Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis
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
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
View: Text | PDF
Research Article Pulmonology

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

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

×

Figure 11

Effect of Cnr1 and Nos2 gene deletion or pharmacological inhibition on Irf5 expression in the lung.

Options: View larger image (or click on image) Download as PowerPoint
Effect of Cnr1 and Nos2 gene deletion or pharmacological inhibition on I...
Irf5 expression in lung tissue from control mice (n = 5) 14 days after bleomycin treatment in WT (n = 20), Cnr1–/– (n = 9), and Nos2–/– mice (n = 11) (A). Irf5 expression in bleomycin-challenged WT mice treated from day 1–14 (14D) or day 7–14 (7D) with vehicle (V), rimonabant (R), MRI-1867 (MRI), or both rimonabant and MRI-1867 at 10 mg/kg, PO. Data from n = 5 (control), 5 (V, 7D), 12 (V, 14D), and 8 mice (rimonabant and MRI-1867 treatments groups) are shown (B). C, control. IL1β protein levels in lung tissue lysates from control mice (n = 4) 14 days after bleomycin treatment in WT (n = 6), Cnr1–/– (n = 5), and Nos2–/– mice (n = 5) (C). Data represent box-and-whisker plots; horizontal lines represent the median and 25th to 75th percentiles, and whiskers represent minimum and maximum values, and were analyzed by 1-way ANOVA followed by Dunnett’s multiple comparisons test. *P < 0.05 indicates significant difference from control group. #P < 0.05 indicates significant effect of either gene deletion or pharmacological inhibition relative to WT vehicle in the bleomycin-challenged group.