Fluvoxamine, an inhibitor of CYP1A2, improves CS-induced pulmonary inflammation through estrogen deficiency

Abstract

Chronic obstructive pulmonary disease (COPD), one of the most prevalent respiratory diseases worldwide, exhibits marked gender disparities, with women disproportionately affected. Current therapeutic modalities for COPD are relatively ineffective as the available drugs cannot considerably delay disease progression or substantially affect inflammation. Therefore, the suppression of inflammatory responses is considered an essential management strategy for COPD. Fluvoxamine, a CYP1A2 inhibitor with anti-inflammatory effects, and CYP1A2 affects estrogen metabolism. However, its potential as a COPD treatment and interaction with estrogen in women are unclear. This study explored fluvoxamine's efficacy in female mice with cigarette smoke (CS)-induced COPD. Administering 8 mg/kg fluvoxamine intraperitoneally markedly reduced CS-induced lung damage, lowering histopathological injury and pro-inflammatory cytokines in bronchoalveolar lavage fluid and serum. RNA-seq analysis revealed that fluvoxamine significantly suppressed the upregulation of inflammation-related genes. Furthermore, the KEGG and GSEA analysis of differentially expressed genes in lung transcriptomics revealed that the metabolism of xenobiotics by cytochrome P450 and JAK-STAT signaling pathway were regulated after fluvoxamine treatment. WB and ELISA assay also demonstrated a significant decrease in CYP1A2 and estrogen levels following treatment with fluvoxamine or tamoxifen. Crucially, fluvoxamine matched tamoxifen (an estrogen inhibitor) in improving lung structural parameters (mean linear intercept, destructive index). These results suggest fluvoxamine mitigates COPD by inhibiting CYP1A2, reducing inflammatory mediators and estrogen. The proposed mechanism combines estrogen metabolism modulation and anti-inflammatory action, offering dual therapeutic benefits. This study positions fluvoxamine as a novel COPD treatment candidate, particularly for women, targeting hormonal and inflammatory pathways. Further research is needed to validate clinical translation.