Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.120
A New Murine Liver Fibrosis Model Induced by Polyhexamethylene Guanidine-Phosphate
Minjeong Kim1,†, Sumin Hur2,†, Kwang H. Kim2, Yejin Cho2, Keunyoung Kim3, Ha Ryong Kim4, Ki Taek Nam2,* and Kyung-Min Lim1,*
1College of Pharmacy, Ewha Womans University, Seoul 03760,
2Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul 03722,
3College of Pharmacy, Kangwon National University, Chuncheon 24341,
4College of Pharmacy, Daegu Catholic University, Daegu 38430, Republic of Korea
*E-mail: kmlim@ewha.ac.kr (Lim KM), kitaek@yuhs.ac (Nam KT)
Tel: +82-2-3277-3055 (Lim KM), +82-2-2228-0754 (Nam KT)
Fax: +82-2-3277-3760 (Lim KM), +82-2-2227-8129 (Nam KT)
The first two authors contributed equally to this work.
Received: July 16, 2021; Revised: August 12, 2021; Accepted: August 13, 2021; Published online: September 28, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Liver fibrosis, Polyhexamethylene guanidine phosphate (PHMG-p), Murine liver fibrosis model, Lumican, IRAK3


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