The sigma-1 receptor agonist fluvoxamine alleviates endotoxin-induced acute lung injury in mice

Ritter, Emese and Csekő, Kata and Hosszú, Ádám and Tóth, Ákos Roland and Hargitai, Dóra and Kereskai, László and Fekete, Andrea and Helyes, Zsuzsanna (2026) The sigma-1 receptor agonist fluvoxamine alleviates endotoxin-induced acute lung injury in mice. FRONTIERS IN PHARMACOLOGY, 17. No. 1818198. ISSN 1663-9812

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Abstract

Introduction: Acute lung inflammation has recently gained increasing attention due to the high acute respiratory distress syndrome complications with subsequent fibrosis during the COVID-19 pandemic. Our group identified that the antifibrotic effect of the antidepressant fluvoxamine (FLU) in various organs is meditated via sigma-1 receptor (S1R) agonism. Since the actions of FLU on the inflammatory components have not been elucidated, this study investigated its effects in a mouse model of interstitial pneumonitis.Methods: Pneumonitis was induced in wild-type (WT) and S1R knockout (S1r−/−) mice by intratracheal administration of lipopolysaccharide: 0.5 mg/kg LPS. Treatment groups were randomized into 1) phosphate-buffered saline (PBS) +vehicle, 2) LPS + vehicle, 3) LPS + FLU (i.p. 20 mg x bwkg-1) or 4) LPS + dexamethasone (i.p. 5 mg x bwkg-1) groups.Results: LPS reduced tidal volume, minute ventilation, peak expiratory, inspiratory and mid-tidal expiratory flows. Similarly to the reference compound dexamethasone FLU counteracted all effects in WT, but not in S1r−/− mice. Furthermore, FLU alleviated LPS-induced macrophage infiltration in both genotypes, but had no effect on lung edema or neutrophil accumulation. FLU downregulated inflammatory cytokines IL-1, IL-6, TNF-α, and MCP-1 in WT mice, similarly to dexamethasone, but not in S1r−/− mice.Conclusion: Overall, FLU mitigates LPS-induced pulmonary inflammation and functional deterioration primarily via S1R signaling, highlighting a receptor-specific mechanism underlying its protective effects. Thus, targeting S1R may be an effective and safe alternative to other therapeutic approaches, including glucocorticoids to treat inflammatory lung injury.

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