Warinda Susutlertpanya1, Hirokazu Wakuda2, Naoyuki Otani3, Takuya Kuramoto1, Li Li4, Masae Kuranari5, Ai Sekiguchi1, Hideo Kudo6, Tomohisa Uchida7, Hiromitsu Imai8, Naoto Uemura9. 1. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita 8795593, Japan. 2. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita 8795593, Japan. Electronic address: wakuda@oita-u.ac.jp. 3. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita 8795593, Japan; Clinical Pharmacology Center, Oita University Hospital, Oita 8795593, Japan. 4. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita 8795593, Japan; Faculty of Medicine, Hebei Medical University, Hebei 50017, China. 5. General Clinical Research Center, Oita University Hospital, Oita 8795593, Japan. 6. Clinical Pharmacology Center, Oita University Hospital, Oita 8795593, Japan. 7. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita 8795593, Japan. 8. Clinical Pharmacology Center, Oita University Hospital, Oita 8795593, Japan; Department of Medical Ethics, Faculty of Medicine, Oita University, Oita 8795593, Japan. 9. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita 8795593, Japan; Clinical Pharmacology Center, Oita University Hospital, Oita 8795593, Japan; General Clinical Research Center, Oita University Hospital, Oita 8795593, Japan.
Abstract
AIMS: In addition to potentially progressing to either cirrhosis or hepatocellular carcinoma, non-alcoholic steatohepatitis (NASH) is currently the leading indication for liver transplantation. Nintedanib has been clinically used to treat idiopathic pulmonary fibrosis for many years, but its effects in an animal model of NASH have not been tested. The purpose of this study was to evaluate the effects of nintendanib on NASH in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-fed mice. MAIN METHODS: Male C57BL/6 mice were fed a CDAHFD for 6 weeks to induce NASH with liver fibrosis, and they were administered nintedanib (60 mg/kg/day) or distilled water orally in the last 2 weeks of the feeding period. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, and non-esterified fatty acids concentrations were measured. Serum cytokeratin 18 fragment (CK18) was detected using ELISA. Liver tissue sections from mice were stained with hematoxylin-eosin and Masson's trichrome to assess the level of steatohepatitis and fibrosis. KEY FINDINGS: CDAHFD-fed mice exhibited higher serum ALT, AST, and ALP levels compared with Control mice. A significant increase in the serum CK18 level was observed in the NASH group compared with the Control group. CDAHFD feeding also enhanced steatohepatitis and hepatic fibrosis pathological features, which were reduced after nintedanib treatment. SIGNIFICANCE: Nintedanib exerted anti-inflammatory and anti-fibrotic effects in CDAHFD-induced NASH mice.
AIMS: In addition to potentially progressing to either cirrhosis or hepatocellular carcinoma, non-alcoholic steatohepatitis (NASH) is currently the leading indication for liver transplantation. Nintedanib has been clinically used to treat idiopathic pulmonary fibrosis for many years, but its effects in an animal model of NASH have not been tested. The purpose of this study was to evaluate the effects of nintendanib on NASH in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-fed mice. MAIN METHODS: Male C57BL/6 mice were fed a CDAHFD for 6 weeks to induce NASH with liver fibrosis, and they were administered nintedanib (60 mg/kg/day) or distilled water orally in the last 2 weeks of the feeding period. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, and non-esterified fatty acids concentrations were measured. Serum cytokeratin 18 fragment (CK18) was detected using ELISA. Liver tissue sections from mice were stained with hematoxylin-eosin and Masson's trichrome to assess the level of steatohepatitis and fibrosis. KEY FINDINGS: CDAHFD-fed mice exhibited higher serum ALT, AST, and ALP levels compared with Control mice. A significant increase in the serum CK18 level was observed in the NASH group compared with the Control group. CDAHFD feeding also enhanced steatohepatitis and hepatic fibrosis pathological features, which were reduced after nintedanib treatment. SIGNIFICANCE: Nintedanib exerted anti-inflammatory and anti-fibrotic effects in CDAHFD-induced NASH mice.
Authors: Philip A Waghorn; Diego S Ferreira; Derek J Erstad; Nicholas J Rotile; Ricard Masia; Chloe M Jones; Chuantao Tu; Mozhdeh Sojoodi; Yin-Ching I Chen; Franklin Schlerman; Jeremy Wellen; Robert V P Martinez; Kenneth K Tanabe; Bryan C Fuchs; Peter Caravan Journal: Sci Rep Date: 2021-03-17 Impact factor: 4.379