Apelin Prevents and Alleviates Crystalline Silica-induced Pulmonary Fibrosis via Inhibiting Transforming Growth Factor Beta 1-triggered Fibroblast Activation

Abstract

Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of the G-protein-coupled receptor (APJ), is abundantly expressed in diverse organs. The apelin-APJ axis helps to control pathological and physiological processes in lung. The role of apelin in the pathological process and its possible therapeutic effects on silicosis have not been elucidated. In this study, we found that lung expression and circulating levels of apelin were markedly decreased in silicosis patients and silica-induced fibrotic mice and associated with the severity. Furthermore, in vivo data demonstrated that pre-treatment from day 3 and post-treatment from day 15 with apelin could both alleviate silica-induced pulmonary fibrosis in mice. Besides, apelin inhibited pulmonary fibroblast activation via transforming growth factor beta 1 (TGF-β1) signaling. Our study suggested that apelin could prevent and reverse silica-induced pulmonary fibrosis by inhibiting the fibroblast activation through TGF-β1 signaling pathway, thus providing a new potential therapeutic strategy for silicosis and other pulmonary fibrosis.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan

“…Additionally, apelin is anti-fibrotic in the heart, and directly suppresses expression of tumour necrosis factor-β and transforming growth factor-β mediated expression of myofibroblast markers (including α-smooth muscle actin and collagen) to attenuate myocardial fibrotic remodelling in vivo ( Pchejetski et al, 2012 ; Sato et al, 2013 ). Intriguingly, apelin has been shown to prevent and alleviate crystalline silica-induced pulmonary fibrosis through inhibition of transforming growth factor-β ( Shen et al, 2023 ), suggesting that apelin agonists might have synergistic effects when used with the transforming growth factor-β ligand trapping therapy, sotatercept, which is on track for FDA approval in PAH ( Torbic and Tonelli, 2024 ).…”

The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

“…The APJ pathway is also closely related to renal fibrosis and improves renal interstitial fibrosis via inhibition of phosphorylated Smad2/3 induced by TGFβ-stimulation ( 19 ). There are studies that in pulmonary fibrosis, the apelin-APJ system inhibits the phosphorylation of Smad2/3 and suppresses extracellular matrix production induced by TGF-β ( 27 ), and in renal tubular epithelial cells, it inhibits phosphorylated Smad2/3 via activation of PKC-ε ( 28 ). It was posited by the authors that the apelin-APJ system could inhibit tumor-promoting CAFs, especially in acquiring myofibroblast-like characteristics.…”