Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation
Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation
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DOI：
10.1016/j.taap.2021.115817
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发表时间：
2022-01-01
影响因子：
3.8
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Tashiro, Shigeki;Tanaka, Masatake;Ogawa, Yoshihiro
对乙酰氨基酚（APAP）引起的肝损伤是西方国家急性肝衰竭的最常见原因。吡非尼酮（PFD）是一种口服生物可利用的吡啶酮衍生物，临床上用于特发性肺纤维化的治疗，具有抗纤维化、抗炎和抗氧化作用。在这里，我们检查了 PFD 对 APAP 诱导的肝损伤的影响。在小鼠模型中，APAP 引起血清丙氨酸氨基转移酶升高，PFD 治疗可减弱这种升高。我们同时进行末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）和重要的碘化丙啶（PI）染色。 APAP 诱导中央静脉周围 TUNEL 阳性/PI 阴性坏死，随后引起 TUNEL 阴性/PI 阳性胶体坏死伴出血，并导致高凝和缺氧相关基因表达上调。 PFD 治疗抑制了这些发现。蛋白质印迹显示 PFD 抑制 APAP 诱导的 c-Jun N 末端激酶 (JNK) 磷酸化，尽管对 JNK 磷酸酶表达没有影响。总之，同时 TUNEL 和活体 PI 染色可用于区分 APAP 诱导的坏死和典型的胶体坏死。我们的结果表明，PFD 通过直接阻断 JNK 磷酸化来抑制 TUNEL 阳性坏死，从而减轻 APAP 诱导的肝损伤。 PFD 有望成为预防 APAP 引起的肝损伤的新选择。
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.