Frontiers in pharmacology · 2026
The sigma-1 receptor agonist fluvoxamine alleviates endotoxin-induced acute lung injury in mice.
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Ritter Emese, Csekő Kata, Hosszú Ádám, Tóth Ákos R, Hargitai Dóra, Kereskai László, Fekete Andrea, Helyes Zsuzsanna
Аннотация
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.
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.