Inhalation of itraconazole mitigates bleomycin-induced lung fibrosis via regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts

作者：Caizhe Pan, Wei Hao, Bi Chen, Lei Wu, Jiayao Song, Qing Zhang, Xinglong Wu, Gui‐Bai Liang, Wenhao Chen, Yingshuo Wang, Yicheng Xie · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05895-0 · 被引用次数：4 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Lung Cancer Treatments and Mutations、Cystic Fibrosis Research Advances

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility. METHODS: An inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration. RESULTS: We found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proport...