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

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.

Therapeutic ultrasound ameliorates pulmonary fibrosis through inhibiting TGF-β/SMAD-mediated epithelial mesenchymal transition

“…This leads to the transfer of SMADs into the nucleus to regulate target gene transcription [33]. TGF-β-triggered SMAD2/3 signaling is pivotal in the induction of pulmonary brosis [34]. Based on these studies, we investigated how TUS treatment affected the TGF-β1/SMAD2/3 signaling pathway.…”

Cannabinoid Signaling in Kidney Disease

“…The results from the Lecru et al study [29] suggest that CB1 activity acts downstream of TGF-β1. Interestingly, CB1 is hypothesized to be a negative mediator of TGF-β1/Smad3 signaling in pulmonary fibrosis [72]. The study performed by Golosova et al [68] highlighted that high doses of AEA led to an increase in Smad3 expression, however surprisingly did not affect TGF-β1 expression.…”