title: Complete activation of autophagic process attenuates liver injury and improves survival in septic mice.
abstract: The accumulation of autophagosomes in the terminal step of the autophagic process has recently emerged as a potentially maladaptive process in the septic heart and lung. However, the role of autophagy in the septic liver has not been ascertained. This study was investigated by first examining the entire sequence of the autophagic process in the liver of septic mice. Second, a novel pharmacotherapeutic approach was utilized to treat sepsis with autophagy enhancer/inhibitor. Sepsis was induced by cecal ligation and puncture (CLP). C57BL/6 mice received autophagy enhancer carbamazepine (CBZ), autophagy inhibitor 3-methyladenine (inhibition of autophagosomal formation), or chloroquine (impairment of autophagosomal clearance). We found that the whole autophagic process was activated at 4 h after CLP; however, it did not proceed to completion during the 4- to 24-h time period, as indicated by accumulated autophagosomes and decreased autophagic flux. Carbamazepine, which induced complete activation of the autophagic process, improved CLP survival. This protective effect was also associated with decreased cell death, inflammatory responses, and hepatic injury. However, disruption of autophagosomal clearance with chloroquine abolished the above protective effects in CBZ-treated CLP mice. 3-Methyladenine, which resulted in inhibition of the autophagosomal formation, did not show any above beneficial effects in CLP mice. Impaired autophagosome-lysome fusion resulting in incomplete activation of autophagy may contribute to sepsis-induced liver injury. Treatment with CBZ may serve a protective role in the septic liver, possibly through the effect of complete activation of autophagic process.
authors.affiliation: *Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University; †Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; ‡Department of Plastic and Reconstructive Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; §Canniesburn Plastic Surgery Unit, Royal Infirmary, Glasgow, UK; ∥Jeffrey Cheah School of Medicine and Health Sciences, Monash University Sunway Campus, Malaysia; ¶Division of General Surgery, Department of Surgery, and **Department of Medical Research, E-Da Hospital, I-Shou University; ††School of Medicine, College of Medicine, Kaohsiung Medical University; ‡‡Hepatobiliary Division, Department of Internal Medicine, §§Translational Research Center and Cancer Center, and ∥∥Department of Obstetrics & Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Lin
authors.forename: Steven
authors.initials: S
authors.lastname: Lo
authors.forename: Daw-Shyong
authors.initials: DS
authors.lastname: Perng
authors.forename: David Bin-Chia
authors.initials: DB
authors.lastname: Wu
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Yu
authors.forename: Shyng-Shiou F
authors.initials: SS
authors.lastname: Yuan
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000563:Amebicides / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001343:Autophagy; D002220:Carbamazepine / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D008099:Liver / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010588:Phagosomes / Q000378:metabolism* / Q000473:pathology; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology
chemical_list: D000563:Amebicides; D000927:Anticonvulsants; D002220:Carbamazepine; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine