The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2013-11, Vol.305 (10), p.G712-G721
• Main Authors: Ang, Abel D, Rivers-Auty, Jack, Hegde, Akhil, Ishii, Isao, Bhatia, Madhav
• Format: Article
• Language: English
• Subjects: Animals; Ceruletide - toxicity; Comparative analysis; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - metabolism; Cytokines; Gene Expression Regulation - physiology; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Lung diseases; Lung Diseases - chemically induced; Lung Diseases - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - metabolism; Pancreatitis - chemically induced; Pancreatitis - genetics; Pancreatitis - metabolism; Protein Kinase C - genetics; Protein Kinase C - metabolism; Rodents
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00044.2013

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.