Roles of Pancreatic Stellate Cells in Pancreatic Inflammation and Fibrosis
2009; Elsevier BV; Volume: 7; Issue: 11 Linguagem: Inglês
10.1016/j.cgh.2009.07.038
ISSN1542-7714
AutoresAtsushi Masamune, Takashi Watanabe, Kazuhiro Kikuta, Tooru Shimosegawa,
Tópico(s)Phagocytosis and Immune Regulation
ResumoOver a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express α-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer. Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow–derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer. Over a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express α-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer. Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow–derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer. Fibrosis is a characteristic feature of chronic pancreatitis (CP) and of the desmoplastic reaction associated with pancreatic cancer. Until recently, however, the molecular mechanisms of pancreatic fibrosis remained largely unknown at least in part as a result of the lack of appropriate in vitro models. In 1998, star-shaped cells in the pancreas, called pancreatic stellate cells (PSCs), were identified and characterized.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar Over a decade, there is accumulating evidence that activated PSCs play a pivotal role in the development of pancreatic fibrosis in CP and in pancreatic cancer.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar, 6Bachem M.G. Schünemann M. Ramadani M. et al.Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.Gastroenterology. 2005; 128: 907-921Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 7Hwang R.F. Moore T. Arumugam T. et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression.Cancer Res. 2008; 68: 918-926Crossref PubMed Scopus (894) Google Scholar, 8Vonlaufen A. Joshi S. Qu C. et al.Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Cancer Res. 2008; 68: 2085-2093Crossref PubMed Scopus (384) Google Scholar In normal pancreas, stellate cells are quiescent and can be identified by the presence of vitamin A–containing lipid droplets in the cytoplasm.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar PSCs show mainly a periacinar distribution and constitute 4% of all pancreatic cells.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar Expression of the intermediate filament proteins, desmin and glial fibrillary acidic protein (GFAP), is also used as a marker of quiescent PSCs. The expression and activation of GFAP have been confirmed in transgenic GFAP-LacZ mice where 2.2 kilobase of the GFAP promoter activity was associated exclusively with PSCs.9Ding Z. Maubach G. Masamune A. et al.Glial fibrillary acidic protein promoter targets pancreatic stellate cells.Dig Liver Dis. 2009; 41: 229-236Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The cell functions of quiescent PSCs remain largely unknown, but periacinar localization suggests a role in maintaining pancreatic acinar cells. In addition, their periductal and perivascular localization suggests that quiescent PSCs might play a role in the regulation of ductal and vascular functions in the pancreas. The physiologic consequences of vitamin A storage in PSCs remain unclear, but it might have a role in maintenance of the quiescent state. McCarroll et al10McCarroll J.A. Phillips P.A. Santucci N. et al.Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis.Gut. 2006; 55: 79-89Crossref PubMed Scopus (126) Google Scholar showed that retinol and its metabolites inhibited the induction of α-smooth muscle actin (α-SMA) expression in quiescent PSCs and induced quiescence in culture-activated PSCs. It is, therefore, tempting to speculate that retinoic acids are involved in the maintenance of a quiescent phenotype through the binding to their nuclear receptors and the regulation of gene expression. In this scenario, the loss of retinoids in the course of PSC activation might not be an epiphenomenon but essential for senescence. In response to pancreatic injury or inflammation, quiescent PSCs undergo morphologic and functional changes to become myofibroblast-like cells, which express α-SMA (Figure 1). This step is called activation. The critical regulatory events that induce PSC activation in vivo are likely to be similar, at least in part, to the events that regulate the activation of primary PSCs in culture in vitro.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar, 6Bachem M.G. Schünemann M. Ramadani M. et al.Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.Gastroenterology. 2005; 128: 907-921Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 7Hwang R.F. Moore T. Arumugam T. et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression.Cancer Res. 2008; 68: 918-926Crossref PubMed Scopus (894) Google Scholar, 8Vonlaufen A. Joshi S. Qu C. et al.Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Cancer Res. 2008; 68: 2085-2093Crossref PubMed Scopus (384) Google Scholar Studies of rat and human primary PSCs in culture have identified a variety of soluble factors, such as cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]–α) and growth factors (platelet-derived growth factor [PDGF], transforming growth factor [TGF]–β1, and activin A), ethanol and its metabolites, oxidative stress, and pressure, as well as extensive changes in the composition and organization of extracellular matrix (ECM), as regulators of PSC activation.11Luttenberger T. Schmid-Kotsas A. Menke A. et al.Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis.Lab Invest. 2000; 80: 47-55Crossref PubMed Scopus (172) Google Scholar, 12Schneider E. Schmid-Kotsas A. Zhao J. et al.Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells.Am J Physiol Cell Physiol. 2001; 281: C532-C543PubMed Google Scholar, 13Mews P. Phillips P. Fahmy R. et al.Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis.Gut. 2002; 50: 535-541Crossref PubMed Scopus (299) Google Scholar, 14Ohnishi N. Miyata T. Ohnishi H. et al.Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis.Gut. 2003; 52: 1487-1493Crossref PubMed Scopus (86) Google Scholar, 15Apte M.V. Haber P.S. Darby S.J. et al.Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.Gut. 1999; 44: 534-541Crossref PubMed Scopus (504) Google Scholar, 16Apte M.V. Phillips P.A. Fahmy R.G. et al.Does alcohol directly stimulate pancreatic fibrogenesis?.Gastroenterology. 2000; 118: 780-794Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 17Masamune A. Kikuta K. Satoh M. et al.Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.J Pharmacol Exp Ther. 2002; 302: 36-42Crossref PubMed Scopus (100) Google Scholar, 18Watanabe S. Nagashio Y. Asaumi H. et al.Pressure activates rat pancreatic stellate cells.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1175-G1181Crossref PubMed Scopus (46) Google Scholar, 19Masamune A. Kikuta K. Satoh M. et al.Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.Tohoku J Exp Med. 2003; 199: 69-84Crossref PubMed Scopus (71) Google Scholar Potential sources of these activating factors include activated macrophages, platelets, pancreatic acinar cells, ductal cells, and endothelial cells in inflamed pancreas. It has been shown that pancreatic cancer cells can also be a source of PSC-activating factors.6Bachem M.G. Schünemann M. Ramadani M. et al.Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.Gastroenterology. 2005; 128: 907-921Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 7Hwang R.F. Moore T. Arumugam T. et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression.Cancer Res. 2008; 68: 918-926Crossref PubMed Scopus (894) Google Scholar, 8Vonlaufen A. Joshi S. Qu C. et al.Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Cancer Res. 2008; 68: 2085-2093Crossref PubMed Scopus (384) Google Scholar Importantly, PSCs by themselves are capable of synthesizing cytokines such as TGF-β1, activin A, and IL-1, suggesting the existence of autocrine loops that might contribute to the perpetuation of PSC activation after stimulation by an initial exogenous signal, thereby promoting the development of fibrosis.11Luttenberger T. Schmid-Kotsas A. Menke A. et al.Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis.Lab Invest. 2000; 80: 47-55Crossref PubMed Scopus (172) Google Scholar, 12Schneider E. Schmid-Kotsas A. Zhao J. et al.Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells.Am J Physiol Cell Physiol. 2001; 281: C532-C543PubMed Google Scholar, 13Mews P. Phillips P. Fahmy R. et al.Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis.Gut. 2002; 50: 535-541Crossref PubMed Scopus (299) Google Scholar, 14Ohnishi N. Miyata T. Ohnishi H. et al.Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis.Gut. 2003; 52: 1487-1493Crossref PubMed Scopus (86) Google Scholar, 15Apte M.V. Haber P.S. Darby S.J. et al.Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.Gut. 1999; 44: 534-541Crossref PubMed Scopus (504) Google Scholar, 16Apte M.V. Phillips P.A. Fahmy R.G. et al.Does alcohol directly stimulate pancreatic fibrogenesis?.Gastroenterology. 2000; 118: 780-794Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 17Masamune A. Kikuta K. Satoh M. et al.Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.J Pharmacol Exp Ther. 2002; 302: 36-42Crossref PubMed Scopus (100) Google Scholar On activation, PSCs lose lipid droplets, more actively proliferate, migrate, produce ECM components, and secrete proinflammatory cytokines and chemokines.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar, 6Bachem M.G. Schünemann M. Ramadani M. et al.Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.Gastroenterology. 2005; 128: 907-921Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 7Hwang R.F. Moore T. Arumugam T. et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression.Cancer Res. 2008; 68: 918-926Crossref PubMed Scopus (894) Google Scholar, 8Vonlaufen A. Joshi S. Qu C. et al.Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Cancer Res. 2008; 68: 2085-2093Crossref PubMed Scopus (384) Google Scholar, 19Masamune A. Kikuta K. Satoh M. et al.Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.Tohoku J Exp Med. 2003; 199: 69-84Crossref PubMed Scopus (71) Google Scholar Cytokines and growth factors produced by acinar cells, inflammatory cells, platelets, ductal cells, endothelial cells, cancer cells, and PSCs by themselves could activate PSCs and induce these cell responses in paracrine and autocrine manners.1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar, 6Bachem M.G. Schünemann M. Ramadani M. et al.Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.Gastroenterology. 2005; 128: 907-921Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 7Hwang R.F. Moore T. Arumugam T. et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression.Cancer Res. 2008; 68: 918-926Crossref PubMed Scopus (894) Google Scholar, 8Vonlaufen A. Joshi S. Qu C. et al.Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Cancer Res. 2008; 68: 2085-2093Crossref PubMed Scopus (384) Google Scholar Accumulating evidence supports major roles for PDGF, which induces proliferation and migration of PSCs, and TGF-β1, which induces PSCs to express α-SMA and ECM proteins, as mediators of the persistently activated and profibrogenic phenotypes of PSCs.11Luttenberger T. Schmid-Kotsas A. Menke A. et al.Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis.Lab Invest. 2000; 80: 47-55Crossref PubMed Scopus (172) Google Scholar, 12Schneider E. Schmid-Kotsas A. Zhao J. et al.Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells.Am J Physiol Cell Physiol. 2001; 281: C532-C543PubMed Google Scholar, 13Mews P. Phillips P. Fahmy R. et al.Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis.Gut. 2002; 50: 535-541Crossref PubMed Scopus (299) Google Scholar, 14Ohnishi N. Miyata T. Ohnishi H. et al.Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis.Gut. 2003; 52: 1487-1493Crossref PubMed Scopus (86) Google Scholar, 15Apte M.V. Haber P.S. Darby S.J. et al.Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.Gut. 1999; 44: 534-541Crossref PubMed Scopus (504) Google Scholar, 16Apte M.V. Phillips P.A. Fahmy R.G. et al.Does alcohol directly stimulate pancreatic fibrogenesis?.Gastroenterology. 2000; 118: 780-794Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 17Masamune A. Kikuta K. Satoh M. et al.Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.J Pharmacol Exp Ther. 2002; 302: 36-42Crossref PubMed Scopus (100) Google Scholar, 18Watanabe S. Nagashio Y. Asaumi H. et al.Pressure activates rat pancreatic stellate cells.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1175-G1181Crossref PubMed Scopus (46) Google Scholar, 19Masamune A. Kikuta K. Satoh M. et al.Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.Tohoku J Exp Med. 2003; 199: 69-84Crossref PubMed Scopus (71) Google Scholar In addition, recent studies have revealed that PSCs have a variety of cell functions (Table 1). Not only do PSCs produce ECM components, they also produce matrix-degrading enzymes of the matrix metalloproteinases (MMPs) family and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]). PSCs have been shown to secrete MMP-2, MMP-9, and MMP-13 and to express TIMP-1 and TIMP-2.20Phillips P.A. McCarroll J.A. Park S. et al.Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover.Gut. 2003; 52: 275-282Crossref PubMed Scopus (241) Google Scholar Thus, PSCs might be involved in the maintenance of normal tissue architecture by regulating ECM turnover. In this scenario, resolution of cerulein-induced pancreatitis in mice involves transient activation of PSCs and deposition of ECM proteins, as well as transient up-regulation of MMPs and TIMPs.21Lugea A. Nan L. French S.W. et al.Pancreas recovery following cerulein-induced pancreatitis is impaired in plasminogen-deficient mice.Gastroenterology. 2006; 131: 885-899Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar On the other hand, MMP-2 produced by PSCs might contribute to the progression of pancreatic cancer.22Schneiderhan W. Diaz F. Fundel M. et al.Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay.J Cell Sci. 2007; 120: 512-519Crossref PubMed Scopus (96) Google ScholarTable 1Responses of PSC to Stimulation and Activationα-SMA expressionProliferationECM production (type I, type III collagen, etc)Cytokine, chemokine production (IL-8, MCP-1, etc)Adhesion molecule (ICAM-1) expressionMigration/chemotaxisContractilityMatrix degradation (MMPs expression)TLRs expressionEndocytosis and phagocytosisAngiogenic responses Open table in a new tab The increased expression of the cytoskeletal protein α-SMA confers increased contractile potential, which is further enhanced by endothelin-1.23Masamune A. Satoh M. Kikuta K. et al.Endothelin-1 stimulates contraction and migration of rat pancreatic stellate cells.World J Gastroenterol. 2005; 11: 6144-6151Crossref PubMed Scopus (40) Google Scholar As mentioned, PSCs are located around the ductal and vascular structures1Apte M.V. Haber P.S. Applegate T.L. et al.Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture.Gut. 1998; 43: 128-133Crossref PubMed Scopus (754) Google Scholar, 2Bachem M.G. Schneider E. Gross H. et al.Identification, culture, and characterization of pancreas stellate cells in rats and humans.Gastroenterology. 1998; 115: 421-432Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar, 3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar; PSC contraction could regulate vascular and ductal tone in the pancreas. PSCs have the ability to produce a wide variety of cytokines and growth factors. PSCs produce IL-1β, IL-6, TNF-α, TGF-β1, and PDGF-BB, all of which contribute to perpetuation of PSC activation.3Omary M.B. Lugea A. Lowe A.W. et al.The pancreatic stellate cell: a star on the rise in pancreatic diseases.J Clin Invest. 2007; 117: 50-59Crossref PubMed Scopus (552) Google Scholar, 4Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis.J Gastroenterol. 2008; 43: 823-832Crossref PubMed Scopus (93) Google Scholar, 5Masamune A. Shimosegawa T. Signal transduction in pancreatic stellate cells.J Gastroenterol. 2009; 44: 249-260Crossref PubMed Scopus (167) Google Scholar, 11Luttenberger T. Schmid-Kotsas A. Menke A. et al.Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis.Lab Invest. 2000; 80: 47-55Crossref PubMed Scopus (172) Google Scholar, 12Schneider E. Schmid-Kotsas A. Zhao J. et al.Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells.Am J Physiol Cell Physiol. 2001; 281: C532-C543PubMed Google Scholar, 13Mews P. Phillips P. Fahmy R. et al.Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis.Gut. 2002; 50: 535-541Crossref PubMed Scopus (299) Google Scholar, 14Ohnishi N. Miyata T. Ohnishi H. et al.Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis.Gut. 2003; 52: 1487-1493Crossref PubMed Scopus (86) Google Scholar, 15Apte M.V. Haber P.S. Darby S.J. et al.Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.Gut. 1999; 44: 534-541Crossref PubMed Scopus (504) Google Scholar, 16Apte M.V. Phillips P.A. Fahmy R.G. et al.Does alcohol directly stimulate pancreatic fibrogenesis?.Gastroenterology. 2000; 118: 780-794Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 17Masamune A. Kikuta K. Satoh M. et al.Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.J Pharmacol Exp Ther. 2002; 302: 36-42Crossref PubMed Scopus (100) Google Scholar, 18Watanabe S. Nagashio Y. Asaumi H. et al.Pressure activates rat pancreatic stellate cells.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1175-G1181Crossref PubMed Scopus (46) Google Scholar, 19Masamune A. Kikuta K. Satoh M. et al.Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.Tohoku J Exp Med. 2003; 199: 69-84Crossref PubMed Scopus (71) Google Scholar, 24Masamune A. Kikuta K. Satoh M. et al.Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells.J Biol Chem. 2002; 277: 141-147Crossref PubMed Scopus (128) Google Scholar, 25Andoh A. Takaya H. Saotome T. et al.Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts.Gastroenterology. 2000; 119: 211-219Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Chemokines (IL-8, monocyte chemoattractant protein [MCP]-1, and RANTES) produced by PSCs contribute to the recruitment of inflammatory cells to the inflamed pancreas.24Masamune A. Kikuta K. Satoh M. et al.Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells.J Biol Chem. 2002; 277: 141-147Crossref PubMed Scopus (128) Google Scholar, 25Andoh A. Takaya H. Saotome T. et al.Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts.Gastroenterology. 2000; 119: 211-219Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Expression of cell adhesion molecules, such as intercellular adhesion molecule-1 in PSCs, also contri
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