Targeting cannabinoid receptor 1 for antagonism in pro-fibrotic alveolar macrophages mitigates pulmonary fibrosis

Pulmonary fibrosis (PF) is a life-threatening disease that requires effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB₁R) and inducible nitric oxide synthase (iNOS) in the lungs and their joint therapeutic targeting were highlighted in PF. However, the cell-specific role of CB₁R in PF has not been explored. Here, we demonstrate that CB₁R in alveolar macrophages (AMs) mediates the release of anandamide into the alveoli, which promotes PF by inducing pro-fibrotic macrophages that are accessible to locally delivered antifibrotic therapy. A multitargeted therapy may improve therapeutic efficacy in PF. Pulmonary delivery of 0.5 mg/kg/d MRI-1867 (zevaquenabant), a peripherally acting hybrid CB₁R/ iNOS inhibitor, was as effective as systemic delivery of 10 mg/kg/d and also matched the efficacy of nintedanib in mitigating bleomycin-induced PF. A systems pharmacology approach revealed that zevaquenabant and nintedanib treatments reversed pathologic changes in both distinct and shared PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and pro-fibrotic mediators in human precision-cut lung slices. These findings establish CB₁R-expressing AMs as a therapeutic target and support local delivery of dual CB₁R/iNOS inhibitor zevaquenabant by inhalation as an effective, well-tolerated, and safe strategy for PF.