title: The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse.
abstract: Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-γ-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis. We compared the inflammatory response and tissue damage of wild-type (WT) and CSE knockout (KO) mice following 10 hourly administrations of 50 μg/kg caerulein or saline control. From this, we found that the CSE KO mice showed significantly less local pancreatic damage as well as acute pancreatitis-associated lung injury compared with the WT mice. There were also lower levels of pancreatic eicosanoid and cytokines, as well as reduced acinar cell NF-κB activation in the CSE KO mice compared with WT mice. Additionally, in WT mice, there was a greater level of pancreatic CSE expression and sulfide-synthesizing activity in caerulein-induced pancreatitis compared with the saline control. When comparing the two saline-treated control groups, we noted that the CSE KO mice showed significantly less pancreatic H2S-synthesizing activity relative to the WT mice. These results indicate that endogenous H2S generated by CSE plays a key proinflammatory role via NF-κB activation in caerulein-induced pancreatitis, and its genetic deletion affords significant protection against acute pancreatitis and associated lung injury.
authors.affiliation: Dept. of Pathology, Univ. of Otago, Christchurch, 2 Riccarton Ave., PO Box 4345, Christchurch 8140, New Zealand. madhav.bhatia@otago.ac.nz.
authors.forename: Abel D
authors.initials: AD
authors.lastname: Ang
authors.forename: Jack
authors.initials: J
authors.lastname: Rivers-Auty
authors.forename: Akhil
authors.initials: A
authors.lastname: Hegde
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000633:toxicity*; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006862:Hydrogen Sulfide / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D002108:Ceruletide; D011493:Protein Kinase C; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: cystathionine-γ-lyase; hydrogen sulfide; inflammation; knockout; pancreatitis