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Dokumenttyp:
journal article 
Autor(en):
Künzli, BM; Nuhn, P; Enjyoji, K; Banz, Y; Smith, RN; Csizmadia, E; Schuppan, D; Berberat, PO; Friess, H; Robson, SC 
Titel:
Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice. 
Abstract:
BACKGROUND& AIMS: Extracellular nucleotides are released from injured cells and bind purinergic-type 2 receptors (P2-Rs) that modulate inflammatory responses. Ectonucleotidases, such as CD39/nucleoside triphosphate diphosphohydrolase-1, hydrolyze extracellular nucleotides to integrate purinergic signaling responses. Because the role of extracellular nucleotides and CD39 in mediating inflammation and fibrosis are understood poorly, we studied the impact of CD39 gene deletion in a model of pancreatic disease. METHODS: Pancreatitis was induced by cyclosporine pretreatment, followed by cerulein injections (50 mug/kg, 6 intraperitoneal injections/day, 3 times/wk); mice were killed at day 2, week 3, and week 6. Experimental parameters were correlated with cytokine levels in blood, RNA, and protein expression of purinergic and fibrosis markers in tissues. Immunohistochemistry and pancreatic morphometry of fibrosis were performed in wild-type and CD39-null mice. Effects of CD39 deletion on proliferation of primary pancreatic stellate cells (PSCs) were investigated in vitro. RESULTS: Wild-type mice developed morphologic features of pancreatitis with the anticipated development of parenchymal atrophy and fibrosis. CD39 and P2-R became overexpressed in vascular and adventitious wild-type tissues. In contrast, CD39-null mice had inflammatory reactions but developed only minor pancreatic atrophy and limited fibrosis. Interferon-gamma became significantly increased in tissues and plasma of CD39-null mice. Wild-type PSCs expressed high levels of CD39 and P2-R. CD39-null PSCs showed decreased rates of proliferation and the expression of procollagen-alpha1 was inhibited significantly in vitro (P< .03). CONCLUSIONS: CD39 deletion decreases fibrogenesis in experimental pancreatitis. Our data implicate extracellular nucleotides as modulators of PSC proliferation and collagen production in pancreatitis. 
Zeitschriftentitel:
Gastroenterology 
Jahr:
2008 
Band / Volume:
134 
Heft / Issue:
Seitenangaben Beitrag:
292-305 
Sprache:
eng 
Print-ISSN:
0016-5085 
TUM Einrichtung:
Chirurgiesche Klinik und Poliklinik