title: Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury.
abstract: Pyroptosis is a programmed cell death associated with caspase-1 and accompanied by the secretion of a large number of pro-inflammatory cytokines. In the acute stage of sepsis, the release of several pro-inflammatory cytokines aggravates hepatic cell death, and acute liver injury is aggravated with the progress of the disease, resulting in acute liver failure with a very high mortality rate. The present study investigated the effect of inhibiting hepatic cell pyroptosis on the septic acute liver injury. Septic acute liver injury mice model was established by cecal ligation and puncture (CLP model). The liver tissues were assessed for inflammatory infiltration by HE, serum concentrations of ALT, AST, IL-1β, and IL-18 were examined by ELISA, hepatic cell pyroptosis was determined by flow cytometry, and expressions of caspase-1 and NLRP3 were assessed by Western blot. CLP-induced acute liver injury was distinct at 24 h post-operation, with the highest hepatic cell pyroptosis rate. The pyroptosis rate and liver injury indexes were positively correlated. Western blot showed that the expressions of pyroptosis-related proteins, caspase-1, and NLRP3, were increased. Normal mouse hepatic cells were cultured in vitro and LPS+ATP introduced to establish the cell model of septic acute liver injury. The expressions of caspase-1, NLRP3, IL-1β, and IL-18 in LPS+ATP group were significantly higher than the control group by Western blot and ELISA. The inhibitors of NLRP3 (Glyburide) and caspase-1 (AC-YVAD-CMK) alone or in combination were used to pre-treat the hepatic cells, which revealed that the pyroptosis rate was decreased and the cell damage alleviated. The in vivo assay in rats showed that post inhibitor treatment, the 10-days survival was significantly improved and the liver damage reduced. Therefore, inhibiting the hepatic cell pyroptosis could alleviate CLP-induced acute liver injury, providing a novel treatment target for septic acute liver injury.
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, P. R. China.
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University Huai'an, P. R. China.
authors.forename: Guo
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Nanjing Medical University Affliated Wuxi Second Hospital Wuxi, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Soochow UniversitySuzhou, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, P. R. China.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University P. R. China.
authors.forename: Xiao-Di
authors.initials: XD
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, Ningxiang People's Hospital of Hunan Province Ningxiang, Hunan, P. R. China.
authors.forename: Xue-Ping
authors.initials: XP
authors.lastname: Wen
authors.affiliation: Department of Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China; Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lv
keywords: Sepsis; acute liver injury; pyroptosis