Bibliographic Details
| Title: |
Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis. |
| Authors: |
Jae-Hyun Lee, Chang-Min Lee, Lee, Joyce H., Mun-Ock Kim, Jin Wook Park, Kamle, Suchitra, Akosman, Bedia, Herzog, Erica L., Xue Yan Peng, Elias, Jack A., Chun Geun Lee |
| Source: |
American Journal of Respiratory Cell & Molecular Biology; Sep2022, Vol. 67 Issue 3, p309-319, 12p |
| Subject Terms: |
PULMONARY fibrosis, CHITINASE, MACROPHAGE activation, LUNG diseases, SMALL molecules |
| Abstract: |
Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-b (transforming growth factor-b) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGFb- stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-b-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
