博莱霉素
癌症研究
特发性肺纤维化
肺纤维化
医学
纤维化
慢性淋巴细胞白血病
信号转导
自噬
免疫学
化学
病理
肺
生物
内科学
细胞生物学
细胞凋亡
白血病
化疗
生物化学
作者
Shanshan Chen,Yuli Wei,Shimeng Li,Miao Yang,Jinying Gu,Yunyao Cui,Zhichao Liu,Jingjing Liang,Luqing Wei,Xiaohe Li,Honggang Zhou,Cheng Yang
标识
DOI:10.1016/j.intimp.2022.109316
摘要
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. Only two drugs are currently approved for the treatment of IPF, but both have limitations and neither drug could prolong survival time of patients. The etiology of IPF is unclear, but there is growing evidence that B cells and B cell receptor signaling play important roles in the pathogenesis of IPF. Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK), which is a key enzyme downstream of B cell receptor signaling pathway, has approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While its role in pulmonary fibrosis remains unknown. In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro.In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indices were evaluated. In vitro experiments were performed using TGF-β1-stimulated fibroblasts to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and to explore the underlying signaling pathway mechanism.In vivo experiments demonstrated that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. An in vitro mechanistic study indicated that zanubrutinib suppresses collagen deposition and myofibroblast activation by inhibiting the TGF-β1/Smad pathway and induces autophagy through the TGF-β1/mTOR pathway.Zanubrutinib alleviated bleomycin-induced lung fibrosis in mice by inhibiting the TGF-β1 signaling pathway.
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