Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute pancreatitis (AP) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement. Differentiation of acinar cells is regulated by p48, a DNA binding subunit of the transcription factor PTF1, and the Notch signaling pathway. Acinar cell apoptosis is triggered by oxygen deprivation, ie, hypoxia, by activation of hypoxia inducible factor-1alpha (HIF-1alpha). The aim of this study was to characterize by Northern blot analyses expression of HIF-1alpha, HIF-1alpha-inducible genes (GLUT-1, VEGF, p53), p48, and genes involved in the Notch signaling pathway (Notch-1, Dll1, RBP-Jk, HES-1) during cerulein-induced AP in mice. Maximal expression of HIF-1alpha, HIF-1alpha-inducible genes, p48, and Notch signaling genes occurred 8-12 hours after induction of AP. Maximal expression of p53 occurred 12-48 hours after induction of AP. These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment, regulation of expression of acinar cell-specific genes, and apoptosis.
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PMID:Increased expression of hypoxia-inducible factor-1alpha, p48, and the Notch signaling cascade during acute pancreatitis in mice. 1470 31

Acute pancreatitis is a complex disorder involving both premature intracellular protease activation and inflammatory cell invasion. An initiating event is the intracellular activation of trypsinogen by cathepsin B (CTSB), which can be induced directly via G protein-coupled receptors on acinar cells or through inflammatory cells. Here, we studied CTSB regulation by another lysosomal hydrolase, cathepsin D (CTSD), using mice with a complete (CTSD-/-) or pancreas-specific conditional CTSD knockout (KO) (CTSDf/f/p48Cre/+). We induced acute pancreatitis by repeated caerulein injections and isolated acinar and bone marrow cells for ex vivo studies. Supramaximal caerulein stimulation induced subcellular redistribution of CTSD from the lysosomal to the zymogen-containing subcellular compartment of acinar cells and activation of CTSD, CTSB, and trypsinogen. Of note, the CTSD KO greatly reduced CTSB and trypsinogen activation in acinar cells, and CTSD directly activated CTSB but not trypsinogen in vitro During pancreatitis in pancreas-specific CTSDf/f/p48Cre/+ animals, markers of severity were reduced only at 1 h, whereas in the complete KO, this effect also included the late disease phase (8 h), indicating an important effect of extra-acinar CTSD on course of the disease. CTSD-/- leukocytes exhibited reduced cytokine release after lipopolysaccharide (LPS) stimulation, and CTSD KO also reduced caspase-3 activation and apoptosis in acinar cells stimulated with the intestinal hormone cholecystokinin. In summary, CTSD is expressed in pancreatic acinar and inflammatory cells, undergoes subcellular redistribution and activation during experimental pancreatitis, and regulates disease severity by potently activating CTSB. Its impact is only minimal and transient in the early, acinar cell-dependent phase of pancreatitis and much greater in the later, inflammatory cell-dependent phase of the disease.
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PMID:Cathepsin D regulates cathepsin B activation and disease severity predominantly in inflammatory cells during experimental pancreatitis. 2922 80