RT Journal Article SR Electronic T1 Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3 JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900350 DO 10.26508/lsa.201900350 VO 2 IS 3 A1 Chang-Min Lee A1 Chuan-Hua He A1 Jin Wook Park A1 Jae Hyun Lee A1 Suchitra Kamle A1 Bing Ma A1 Bedia Akosman A1 Roberto Cotez A1 Emily Chen A1 Yang Zhou A1 Erica L Herzog A1 Changwan Ryu A1 Xueyan Peng A1 Ivan O Rosas A1 Sergio Poli A1 Carol Feghali Bostwick A1 Augustine M Choi A1 Jack A Elias A1 Chun Geun Lee YR 2019 UL https://www.life-science-alliance.org/content/2/3/e201900350.abstract AB TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1–mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1–stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-β1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-β receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-β1 signaling and effector responses and FOXO3 playing a critical role in TGF-β1 induction of SMAD7. These pathways were disease relevant because the levels of CHIT1 were increased and inversely correlated with SMAD7 in tissues from patients with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease. These studies demonstrate that CHIT1 regulates TGF-β1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis.