Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A New Murine Liver Fibrosis Model Induced by Polyhexamethylene Guanidine-Phosphate

  • Kim, Minjeong (College of Pharmacy, Ewha Womans University) ;
  • Hur, Sumin (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University) ;
  • Kim, Kwang H. (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University) ;
  • Cho, Yejin (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University) ;
  • Kim, Keunyoung (College of Pharmacy, Kangwon National University) ;
  • Kim, Ha Ryong (College of Pharmacy, Daegu Catholic University) ;
  • Nam, Ki Taek (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University) ;
  • Lim, Kyung-Min (College of Pharmacy, Ewha Womans University)
  • Received : 2021.07.16
  • Accepted : 2021.08.13
  • Published : 2022.03.01
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Abstract

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 in vivo 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.

Keywords

Acknowledgement

K.M.L. is supported by National Research Foundation (NRF) funded by Ministry of Science and ICT (MSIT) (2018R1A5A2025286). K.T.N. is supported by the Korea Mouse Phenotyping Project (NRF-2016M3A9D5A01952416).

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