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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 5

Effect of Cnr1 and Nos2 gene deletion on fibrosis development and survival in mice.

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Effect of Cnr1 and Nos2 gene deletion on fibrosis development and surviv...
Collagen deposition and myofibroblast activation in lung visualized by Masson trichrome staining and α-SMA immunostaining at 14 days after bleomycin challenge (A), as quantified by Ashcroft scoring (B), hydroxyproline (hyp) content (C), and α-SMA staining (D). Survival curve of mice after bleomycin challenge. Survival by day 18 was analyzed by using log-rank (Mantel-Cox) test comparing WT, Cnr1–/–, and Nos2–/– mice (E). Data represent box-and-whisker plots; horizontal lines represent the median and 25th to 75th percentiles, and whiskers represent minimum and maximum values from n = 5 (control), 20 (WT), 9 (Cnr1–/–), and 11 (Nos2–/–) mice. Data were analyzed by 1-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05 indicates significant difference from control group in WT. #P < 0.05 indicates significant effect of gene deletion relative to WT in the bleomycin-challenged group. Scale bar: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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