Abstract
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.
Highlights
Pulmonary fibrosis is a group of chronic, progressive, and usually lethal lung diseases that can be idiopathic or secondary to various diseases, characterized by excessive production and massive deposition of extracellular matrix (ECM) in lung interstitium (Barratt et al, 2018)
Using both in vitro and in vivo models of pulmonary fibrosis, we demonstrated that the expression of cannabinoid type 1 receptors (CB1R) increased in lung fibroblasts in response to pulmonary fibrosis, and the pharmacologic activation of CB1R with its specific agonist ACPA protected against BLM-induced pulmonary fibrosis, significantly decreasing lung fibroblast migration and the excessive expression of ECM proteins stimulated by BLM in vivo or TGF-β1 in vitro, rather than the basal expression of ECM proteins in normal control lung fibroblasts
We demonstrated that CB1R-selective agonist ACPA dose-dependently downregulated the activation of TGF-β-Smad2/3 signaling and the levels of its downstream effectors snail and slug, which are the transcription factors to regulate the expression of ECM proteins
Summary
Pulmonary fibrosis is a group of chronic, progressive, and usually lethal lung diseases that can be idiopathic or secondary to various diseases, characterized by excessive production and massive deposition of extracellular matrix (ECM) in lung interstitium (Barratt et al, 2018). Available therapeutic options for pulmonary fibrosis, including two FDA-approved IPF drugs (nintedanib and pirfenidone) that slow the progression of the disease, have barely improved the outcomes of patients (Trachalaki et al, 2021). In the pathogenesis of pulmonary fibrosis, lung fibroblasts are activated under the stimulation of profibrotic cytokines and exhibit a series of cell behavior changes, such as proliferation, migration, and ECM production, which is associated with severity of the disease in patients with pulmonary fibrosis and mouse models of pulmonary fibrosis (Xia et al, 2014; DePianto et al, 2015; Kasam et al, 2020). TGF-β family proteins, especially TGFβ1, released by injured lung epitheliums, immune cells, and fibrocytes during pulmonary fibrosis, are considered the principal profibrotic cytokines that drives fibrotic responses (Fernandez and Eickelberg, 2012; Martinez et al, 2017; Aschner et al, 2020; Lee et al, 2020). The indirect modulation of TGF-β signals might be an alternative option for therapy of pulmonary fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
