Department of Medical Physics and Engineering, Division of Medical Technology and Science, Faculty of Health Science, Graduate School of Medicine, Osaka University.
Division of Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University.
Magn Reson Med Sci. 2018 Oct 10;17(4):331-337. doi: 10.2463/mrms.mp.2017-0163. Epub 2018 Mar 9.
High Mobility Group Box1 (HMGB1), which is one of the damage-associated molecular pattern molecules relating to various inflammatory diseases, has gained interest as a therapeutic target because of its involvement in wound healing processes. In the present study, we investigated HMGB1 as a potential therapeutic target in a model of lung fibrosis using a preclinical hyperpolarized Xe (HPXe) MRI system.
Lung injury was induced by intra-peritoneal injection of bleomycin (BLM) in 19 mice. Three weeks post-injection (when fibrosis was confirmed histologically), administration of ethyl pyruvate (EP) and alogliptin (ALG), which are down- and up-regulators of HMGB1, respectively, was commenced in six and seven of the 19 mice, respectively, and continued for a further 3 weeks. A separate sham-instilled group was formed of five mice, which were administered with saline for 6 weeks. Over the second 3-week period, the effects of disease progression and pharmacological therapy in the four groups of mice were monitored by HPXe MRI metrics of fractional ventilation and gas-exchange function.
Gas-exchange function in BLM mice was significantly reduced after 3 weeks of BLM challenge compared to sham-instilled mice (P < 0.05). Ethyl pyruvate was found to improve HPXe MRI metrics of both ventilation and gas exchange, and repair tissue damage (assessed histologically), to a similar level as sham-instilled mice (P < 0.05), whilst ALG treatment caused no significant improvement of pulmonary function.
This study demonstrates the down-regulator of HMGB1, EP, as a potential therapeutic agent for pulmonary fibrosis, as assessed by a non-invasive HPXe MRI protocol.
高迁移率族蛋白 B1（HMGB1）是与各种炎症性疾病相关的损伤相关分子模式分子之一，由于其参与伤口愈合过程，因此作为治疗靶点引起了关注。在本研究中，我们使用临床前极化氙（HPXe）MRI 系统，在肺纤维化模型中研究了 HMGB1 作为潜在治疗靶点的作用。
在 19 只小鼠中通过腹腔内注射博来霉素（BLM）诱导肺损伤。在注射后 3 周（当组织学证实纤维化时），分别在 19 只小鼠中的 6 只和 7 只中开始给予作为 HMGB1 下调和上调调节剂的乙基丙酮酸（EP）和阿格列汀（ALG），并持续 3 周。形成一个单独的假注入组，由 5 只接受生理盐水 6 周的小鼠组成。在第二个 3 周期间，通过 HPXe MRI 分数通气和气体交换功能指标监测四组小鼠疾病进展和药物治疗的效果。
与假注入小鼠相比，BLM 小鼠在 BLM 挑战 3 周后气体交换功能明显降低（P < 0.05）。发现乙基丙酮酸可改善 HPXe MRI 通气和气体交换的指标，并修复组织损伤（组织学评估），使其达到与假注入小鼠相似的水平（P < 0.05），而 ALG 治疗对肺功能没有显著改善。
这项研究通过非侵入性 HPXe MRI 方案表明，HMGB1 的下调剂 EP 可作为治疗肺纤维化的潜在治疗剂。
