TY - JOUR
T1 - Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation
AU - Tashiro, Shigeki
AU - Tanaka, Masatake
AU - Goya, Takeshi
AU - Aoyagi, Tomomi
AU - Kurokawa, Miho
AU - Imoto, Koji
AU - Kuwano, Akifumi
AU - Takahashi, Motoi
AU - Suzuki, Hideo
AU - Kohjima, Motoyuki
AU - Kato, Masaki
AU - Ogawa, Yoshihiro
N1 - Funding Information:
This work was supported in part by Takeda Science Foundation [grant number TKDS20190416055 ], Smoking Research Foundation [grant numbers 2018G015 and 2021Y010 ] and JSPS KAKENHI [grant numbers JP17K09430 , JP18H05039 , JP19H01054 , JP19K17496 , JP20K22877 , and JP20H04949 ]. We would like to thank Enago ( www.enago.jp ) for the English language review.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.taap.2021.115817
DO - 10.1016/j.taap.2021.115817
M3 - Article
C2 - 34890640
AN - SCOPUS:85121217526
VL - 434
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
M1 - 115817
ER -