Redox signaling in acute pancreatitisroles of pgc-1α and sulfiredoxin

Resumen

Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to local and systemic complications. The general aim of this PhD Thesis was to find out new mechanisms involved in redox regulation of the antioxidant defense and inflammatory cascade in acute pancreatitis, and also to assess their impact in its pathophysiology. Firstly, we studied the redox regulation of the trans-sulfuration pathway in pancreas with acute pancreatitis. For this purpose, acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Acute pancreatitis blocked the trans-sulfuration pathway through nitration of cystathionine β-synthase promoting homocysteine accumulation upon S-adenosylmethionine treatment. Secondly, sulfiredoxin knock-out mice were used to assess the role of sulfiredoxin in the regulation of the inflammatory cascade and cell death in acute pancreatitis. Sulfiredoxin up-regulation and its translocation into the mitochondria prevented mitochondrial nitrosative stress and necroptosis during acute pancreatitis. Finally, we assessed the contribution of PGC-1α to the regulation of the antioxidant defense and inflammatory response in this disease. Acute pancreatitis was induced by cerulein in lean and obese mice; subsequently, PGC-1α knock-out mice with cerulein-induced acute pancreatitis were used. PGC-1α protein levels were markedly decreased in pancreas from obese mice with pancreatitis. PGC-1α formed an inhibitory complex with NF-B and selectively repressed NF-B towards Il-6 in pancreas with acute pancreatitis. Hence, in acute pancreatitis PGC-1α knock-out mice exhibited very high plasma and pancreatic levels of IL-6 levels, which are considered a marker of severity in this disease. PGC-1α was inactivated by acetylation during acute pancreatitis in wild type mice and hence, its antioxidant targets genes were downregulated. In summary, we provide here new mechanisms related to cytosolic and mitochondrial nitrosative stress, sulfiredoxin and PGC-1α critically involved in the regulation of the inflammatory cascade and cell death in acute pancreatitis, which can decisively contribute to a better understanding of the pathophysiology of this disease and the associated redox molecular mechanisms.