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

Area of Science:

• Pulmonary Medicine
• Pharmacology
• Immunology

Background:

• Pulmonary fibrosis (PF) is a severe lung disease with limited treatment options.
• Cannabinoid receptor 1 (CB1R) and inducible nitric oxide synthase (iNOS) play roles in PF pathogenesis.
• The specific cellular functions of CB1R in PF remain largely unexplored.

Purpose of the Study:

• To investigate the cell-specific role of CB1R in pulmonary fibrosis.
• To evaluate the therapeutic potential of targeting CB1R and iNOS in PF.
• To assess the efficacy of inhaled zevaquenabant for PF treatment.

Main Methods:

• Investigated CB1R's role in alveolar macrophages (AMs) and their mediation of pro-fibrotic factors.
• Utilized a bleomycin-induced PF mouse model.
• Administered zevaquenabant (a CB1R/iNOS inhibitor) via pulmonary and systemic routes.
• Employed a systems pharmacology approach and human precision-cut lung slices for analysis.

Main Results:

• CB1R in AMs promotes PF by inducing pro-fibrotic macrophages.
• Pulmonary delivery of zevaquenabant was as effective as systemic delivery and nintedanib in mitigating PF.
• Zevaquenabant and nintedanib reversed shared and distinct PF-related pathways in mice and humans.
• Zevaquenabant reduced fibrosis and pro-fibrotic mediators in human lung tissue.

Conclusions:

• CB1R-expressing AMs are a viable therapeutic target for PF.
• Inhaled zevaquenabant represents a safe, effective, and well-tolerated strategy for PF treatment.
• Targeting both CB1R and iNOS offers a promising multitargeted therapeutic approach for PF.