Kim Minjeong, Hur Sumin, Kim Kwang H, Cho Yejin, Kim Keunyoung, Kim Ha Ryong, Nam Ki Taek, Lim Kyung-Min
College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea.
Biomol Ther (Seoul). 2022 Mar 1;30(2):126-136. doi: 10.4062/biomolther.2021.120.
Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.
肝纤维化是伤口愈合过程的一部分，有助于肝脏从各种肝损伤性刺激所造成的损伤中恢复。然而，肝纤维化常常会发展为危及生命的肝硬化和肝细胞癌。为了克服当前肝纤维化模型在研究肝纤维化病理生理学及制定有效治疗策略方面的局限性，我们利用聚六亚甲基胍磷酸盐（PHMG-p）开发了一种新的肝纤维化小鼠模型，PHMG-p是一种已知会在人类中诱发肺纤维化的加湿器消毒剂。雄性C57/BL6小鼠每周两次腹腔注射PHMG-p（0.03%和0.1%），持续5周。随后，对肝脏组织进行组织学检查，并进行RNA测序以评估受PHMG-p影响的关键基因和信号通路的表达。注射PHMG-p导致体重减轻约15%，身体状况恶化。尸检显示肝脏出现弥漫性纤维化病变，对肺部无影响。组织学、胶原染色、平滑肌肌动蛋白和胶原的免疫组织化学以及纤维化基因的聚合酶链反应分析表明，PHMG-p在肝中央周围、门静脉周围和包膜区域诱发了肝纤维化。RNA测序显示，PHMG-p影响了与人类肝纤维化相关的多个信号通路，尤其是亮蛋白聚糖和IRAK3上调，以及与肝纤维化发病机制密切相关的GSTp1和GSTp2下调。我们共同证明，PHMG-p诱导的肝纤维化模型可用于研究人类肝纤维化。
