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Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis

Authors
 Jae-Hyun Lee  ;  Chang-Min Lee  ;  Joyce H Lee  ;  Mun-Ock Kim  ;  Jin Wook Park  ;  Suchitra Kamle  ;  Bedia Akosman  ;  Erica L Herzog  ;  Xue Yan Peng  ;  Jack A Elias  ;  Chun Geun Lee 
Citation
 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol.67(3) : 309-319, 2022-09 
Journal Title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
ISSN
 1044-1549 
Issue Date
2022-09
MeSH
Aminoglycosides* / pharmacology ; Aminoglycosides* / therapeutic use ; Animals ; Antifibrotic Agents* / pharmacology ; Antifibrotic Agents* / therapeutic use ; Bleomycin / pharmacology ; Chitinases* / antagonists & inhibitors ; Fibroblasts / metabolism ; Humans ; Lung / drug effects ; Lung / pathology ; Mice ; Mice, Inbred C57BL ; Pulmonary Fibrosis* / chemically induced ; Pulmonary Fibrosis* / drug therapy ; Transforming Growth Factor beta / metabolism
Keywords
TGF-β ; TGFBRAP1 ; chitinase 1 ; kasugamycin ; pulmonary fibrosis
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-β (transforming growth factor-β) 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 TGF-β-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-β-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.
Full Text
https://www.atsjournals.org/doi/10.1165/rcmb.2021-0156OC?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed&
DOI
10.1165/rcmb.2021-0156OC
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Hyun(이재현) ORCID logo https://orcid.org/0000-0002-0760-0071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191974
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