Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis, a constant feature of chronic pancreatitis. PSC activation occurs in response to profibrogenic mediators such as cytokines and involves proliferation, transition towards a myofibroblastic phenotype and enhanced production of extracellular matrix proteins. Previously, we have shown that PSC activation correlates with the activity of the Ras-Raf-ERK (extracellular signal-regulated kinase) signalling cascade [Gut 51 (2002) 579]. Using a rat culture model of PSCs, we have now evaluated the effects of lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor that interferes with protein isoprenylation, on PSC viability and activation as well as on signalling through Ras proteins. Apoptotic cells were detected applying the TUNEL assay. Proliferation of PSCs was quantitated using the bromodeoxyuridine DNA incorporation assay. Expression of alpha-smooth muscle actin (an indicator of the myofibroblastic phenotype), ERK activation and membrane translocation of the Ras superfamily member RhoA were analysed by immunoblotting. Lovastatin inhibited serum- and platelet-derived growth factor-stimulated PSC proliferation in a dose-dependent manner. At drug concentrations above the level required for growth inhibition, a strong increase of apoptotic cells was observed. Furthermore, lovastatin inhibited induction of alpha-smooth muscle actin expression in the course of primary culture. Immunoblot experiments indicated that lovastatin suppressed both Ras-mediated ERK 1/2 activation and platelet-derived growth factor-induced membrane translocation of RhoA. Together, our data suggest that lovastatin, through the interruption of Ras signalling, interferes with PSC activation. The antifibrotic efficiency of statins should be tested in animal models of chronic pancreatitis.
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PMID:Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin. 1269 70

Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. With the identification and characterization of pancreatic stellate cells (PSCs), the pathogenesis of CP and pancreatic fibrosis is now better understood. Molecular mediators shown to regulate the pathogenesis include transforming growth factor-beta, platelet-derived growth factor, and proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha. Besides these, the roles of cyclooxygenase (COX)-2 and apoptosis-related proteins have also been implicated in the pathogenesis. Furthermore, molecular pathways involving mitogen-activated protein kinases, phosphatidylinositol 3-kinase, Ras superfamily G proteins, serine threonine protein kinase Raf-1 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) have been elucidated. Newer pathobiologic concepts concerning pain generation have also been put forward. Understanding the pathogenesis has led to the identification of novel molecular targets and the development of newer potential therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include antioxidants, a Japanese herbal medicine called Saiko-keisi-to (TJ 10), the PPAR-gamma ligand troglitazone, the protease inhibitor Camostat mesilate, and Lovastatin.
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PMID:Chronic pancreatitis: evolving paradigms. 1684 81