Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and eventually fatal lung disease with a complex etiology. Approved drugs, nintedanib and pirfenidone, modify disease progression, but IPF remains incurable and there is an urgent need for new therapies. We identified chitotriosidase (CHIT1) as new driver of fibrosis in IPF and a novel therapeutic target. We demonstrate that CHIT1 activity and expression are significantly increased in serum (3-fold) and induced sputum (4-fold) from IPF patients. In the lungs CHIT1 is expressed in a distinct subpopulation of profibrotic, disease-specific macrophages, which are only present in patients with ILDs and CHIT1 is one of the defining markers of this fibrosis-associated gene cluster. To define CHIT1 role in fibrosis, we used the therapeutic protocol of the bleomycin-induced pulmonary fibrosis mouse model. We demonstrate that in the context of chitinase induction and the macrophage-specific expression of CHIT1, this model recapitulates lung fibrosis in ILDs. Genetic inactivation of Chit1 attenuated bleomycin-induced fibrosis (decreasing the Ashcroft scoring by 28%) and decreased expression of profibrotic factors in lung tissues. Pharmacological inhibition of chitinases by OATD-01 reduced fibrosis and soluble collagen concentration. OATD-01 exhibited anti-fibrotic activity comparable to pirfenidone resulting in the reduction of the Ashcroft score by 32% and 31%, respectively. These studies provide a preclinical proof-of-concept for the antifibrotic effects of OATD-01 and establish CHIT1 as a potential new therapeutic target for IPF. Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Piotr Sklepkiewicz, Barbara A Dymek, Michal Mlacki, Robert Koralewski, Marzena Mazur, Patrycja Nejman-Gryz, Serdar Korur, Agnieszka Zagozdzon, Aleksandra Rymaszewska, Jan H von der Thüsen, Anna M Siwińska, Nazan Cemre Güner, Łukasz Cheda, Magdalena Paplinska-Goryca, Małgorzata Proboszcz, Thierry P P van den Bosch, Katarzyna Górska, Jakub Golab, Rafał M Kamiński, Rafał Krenke, Adam Golebiowski, Karolina Dzwonek, Pawel Dobrzanski. Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis. European journal of pharmacology. 2022 Mar 15;919:174792

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PMID: 35122869

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