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Targeting of cannabinoid receptor 1 for antagonism in profibrotic alveolar macrophages mitigates pulmonary fibrosis

ABSTRACT: Pulmonary fibrosis (PF) is a life-threatening disease in need of effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB1R) and iNOS activation in lungs were highlighted in PF to improve efficacy by dual-target therapy. However, cell-specific role of CB1R in PF has not been explored. Here, we demonstrated that CB1R in alveolar macrophages (AMs) is responsible to release anandamide into alveoli and promote PF. Activation of CB1R in AMs orchestrated profibrotic lung microenvironment with inducing profibrotic macrophages. Thus, CB1R in AMs represents a target for anti-fibrotic therapy via pulmonary delivery. PF necessitates multi-targeted therapy to improve therapeutic efficacy. Pulmonary delivery of MRI-1867 (zevaquenabant), a peripherally acting hybrid CB1R/iNOS inhibitor, at 0.5 mg/kg/day is as effective as systemic delivery of 10 mg/kg/day, and nintedanib in mitigating bleomycin-induced PF. Systems pharmacology approach revealed that MRI-1867 and nintedanib treatments reversed alterations in distinct and shared multiple PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and fibroproliferative mediators in human precision-cut lung slices. Therefore, pulmonary delivery of zevaquenabant provides a more targeted, tolerable and safer therapeutic modality in PF by simultaneously targeting CB1R and iNOS in local fibrotic microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE273132 | GEO | 2025/06/06

REPOSITORIES: GEO

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