Bases moleculares de la depleción de glutatión y de la necrosis celular en la pancreatitis aguda. Papel de las proteín quinasas activadas por mitógenos.

by Pereda Cervera, Javier

Abstract (Summary)
ABSTRACT Acute pancreatitis is an inflammation initially localized in the pancreatic gland which may lead to local and systemic complications. The development of severe acute pancreatitis is mediated by pathophysiological mechanisms involved in the systemic inflammatory response, cytokines and oxidative stress being their components of major importance. Nevertheless, it is still unknown why an episode of acute pancreatitis remains mild or progresses to a severe form. Glutathione depletion occurs in pancreas during acute pancreatitis and it has been related to necrosis cell death and severity of the disease. The aim of this study is to clarify the mechanism involved in glutathione depletion in experimental acute pancreatitis. Taurocholate-induced acute pancreatitis was used as a severe experimental model of the disease whereas caerulein-induced acute pancreatitis was used as a mild experimental model. Results showed that ineffective induction of ?-glutamil cistein synthetase occurs after taurocholate-induced acute pancreatitis. However, caerulein induced pancreatitis produced high expresion of this enzyme. Taurocholate-induced acute pancreatitis showed early activation of the three major families of mitogen-activated protein kinases. In this model, pentoxifylline prevented JNK and ERK activation while oxypurinol prevented p38 activation. Combined treatment of pentoxifylline and oxypurinol almost abolished MAPK phosphorylation in the pancreas. TNF-? did not play an important role in glutathione depletion because this depletion associated with caerulein-induced pancreatitis occurred similarly in wild type mice, TNF-? knockout mice and TNF-? receptor knockout mice. ERK inhibition prevented taurocholate-induced glutathione depletion in acinar cells and AR42J cells. However, JNK and p38 were not implicated in glutathione depletion produced by taurocholate in this cell line. AEBSF, a serin protease inhibitor, prevented glutathione depletion in AR42J cells. In addition, AEBSF diminished taurocholate-induced necrosis increasing apoptosis cell death. Conversely, lysosomal proteases, proteasome, calcium and ?-GT did not play a significant role in glutathione depletion in AR42J. Therefore, our results suggest that glutathione depletion occurs not by lysosomal but MAP kinase-dependent, calcium-independent protease or peptidase which is inhibited with AEBSF.
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Bibliographical Information:

Advisor:Sastre Belloch, Juan José; López Rodas, Gerardo

School:Universitat de València

School Location:Spain

Source Type:Master's Thesis



Date of Publication:09/29/2006

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