title: Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.
abstract: Previously, we have shown that hydrogen sulphide (H2S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL-propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre-mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2S exerted on the impaired autophagy during AP was further attributed to over-activation of autophagy rather than hampered autophagosome-lysosome fusion. To elucidate the molecular mechanism that underlies H2S-mediated over-activation of autophagy during AP, we evaluated phosphorylations of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC-51-Like kinase 1 (ULK1). Our findings suggested that H2S exacerbated taurocholate-induced AP by over-activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2S to restore over-activated autophagy might be a promising therapeutic approach against AP-related injuries.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Le
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Guangquan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Bai
authors.affiliation: Central Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Dongbo
authors.initials: D
authors.lastname: Xue
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D018450:Disease Progression; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010195:Pancreatitis / Q000473:pathology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014362:Trypsinogen / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000480:Alkynes; C009055:propargylglycine; D014362:Trypsinogen; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005998:Glycine; D006862:Hydrogen Sulfide
keywords: AMPK; acute pancreatitis; hydrogen sulphide; impaired autophagy; mTOR