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A3870 - Chitotriosidase Interacts with TGFbrap1 and FoxO3a, Regulates TGF-β Signaling and Smad7 Expression in the Pathogenesis of Pulmonary Fibrosis
Author Block: C. Lee1, J. Park1, J. Lee2, E. Chen1, S. Kamle1, C. He1, E. Herzog3, I. O. Rosas4, C. Bostwick5, C. Lee1, J. A. Elias1; 1Brown University, Providence, RI, United States, 2Younsei University, Seoul, Korea, Republic of, 3Pulmonary Medicine, Yale University School of Medicine, New Haven, CT, United States, 4Brighams Womens Hosp, Boston, MA, United States, 5Medical University of South Carolina, Charleston, SC, United States.
Background Chitotriosidase (Chitnase 1, Chit1), a major true chitinase in humans, is known to be implicated in various inflammatory and tissue remodeling responses. However, the specific contribution of Chit1 to the pathogenesis of pulmonary fibrosis has not been clearly defined. Hypothesis We hypothesized that Chit1 plays a significant role in the pathogenesis of pulmonary fibrosis. Methods In this study, we determined specific role and the mechanism that Chit1 uses to contribute to pulmonary fibrosis using mice with genetic modifications of Chit1, and in fibroblasts cells in culture. For clinical relevance, the expression levels of Chit1 and Smad7 in lungs from patients with pulmonary fibrosis and controls was evaluated. Results. Our studies demonstrated that Chit1 significantly enhances TGF-β-stimulated fiboblast proliferation, myofibroblast transformation, and canonical and noncanonical TGF-β signaling. The mice with both Chit1 and TGF-β overexpression showed impressive fibrotic tissue responses with increased expression of extracellular matrix accumulation in the lung compared to TGF-β or Chit1 only transgenic lungs. Our studies further demonstrated that Chit1 enhances TGF-β-stimulated Smad2/3 and MAPK/Erk activation and inhibits TGF-β stimulated Smad7 expression via interaction with Tgfbrap1 and FoxO3a, respectively. In support of these findings in animal model of pulmonary fibrosis and fibroblasts cells in culture, Chit1 expression was increased in the lungs or blood of the patients with idiopathic pulmonary fibrosis (IPF) and Scleroderma-associated interstitial lung disease (ILD) patients. In these patients the expression of Chit1 levels were inversely correlated with the expression of Smad7. Conclusion These studies identify Chit1 as a fibrogenic modifier contributing to the pathogenesis of pulmonary fibrosis by regulating TGF-β canonical and non-canonical signaling through interaction with Tgfbrap1 and FoxO3a.