AM251, a cannabinoid receptor 1 antagonist, prevents human fibroblasts differentiation and collagen deposition induced by TGF-β – An in vitro study

Correia‐Sá, Inês; Carvalho, Cláudia; Serrão, Paula; Machado, Vera; Carvalho, Sofia; Marques, Marisa; Vieira-Coelho, Maria Augusta

doi:10.1016/j.ejphar.2020.173738

Cited by 13 publications

(15 citation statements)

References 38 publications

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“…On the other hand, the phytocannabinoids (THC, cannabidiol, cannabichromene, and cannabinol) and synthetic preparations (Cesamet, Marinol, and Sativex) are candidates for development as anti-inflammatory and antifibrotic agents ( Zurier and Burstein, 2016 ). In the present study, we found that CB 1 R expression dramatically increased in lung tissues and fibroblasts in response to experimental pulmonary fibrosis, but showed that its selective agonist ACPA exhibited marked antifibrotic effect both in vitro and in vivo models of pulmonary fibrosis, which was inconsistent with CB 1 R inhibition that ameliorated fibrosis ( Bronova et al, 2015 ; Cinar et al, 2017 ; Correia-Sá et al, 2021 ). This inconsistency is due to different tissues (lungs, liver, kidneys, or skin), cell types (macrophages vs. fibroblasts), pathologic stages of fibrotic diseases (inflammatory stage vs. fibrosis stage), and various types of G-protein signaling triggered by CB 1 R. Previous studies have paid close attention to inflammation period and macrophage functions in pulmonary fibrosis, and the inhibition of CB 1 R exhibited anti-inflammatory properties ( Cinar et al, 2017 ).…”

Section: Discussioncontrasting

confidence: 52%

“…Although the CB 1 R was consistently found highly activated in the pathogenesis of pulmonary fibrosis, the role of activated CB 1 R in fibrosis is controversial. Correia-Sá et al found that CB 1 R agonist ACEA increases, and antagonist AM251 reduces, collagen deposition induced by TGF-β in the fibroblasts obtained from abdominal human skin ( Correia-Sá et al, 2021 ). However, it has been recently proposed that cannabinoids, natural CB 1 R agonists, may manifest as profibrotic or antifibrotic agents in skin fibrosis ( Pryimak et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation

et al. 2022

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Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB1R) has been indicated in fibrotic diseases, but whether or not the activation of CB1R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB1R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-β)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-β was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB1R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-β-challenged primary lung fibroblasts in vitro. CB1R-specific agonist ACPA significantly diminished the activation of TGF-β–Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-β-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB1R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-β-Smad2/3 signaling by targeting CB1R.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation

et al. 2022

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“…To further investigate the effects of AZD6738 in HConFs, we conducted a TGF-β1-treated model (10 ng/ml) in cultured HConFs, which was a well-established model for inducing cellular proliferation, migration, and fibrosis in vitro ( Vaamonde-Garcia et al, 2019 ; Willard et al, 2020 ; Correia-Sá et al, 2021 ). After 10 ng/ml TGF-β1 stimulation, HConFs became aggregated and protrude more pseudopodia, which was inhibited by AZD6738 ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…The cells were treated with 0.1, 0.25, 0.5, 1, 2, 5 and 10 μM AZD6738 (Cat No. HY-19323; MedChemExpress, NJ, United States), 0.1% dimethyl sulfoxide (DMSO; diluted with cell culture medium) and 10 ng/ml TGF-β1 (PeproTech, NJ, United States) for 24 or 48 h. For the group treated with 0.1 and 5 μM AZD6738, cells were treated with 10 ng/ml TGF-β1 ( Willard et al, 2020 ; Correia-Sá et al, 2021 ), treatment for 48 h simultaneously. The blank control group was set in all experiments, cells were treated with a culture medium only.…”

Section: Methodsmentioning

confidence: 99%

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

Longxiang

Lan

et al. 2022

Front. Pharmacol.

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Trabeculectomy can effectively reduce intraocular pressure (IOP) in glaucoma patients, the long-term surgical failure is due to the excessive proliferation and fibrotic response of conjunctival fibroblasts which causes the subconjunctival scar and non-functional filtering bleb. In this study, we demonstrated that AZD6738 (Ceralasertib), a novel potent ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, can inhibit the fibrotic response of conjunctival fibroblasts for the first time. Our in vitro study demonstrated that AZD6738 inhibited the level and the phosphorylation of checkpoint kinase 1 (CHK1), reduced TGF-β1-induced cell proliferation and migration, and induced apoptosis of human conjunctival fibroblasts (HConFs) in the high-dose group (5 μM). Low-dose AZD6738 (0.1 μM) inhibited the phosphorylation of CHK1 and reduce fibrotic response but did not promote apoptosis of HConFs. Further molecular research indicated that AZD6738 regulates survival and apoptosis of HConFs by balancing the CHK1/P53 and PI3K/AKT pathways, and inhibiting TGF-β1-induced fibrotic response including myofibroblast activation and relative extracellular matrix (ECM) protein synthesis such as fibronectin (FN), collagen Ⅰ (COL1) and collagen Ⅳ (COL4) through a dual pharmacological mechanism. Hence, our results show that AZD6738 inhibits fibrotic responses in cultured HConFs in vitro and may become a potential therapeutic option for anti-subconjunctival scarring after trabeculectomy.

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“…In mice, genetic and pharmacological inactivation of CB1 has been reported to decrease liver fibrogenesis by reducing the TGF-β1 levels, thus decreasing the accumulation of fibrogenic cells after apoptosis and inhibiting the growth of hepatic myofibroblasts [ 45 ]. Likewise, the treatment of skin-derived human fibroblasts with AM251 (a CB1 selective antagonist) has been proven to inhibit both fibroblast differentiation into myofibroblast and collagen deposition [ 46 ]. Therefore, the significant increase in collagen deposition we reported in the term chorionic villi of preeclamptic patients might well be a result of the CB1-enhanced expression characteristic of these pathological villi.…”

Section: Discussionmentioning

confidence: 99%

Preeclampsia Correlates with an Increase in Cannabinoid Receptor 1 Levels Leading to Macromolecular Alterations in Chorionic Villi of Term Placenta

Lombó

Giommi

Paolucci

et al. 2022

IJMS

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Preeclampsia is a human pregnancy-specific disease characterized by abnormal placentation that usually presents with maternal hypertension and proteinuria. The main hallmark of preeclampsia, impaired trophoblast migration, and the subsequent disruption of uterine arteries remodeling lead to several molecular alterations in the placental compartments with those occurring in the chorionic villi being of the utmost importance. Given the essential role of the endocannabinoid system during preimplantation and trophoblast migration, we have combined the histological and hyperspectral imaging analyses to shed light on the involvement of two cannabinoid receptors in the macromolecular alterations related to preeclampsia. The results obtained by immunohistochemistry showed a significant increase in the protein levels of cannabinoid receptor 1 (CB1) in the preeclamptic chorionic villi. However, no changes were reported regarding transient receptor potential vanilloid 1 (TRPV-1) levels either in the bulk placental samples or chorionic villi when comparing control and preeclamptic patients. Histological analysis and Fourier-transform infrared spectroscopy (FTIRI) showed an increase in collagen deposition together with higher levels of lipid peroxidation and phosphorylated compounds in the pathological villi. Since CB1 enhancement has been described as promoting fibrosis and oxidative stress in several tissues, we proposed that the higher receptor abundance in preeclampsia could be triggering similar molecular effects in preeclamptic term placentas.

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AM251, a cannabinoid receptor 1 antagonist, prevents human fibroblasts differentiation and collagen deposition induced by TGF-β – An in vitro study

Cited by 13 publications

References 38 publications

ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation

ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

Preeclampsia Correlates with an Increase in Cannabinoid Receptor 1 Levels Leading to Macromolecular Alterations in Chorionic Villi of Term Placenta

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