Nerandomilast (BI 1015550) attenuating pulmonary fibrosis in a mouse model of rheumatoid arthritis-associated interstitial lung disease by modulating the TGF-β1/PI3K/Akt signaling pathway

Abstract

Background Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular manifestation of rheumatoid arthritis, leading to increased mortality and impaired quality of life. However, effective therapeutic strategies remain limited, highlighting the need to explore novel treatments for RA-ILD. This study aimed to evaluate the ability of nerandomilast (BI 1015550) to attenuate joint inflammation and pulmonary fibrosis in a murine model of RA-ILD, with particular emphasis on the potential involvement of the transforming growth factor-beta 1 (TGF-beta 1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating its antifibrotic effects. Methods A total of 20 male DBA/1 mice (a classic collagen-induced arthritis-susceptible strain) aged 8 weeks were randomly assigned to four groups: control (n=3), RA-ILD (n=5), nerandomilast (BI 1015550) (n=6), and nintedanib (n=6). RA-ILD was induced in all mice except those in the control group using bovine type II collagen (bCII). Nerandomilast and nintedanib were orally administered to the respective treatment groups on alternate days for 12 weeks. Serum tumor necrosis factor-alpha (TNF-alpha) levels were measured using enzyme-linked immunosorbent assay (ELISA), while immunohistochemistry was performed to evaluate TNF-alpha and matrix metalloproteinase-3 (MMP3) expression in knee joint tissues. In addition, the expression levels of Col-IV, fibronectin, MMP3, TNF-alpha, TGF-beta 1, total and phosphorylated PI3K, and total and phosphorylated Akt in lung tissues were quantified by Western blot analysis. Results Nerandomilast significantly reduced serum TNF-alpha levels in RA-ILD mice (P<0.05). Treatment with nerandomilast alleviated pulmonary inflammatory cell infiltration and collagen deposition, while significantly reducing alveolar inflammation and Ashcroft scores (P<0.05). Compared with the RA-ILD group, the nerandomilast-treated group exhibited markedly lower protein expression levels of Col-IV, fibronectin, MMP3, TGF-beta 1, and TNF-alpha in lung tissues (P<0.05). Furthermore, the nerandomilast group showed significantly decreased p-PI3K/PI3K and p-Akt/Akt expression ratios compared with the RA-ILD group (P<0.05). Conclusions Nerandomilast exerts significant protective effects against pulmonary inflammation and fibrosis in RA-ILD mice, potentially through the downregulation of TNF-alpha expression and modulation of the TGF-beta 1/PI3K/Akt signaling pathway.