Department of Pulmonology and Orthopedic Surgery, Children's Hospital, School of Medicine, Zhejiang University, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
School of Life Sciences, Fudan University, Shanghai, 200438, China.
J Transl Med. 2024 Nov 25;22(1):1058. doi: 10.1186/s12967-024-05895-0.
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.
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.
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 proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts.
These insights into the molecular mechanisms underlying ITR's therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.
特发性肺纤维化 (IPF) 是导致全球死亡率的重要因素。目前，针对这种疾病还没有有效的抗纤维化治疗方法。虽然伊曲康唑 (ITR) 已显示出在减轻肺纤维化方面的潜力，但由于其口服给药的药代动力学不理想，增加了不良反应的风险，从而限制了其临床应用。
本研究设计了一种可吸入的伊曲康唑制剂，旨在增强其在肺部的分散性。首先，进行了药代动力学研究，以研究吸入给药后伊曲康唑的血液浓度和组织残留。此外，使用博来霉素诱导的小鼠肺纤维化模型比较了吸入和口服给药伊曲康唑的治疗效果。最后，使用单细胞 RNA 测序 (scRNAseq) 探讨了伊曲康唑吸入给药的作用机制。
我们发现，吸入给药后，大量药物在肺部组织中长时间积累，从而最大限度地发挥药物的治疗效果。每天吸入伊曲康唑 21 天可显著减轻博来霉素诱导的小鼠肺纤维化和炎症。此外，我们的研究结果表明，伊曲康唑吸入可减少疾病成纤维细胞的比例，同时促进修复性成纤维细胞在小鼠模型中的增殖。此外，它还能有效逆转激活的吞噬性巨噬细胞的比例。机制上，伊曲康唑吸入通过调节 SPP1 和 C3 信号通路发挥作用，该通路在吞噬性巨噬细胞和疾病成纤维细胞之间的相互作用中起着关键作用。
这些关于伊曲康唑治疗 IPF 的分子机制的见解强调了吸入给药所带来的有利药代动力学特征，为这种有前途的制剂用于临床转化提供了依据。
