonin reuptake by SERT