Dual-targeting of peripheral cannabinoid-1 receptors and inducible NO synthase in pulmonary fibrosis

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options that may benefit from simultaneously targeting multiple pathways to improve therapeutic efficacy. Endocannabinoids (ECs) acting via the CB1R promote fibrosis, but their role in IPF has not been established. Activity of the enzyme inducible nitric oxide synthase (iNOS) is also increased in fibrosis and correlates with IPF progression. Aims and objectives: We tested the involvement of the EC/CB1R system and iNOS in the pathogenesis of IPF and the therapeutic impact of their simultaneous targeting using MRI-1867, an orally bioavailable, peripherally restricted CB1R/iNOS hybrid inhibitor in mice. Methods: We used the bleomycin-induced mouse PF (BL-PF) model, as well as BALF and lung tissue samples from patients with IPF and respective controls. Results: The EC anandamide was increased in the lung of bleomycin-treated mice and in BALF samples from IPF patients, in whom its level negatively correlated with pulmonary function tests. CB1R and iNOS protein levels were significantly elevated in lung tissue from patients with severe IPF or from bleomycin-treated mice. Upregulation of these two targets in the fibrotic lung was independent of one another. Moreover, MRI-1867 treatment arrested the progression of established fibrosis in BL-PF and dramatically improved survival rate, compared to vehicle or CB1R antagonism alone. Conclusion: We identified CB1R as a novel therapeutic target in IPF. Dual-targeting of CB1R and iNOS for inhibition offers a novel therapeutic approach with improved efficacy.