AXL Is a Potential Target for the Treatment of Intestinal Fibrosis.

Inflammatory Bowel Diseases
Calen A SteinerPeter D R Higgins

Abstract

Fibrosis is the final common pathway to intestinal failure in Crohn's disease, but no medical therapies exist to treat intestinal fibrosis. Activated myofibroblasts are key effector cells of fibrosis in multiple organ systems, including the intestine. AXL is a receptor tyrosine kinase that has been implicated in fibrogenic pathways involving myofibroblast activation. We aimed to investigate the AXL pathway as a potential target for the treatment of intestinal fibrosis. To establish proof of concept, we first analyzed AXL gene expression in 2 in vivo models of intestinal fibrosis and 3 in vitro models of intestinal fibrosis. We then tested whether pharmacological inhibition of AXL signaling could reduce fibrogenesis in 3 in vitro models of intestinal fibrosis. In vitro testing included 2 distinct cell culture models of intestinal fibrosis (matrix stiffness and TGF-β1 treatment) and a human intestinal organoid model using TGF-β1 cytokine stimulation. Our findings suggest that the AXL pathway is induced in models of intestinal fibrosis. We demonstrate that inhibition of AXL signaling with the small molecule inhibitor BGB324 abrogates both matrix-stiffness and transforming growth factor beta (TGF-β1)-induced fibrogenesis in human c...Continue Reading

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Citations

Nov 24, 2020·Expert Review of Gastroenterology & Hepatology·Joseph SleimanFlorian Rieder
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Aug 6, 2021·Digestive Diseases and Sciences·Calen A Steiner, Florian Rieder
Aug 10, 2021·Expert Opinion on Investigational Drugs·Berta CaballolAzucena Salas

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