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Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.

Authors :
Ahangari F
Becker C
Foster DG
Chioccioli M
Nelson M
Beke K
Wang X
Justet A
Adams T
Readhead B
Meador C
Correll K
Lili LN
Roybal HM
Rose KA
Ding S
Barnthaler T
Briones N
DeIuliis G
Schupp JC
Li Q
Omote N
Aschner Y
Sharma L
Kopf KW
Magnusson B
Hicks R
Backmark A
Dela Cruz CS
Rosas I
Cousens LP
Dudley JT
Kaminski N
Downey GP
Source :
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Dec 15; Vol. 206 (12), pp. 1463-1479.
Publication Year :
2022

Abstract

Rationale: 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.

Details

Language :
English
ISSN :
1535-4970
Volume :
206
Issue :
12
Database :
MEDLINE
Journal :
American journal of respiratory and critical care medicine
Publication Type :
Academic Journal
Accession number :
35998281
Full Text :
https://doi.org/10.1164/rccm.202010-3832OC