• Farida Ahangari, Christine Becker, Daniel G Foster, Maurizio Chioccioli, Meghan Nelson, Keriann Beke, Xing Wang, Aurelien Justet, Taylor Adams, Benjamin Readhead, Carly Meador, Kelly Correll, Loukia N Lili, Helen M Roybal, Kadi-Ann Rose, Shuizi Ding, Thomas Barnthaler, Natalie Briones, Giuseppe DeIuliis, Jonas C Schupp, Qin Li, Norihito Omote, Yael Aschner, Lokesh Sharma, Katrina W Kopf, Björn Magnusson, Ryan Hicks, Anna Backmark, Charles S Dela Cruz, Ivan Rosas, Leslie P Cousens, Joel T Dudley, Naftali Kaminski, and Gregory P Downey.
• Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
• Am. J. Respir. Crit. Care Med. 2022 Dec 15; 206 (12): 146314791463-1479.

AbstractRationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-β (adenovirus transforming growth factor-β) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.

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