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Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis
Resat Cinar, … , William A. Gahl, George Kunos
Resat Cinar, … , William A. Gahl, George Kunos
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e92281. https://doi.org/10.1172/jci.insight.92281.
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Research Article Pulmonology

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

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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.

Authors

Resat Cinar, Bernadette R. Gochuico, Malliga R. Iyer, Tony Jourdan, Tadafumi Yokoyama, Joshua K. Park, Nathan J. Coffey, Hadass Pri-Chen, Gergő Szanda, Ziyi Liu, Ken Mackie, William A. Gahl, George Kunos

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Figure 2

Increased CB1R and iNOS protein in lung samples from IPF patients.

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Increased CB1R and iNOS protein in lung samples from IPF patients.
CB1R ...
CB1R and iNOS immunohistochemistry in human lung tissue sections from idiopathic pulmonary fibrosis (IPF) patients and controls without fibrotic lung disease (A). Fibrosis visualized by Masson trichrome–stained sections from the same subjects (B). Data represent box-and-whisker plots; horizontal lines represent the median and 25th to 75th percentiles, and whiskers represent minimum and maximum values from 5 normal volunteers or 10 IPF subjects. Data were analyzed by t test. *P < 0.05 indicates significant difference relative to control group. Scale bar: 25 μm (A, right columns); 50 μm (B, right columns); 100 μm (A and B, left columns).

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