Adenosine A3 Receptor (A3AR) Agonist for the Treatment of Bleomycin-Induced Lung Fibrosis in Mice

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 A(3)AR 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 A(3)AR agonist on lung stiffness, studying the airway resistance to inflation, oxidative stress (8-OHdG and MDA), inflammation, pro- and anti-inflammatory marker levels (IL-1 beta, IL-6, TNF-alpha, IL-10 and IL-17A) and fibrosis establishment, evaluating transforming growth factor (TGF)-beta expression and alpha-smooth muscle actin (alpha-SMA) deposition in lungs. Bleomycin administration increased lung stiffness, TGF-beta levels, alpha-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 A(3)AR agonists in lung fibrosis by demonstrating reduced disease progression, as indicated by decreased inflammation, TGF-beta expression and fibrotic remodeling.