دورية أكاديمية
أعرض في EDS

NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice.

التفاصيل البيبلوغرافية
العنوان: NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice.
المؤلفون: Awla D; Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden., Zetterqvist AV; Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden., Abdulla A; Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden., Camello C; Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain., Berglund LM; Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden., Spégel P; Department of Clinical Sciences, Molecular Metabolism, Lund University, Malmö, Sweden., Pozo MJ; Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain., Camello PJ; Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain., Regnér S; Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden., Gomez MF; Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden., Thorlacius H; Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
المصدر: Gastroenterology [Gastroenterology] 2012 Nov; Vol. 143 (5), pp. 1352-1360.e7. Date of Electronic Publication: 2012 Jul 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE
أسماء مطبوعة: Publication: Philadelphia, PA : W.B. Saunders
Original Publication: Baltimore.
مواضيع طبية MeSH: Acinar Cells/*metabolism , NFATC Transcription Factors/*metabolism , Neutrophils/*physiology , Pancreatitis/*metabolism , Trypsinogen/*metabolism, Acinar Cells/drug effects ; Amylases/blood ; Amylases/drug effects ; Animals ; Aorta/metabolism ; Cell Nucleus/metabolism ; Chemokine CXCL2/drug effects ; Chemokine CXCL2/metabolism ; Lung/metabolism ; Mice ; NFATC Transcription Factors/antagonists & inhibitors ; NFATC Transcription Factors/drug effects ; NFATC Transcription Factors/genetics ; Neutrophils/drug effects ; Pancreatitis/chemically induced ; Pancreatitis/genetics ; Pancreatitis/pathology ; Peroxidase/drug effects ; Peroxidase/metabolism ; Pyrazoles/pharmacology ; Signal Transduction ; Spleen/metabolism ; Statistics, Nonparametric ; Taurocholic Acid ; Trypsinogen/drug effects
مستخلص: Background & Aims: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice.
Methods: We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes.
Results: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l-arginine-induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells.
Conclusions: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.
(Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
المشرفين على المادة: 0 (A 285222)
0 (Chemokine CXCL2)
0 (Cxcl2 protein, mouse)
0 (NFATC Transcription Factors)
0 (Nfatc3 protein, mouse)
0 (Pyrazoles)
5E090O0G3Z (Taurocholic Acid)
9002-08-8 (Trypsinogen)
EC 1.11.1.7 (Peroxidase)
EC 3.2.1.- (Amylases)
تواريخ الأحداث: Date Created: 20120731 Date Completed: 20130114 Latest Revision: 20220408
رمز التحديث: 20240628
DOI: 10.1053/j.gastro.2012.07.098
PMID: 22841788
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-0012
DOI:10.1053/j.gastro.2012.07.098