Cromolyn sodium and masitinib combination inhibits fibroblast‐myofibroblast transition and exerts additive cell‐protective and antioxidant effects on a bleomycin‐induced in vitro fibrosis model

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA‐approved mast cell stabilizer. This study aims to investigate the anti‐fibrotic and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H 2 O 2 ) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple‐immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl‐2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H 2 O 2 ‐induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti‐fibrotic, cell‐protective, and antioxidant effects of the masitinib‐cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.