Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Department Molecular Microbiology and Immunology and.
Am J Respir Cell Mol Biol. 2022 Sep;67(3):309-319. doi: 10.1165/rcmb.2021-0156OC.
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 bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. 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 lungs and 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.
肺纤维化是一种严重的肺部疾病，治疗选择有限。CHIT1（几丁质酶 1）是 18 糖苷水解酶家族的成员，通过调节 TGF-β（转化生长因子-β）信号和效应功能，有助于肺纤维化的发病机制。因此，CHIT1 是肺纤维化的潜在治疗靶点。本研究旨在鉴定和表征具有强大抗纤维化活性和最小毒性的可药用 CHIT1 抑制剂，用于肺纤维化的治疗应用。对小分子文库的广泛筛选确定了氨基糖苷类抗生素井冈霉素（KSM）是一种有效的 CHIT1 抑制剂。肺纤维化患者的肺中检测到 CHIT1 浓度升高。在博来霉素和 TGF-β 刺激的肺纤维化小鼠模型中，KSM 在预防和治疗条件下均表现出令人印象深刻的抗纤维化作用。研究还表明，KSM 抑制纤维化巨噬细胞激活、成纤维细胞增殖和肌成纤维细胞转化。最近鉴定的 CHIT1 相互作用的信号分子 TGFBRAP1 的缺失突变，在肺中和成纤维细胞反应中模拟了 KSM 的抗纤维化作用。KSM 抑制 CHIT1 和 TGFBRAP1 之间的物理关联，表明 KSM 的抗纤维化作用至少部分是通过调节 TGFBRAP1 介导的。这些研究表明，KSM 是一种新型的 CHIT1 抑制剂，具有强大的抗纤维化作用，可进一步开发为肺纤维化的有效和安全治疗药物。
