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

Çınar, Reşat; Gochuico, Bernadette R.; Iyer, Malliga R.; Jourdan, Tony; Yokoyama, Tadafumi; Park, Joshua K.; Coffey, Nathan J.; Pri‐Chen, Hadass; Szanda, Gergö; Liu, Ziyi; Mackie, Ken; Gahl, William A.; Kunos, George

doi:10.1172/jci.insight.92281

Cited by 60 publications

(83 citation statements)

References 73 publications

(94 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous work by Cinar and colleagues emphasized the anti-fibrogenic role of MRI-1867, in both the liver (Cinar et al, 2016) and the lungs (Cinar et al, 2017). Therefore, we also investigated its anti-fibrogenic FIGURE 4 MRI-1867 and peripheral CB 1 receptor blockade effectively restore metabolic and kidney morphological changes in diet-induced obese (DIO) mice in comparison with inducible NOS inhibition or pair feeding.…”

Section: Dual Blockade Of Cb 1 Receptors and Inos Decreases Kidneymentioning

confidence: 94%

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Udi

Hinden

Ahmad

et al. 2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB 1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB 1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD.Experimental Approach: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB 1 receptor/iNOS antagonist, MRI-1867(3 mg·kg −1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB 1 receptor antagonist (JD5037; 3 mg·kg −1 ), iNOS antagonist (1400W; 10 mg·kg −1 ), and pair feeding. Mice with highfat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls.Key Results: Enhanced expression of CB 1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB 1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling.Conclusions and Implications: Collectively, our results highlight the therapeutic relevance of blocking CB 1 receptors and iNOS in ameliorating obesity-induced CKD.---

show abstract

Section: Dual Blockade Of Cb 1 Receptors and Inos Decreases Kidneymentioning

confidence: 94%

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Udi

Hinden

Ahmad

et al. 2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Increase in iNOS levels is considered as an early indicator of the inflammatory process and abnormally expressed iNOS genes are considered as therapeutic targets for pulmonary diseases . The expression of iNOS can be induced by TNF‐α .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms involved in inflammatory pulmonary fibrosis induced by lunar dust simulant in rats

Sun

Liu

Zhang

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

Lunar dust is one of the biggest risk factors in the future manned exploration mission. Much is not known about the pulmonary toxicity of lunar dust. The aim of this study was to evaluate the lung inflammation and oxidative stress induced by subacute exposure to lunar dust stimulant (LDS) in rats. Wistar rats were intratracheally administered LDS, twice a week for 3 weeks. Inflammatory cell counting and cytokine assays using bronchoalveolar lavage fluid (BALF) were performed. Lung tissues were processed for histopathological examination and immunohistochemical staining. Biomarkers of oxidative stress and genes and proteins related to inflammation and fibrosis in lung tissue were also determined. The neutrophil count in the BALF of LDS‐exposed groups was higher than that in controls (P < .05). LDS caused a significant increase in some of biochemical indicators and proinflammatory factors levels in BALF compared with control group. The normal balance between oxidation and antioxidation was broken by LDS. Pathological characteristics of lung tissue and immunohistochemical results for α‐smooth muscle actin (α‐SMA) indicated that inflammatory response was an extremely important passage to pulmonary fibrosis. Real‐time PCR analysis showed elevated levels of nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate oxidase (NOX) mRNA in the lungs (P < .05). Western blotting results were consistent with immunohistochemistry and qPCR results. These results indicate that inhalation of lunar dust may cause inflammatory pulmonary fibrosis. NOX4 may be a key potential therapeutic target for inflammatory injury and fibrosis in the lung.

show abstract

“…In addition, CB2/PPARγ agonist with CB1 antagonistic property, VCE-004.3, was proposed for the treatment of SSc, based on promising in vitro results [211]. Dual CB1/iNOS inhibitor, MRI-1867 (10 mg/kg), exhibited antifibrotic activity in the rodent model of pulmonary fibrosis [212]. Alteration in ECS proteins expression was shown in psoriasis, with an increase in CB1 in psoriatic arthritis, CB2 in psoriasis vulgaris, and GPR55 in both forms of the disease.…”

Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

View full text Add to dashboard Cite

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

show abstract

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

Cited by 60 publications

References 73 publications

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Mechanisms involved in inflammatory pulmonary fibrosis induced by lunar dust simulant in rats

A Guide to Targeting the Endocannabinoid System in Drug Design

Contact Info

Product

Resources

About

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

Cited by 60 publications

References 73 publications

Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Mechanisms involved in inflammatory pulmonary fibrosis induced by lunar dust simulant in rats

A Guide to Targeting the Endocannabinoid System in Drug Design

Contact Info

Product

Resources

About

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease