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Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis
Resat Cinar1, Bernadette R Gochuico2, Malliga R Iyer1
1Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), and.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy. To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CB1R) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CB1R system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls. In addition, we investigated the antifibrotic efficacy in the mouse PF model of an orally bioavailable and peripherally restricted CB1R/iNOS hybrid inhibitor. We report that increased activity of the endocannabinoid/CB1R system parallels disease progression in the lungs of patients with idiopathic PF and in mice with bleomycin-induced PF and is associated with increased tissue levels of interferon regulatory factor-5. Furthermore, we demonstrate that simultaneous engagement of the secondary target iNOS by the hybrid CB1R/iNOS inhibitor has greater antifibrotic efficacy than inhibition of CB1R alone. This hybrid antagonist also arrests the progression of established fibrosis in mice, thus making it a viable candidate for future translational studies in IPF.
Insights
Idiopathic pulmonary fibrosis (IPF) treatment needs new targets. A dual inhibitor targeting the endocannabinoid/cannabinoid receptor 1 (CB1R) system and inducible nitric oxide synthase (iNOS) shows promise for treating lung fibrosis.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Fibrosis Research
Background:
- Idiopathic pulmonary fibrosis (IPF) is a severe lung disease with limited treatment options.
- Complex IPF pathogenesis necessitates targeting multiple pathways for improved therapeutic outcomes.
- The endocannabinoid/cannabinoid receptor 1 (CB1R) system and inducible nitric oxide synthase (iNOS) are explored as potential therapeutic targets.
Purpose of the Study:
- To investigate the role of the endocannabinoid/CB1R system and its interaction with iNOS in IPF.
- To evaluate the antifibrotic efficacy of a novel CB1R/iNOS dual inhibitor in a preclinical model of pulmonary fibrosis.
Main Methods:
- Analysis of lung fibrosis, endocannabinoid/CB1R system, and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF).
- Examination of lung tissue and bronchoalveolar lavage fluid (BALF) from IPF patients and controls.
- Assessment of a peripherally restricted CB1R/iNOS hybrid inhibitor in the mouse PF model.
Main Results:
- Increased endocannabinoid/CB1R system activity correlated with IPF progression in both mice and human samples.
- Elevated tissue levels of interferon regulatory factor-5 were observed.
- The dual CB1R/iNOS inhibitor demonstrated superior antifibrotic efficacy compared to CB1R inhibition alone.
- The hybrid antagonist halted established fibrosis progression in mice.
Conclusions:
- The endocannabinoid/CB1R system is implicated in IPF pathogenesis.
- Simultaneous inhibition of CB1R and iNOS offers enhanced antifibrotic effects.
- A CB1R/iNOS hybrid inhibitor represents a promising candidate for future IPF translational studies.