Abstract
Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment. The present investigation explored the action of MRS5980, a new, highly potent and selective A3AR agonist, in an established murine model of lung fibrosis. The effects of either vehicle or MRS5980 were studied in mice following intratracheal bleomycin administration. We evaluated the role of the A3AR agonist on lung stiffness, studying the airway resistance to inflation, oxidative stress (8-OHdG and MDA), inflammation, pro- and anti-inflammatory marker levels (IL-1β, IL-6, TNF-α, IL-10 and IL-17A) and fibrosis establishment, evaluating transforming growth factor (TGF)-β expression and α-smooth muscle actin (α-SMA) deposition in lungs. Bleomycin administration increased lung stiffness, TGF-β levels, α-SMA deposition, and inflammatory and oxidative stress markers. The treatment with MRS5980 attenuated all the analyzed functional, biochemical and histopathological markers in a dose-dependent manner. Our findings support the therapeutic potential of A3AR agonists in lung fibrosis by demonstrating reduced disease progression, as indicated by decreased inflammation, TGF-β expression and fibrotic remodeling.
Funder
Fondazione Cassa di Risparmio di Firenze
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference43 articles.
1. Update in Idiopathic Pulmonary Fibrosis;Frankel;Curr. Opin. Pulm. Med.,2009
2. Role of Histamine H4 Receptor Ligands in Bleomycin-Induced Pulmonary Fibrosis;Lucarini;Pharmacol. Res.,2016
3. Prostaglandin E2 Inhibits Fibroblast to Myofibroblast Transition via E. Prostanoid Receptor 2 Signaling and Cyclic Adenosine Monophosphate Elevation;Kolodsick;Am. J. Respir. Cell. Mol. Biol.,2003
4. Sauleda, J., Núñez, B., Sala, E., and Soriano, J. Idiopathic Pulmonary Fibrosis: Epidemiology, Natural History, Phenotypes. Med. Sci., 2018. 6.
5. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline;Raghu;Am. J. Respir. Crit. Care Med.,2015
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献