Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells

Schneider, Eric L.; Schmid‐Kotsas, Alexandra; Zhao, Jinshun; Weidenbach, H; Schmid, Roland M.; Menke, André; Adler, Guido; Waltenberger, Johannes; Grünert, A.; Bachem, Max G.

doi:10.1152/ajpcell.2001.281.2.c532

Cited by 205 publications

(170 citation statements)

References 44 publications

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“…[51][52][53] As a result of increased recruitment of inflammatory cells, activated mononuclear cells release profibrotic cytokines and chemokines, such as TGF-b, TNF-a and MCP-1, which in turn activate hPSCs and promote fibrosis in CP. 4,52,53 The chemokine MCP-1, one of the major monocyte chemoattractants, is highly expressed in fibroblasts in CP, induces TGF-b upregulation and is associated with the progression of pancreatic fibrosis. 52,54 Blocking of MCP-1 attenuates the degree of fibrosis in experimental CP.…”

Section: Discussionmentioning

confidence: 99%

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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Section: Discussionmentioning

confidence: 99%

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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“…15,17 After TGFb1 treatment, RNA isolation and RT-PCR or Western blot analysis was performed as described above.…”

Section: Response To Tgfb1 Stimulationmentioning

confidence: 99%

“…These include cytokines (eg IL-1), growth factors (PDGF, TGFb1), ethanol and acetaldehyde. 11,15,16 Platelet-derived growth factor (PDGF) seems to be the most potent mitogen, whereas transforming growth factor b 1 (TGFb1) predominantly induces matrix synthesis. 15,17 Different methods for isolation of these cells have been published, using either dispersed acini, enzymatic tissue digestion and density centrifugation, or outgrowth of PSC from pancreatic tissue.…”

mentioning

confidence: 99%

“…11,15,16 Platelet-derived growth factor (PDGF) seems to be the most potent mitogen, whereas transforming growth factor b 1 (TGFb1) predominantly induces matrix synthesis. 15,17 Different methods for isolation of these cells have been published, using either dispersed acini, enzymatic tissue digestion and density centrifugation, or outgrowth of PSC from pancreatic tissue. 18,8,9,19 These methods need fairly large amounts of tissue to obtain a sufficient number of cells.…”

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confidence: 99%

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Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

Jesnowski

Fürst

Ringel

et al. 2005

Laboratory Investigation

132

134

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Tissue fibrosis is one of the characteristics of chronic pancreatitis and pancreatic adenocarcinoma. Activated pancreatic stellate cells (PSC) play a central role in this process. However, analysis of the molecular mechanisms leading to PSC activation is hampered by the lack of an established human PSC line. To overcome this problem, we immortalized and characterized primary human PSC. The cells were isolated by the outgrowth method and were immortalized by transfection with SV40 large T antigen and human telomerase (hTERT). Primary human PSC served as controls. An immortalized line, RLT-PSC, was analyzed for the expression of stellate cell markers. Moreover, the effects of transforming growth factor b 1(TGFb1) or platelet-derived growth factor stimulation and of cultivation on basement membrane components or N-acetylcysteine (NAC) treatment on gene and protein expression and proliferation were analyzed. Immortal RLT-PSC cells retained the phenotype of activated PSC proven by the expression of a-smooth muscle actin (aSMA), vimentin, desmin and glial fibrillary acidic protein (GFAP). TGFb1 treatment upregulated the expression of aSMA, collagen type I (Col I), fibronectin and TGFb1. Incubation of RLT-PSC cells and primary human activated PSC on Matrigel plus NAC treatment resulted in a deactivated phenotype as evidenced by a decrease of aSMA, connective tissue growth factor and Col I expression and by a decreased proliferation of the cells. Moreover, this treatment restored the ability of the cells to store vitamin A in cytoplasmic vesicles. In conclusion, we have established an immortal pancreatic stellate cell line, without changing the characteristic phenotype. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC. Cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.

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“…PSCs are considered the major ECM producing cells in pancreas 49,50 . Previous studies have shown that PSCs are transiently activated in experimental models of pancreatitis in rodents and contribute to organ repair.…”

Section: Pancreatic Stellate Cells Were Persistently Activated In Plgmentioning

confidence: 99%

Pancreas Recovery Following Cerulein-Induced Pancreatitis Is Impaired in Plasminogen-Deficient Mice

Lugea

French

et al. 2006

Gastroenterology

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Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells

Cited by 205 publications

References 44 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

Pancreas Recovery Following Cerulein-Induced Pancreatitis Is Impaired in Plasminogen-Deficient Mice

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