Selective Serotonin Reuptake Inhibitors Targeting Autophagy/Mitophagy Pathways in an asthma model.

Background: Chronic airway inflammation, remodeling, and hyperresponsiveness are hallmarks of neutrophilic asthma. Both its pathogenesis and severity have been related to mitophagy and autophagy. Selective serotonin reuptake inhibitors (SSRIs), which are antidepressants, have been shown in several experiments to have anti-inflammatory properties. Consequently, the purpose of this study was to examine how two SSRIs—fluoxetine and citalopram—affect autophagy and mitophagy in neutrophilic asthma and how they differ from the glucocorticoid dexamethasone as a reference anti-inflammatory medication in terms of their effects on airway inflammation.Methods: The asthma model was established in mice using ovalbumin (OVA) sensitization and subsequent OVA challenges. The administration of citalopram, fluoxetine, and dexamethasone preceded each challenge. In addition to estimating total and differential cell counts in bronchoalveolar lavage (BAL) fluid, airway hyperresponsiveness was assessed before sensitization and following the last challenge. IgE, inflammatory markers, oxidant, antioxidant parameters, and p-mTOR were all measured. Additionally, the expression of autophagy and mitophagy markers was determined, and histopathological changes were evaluated.Results: SSRIs substantially improved airway hyperresponsiveness and reduced BAL fluid neutrophilic count and inflammatory cell infiltration, goblet cell hyperplasia, and airway fibrosis in histological sections compared to dexamethasone. SSRIs also significantly reduced IgE, inflammatory markers, and oxidative stress compared to dexamethasone. In addition, the expression of proteins linked to autophagy and mitophagy was inhibited, likely due to the elevated expression of p-mTOR. Conclusion: SSRIs can attenuate airway inflammation and hyperresponsiveness by suppressing autophagy and mitophagy, possibly through their modulatory effect on p-mTOR.