Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation.

Abstract

Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury. In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions. In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.

• Authors: Shigeki Tashiro, Masatake Tanaka, Takeshi Goya, Tomomi Aoyagi, Miho Kurokawa, Koji Imoto, Akifumi Kuwano, Motoi Takahashi, Hideo Suzuki, Motoyuki Kohjima, Masaki Kato, Yoshihiro Ogawa
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 434 Pg. 115817 (01 01 2022) ISSN: 1096-0333 [Electronic] United States
• PMID: 34890640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Analgesics, Non-Narcotic
• Anti-Inflammatory Agents, Non-Steroidal
• Pyridones
• Acetaminophen
• pirfenidone
• JNK Mitogen-Activated Protein Kinases

Topics

• Acetaminophen (toxicity)
• Analgesics, Non-Narcotic (toxicity)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Chemical and Drug Induced Liver Injury (drug therapy)
• Gene Expression Regulation, Enzymologic (drug effects)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice
• Phosphorylation
• Pyridones (therapeutic use)