Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells

Apte, Minoti V.; Phillips, Phoebe A.; Fahmy, Roger G.; Darby, Samantha J.; Rodgers, Sally C.; McCaughan, Geoffrey W.; Korsten, Mark A.; Pirola, Romano C.; Naidoo, Daya; Wilson, Jeremy S.

doi:10.1016/s0016-5085(00)70148-x

Cited by 238 publications

(221 citation statements)

References 54 publications

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“…As we know, tissue injury is the first step of fibrosis. Apte et al [16] showed that activated PSCs around the pancreatic micrangium express α-SMA, which could aggravate fibrosis of the pancreas, because of vasoconstriction and pancreatic ischemia caused by α-SMA. Emodin could protect pancreatic cells and organs from impairment.…”

Section: Discussionmentioning

confidence: 99%

Effect of emodin on pancreatic fibrosis in rats

Wang

Gao²,

Yu³

et al. 2007

WJG

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AIM:To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis. METHODS:Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was infused into the pancreatic duct to induce chronic pancreatitis in rats (except for normal group). Emodin-treated rats were fed with different doses of emodin (20, 40 and 80 mg/kg body weight) for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factorbeta-1 (TGF-β1) was localized by immunochemistry. RESULTS:In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 ± 19.3 µg/L vs 112.7 ± 26.5 µg/L, P < 0.05; LN 44.3 ± 10.4 µg/L vs 86.2 ± 16.5 µg/L, P < 0.05); the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group (36% ± 5% vs 42% ± 6%, P < 0.05); with the increased doses of emodin, the expression of TGF-β1 was declined, compared with those in control group. CONCLUSION:Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.

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Section: Discussionmentioning

confidence: 99%

Effect of emodin on pancreatic fibrosis in rats

Wang

Gao²,

Yu³

et al. 2007

WJG

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“…These findings are supported by the known participation of reactive oxygen species in the activation process of stellate cells. 61,62 Also treatment of primary human PSC grown on plain TC plates with NAC induced a decrease of aSMA, but to a smaller extent than did Matrigel cultivation. NAC reduced CTGF expression to similar levels as Matrigel cultivation, but had no effect on GFAP and WAF1 expression.…”

Section: Deactivation Of Pancreatic Stellate Cells R Jesnowski Et Almentioning

confidence: 99%

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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“…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)-a] and growth factors [plateletderived growth factor (PDGF), transforming growth factor (TGF)-b1, and activin A], ethanol and its metabolites, oxidative stress, and pressure, as well as extensive changes in the composition and organization of ECM, as regulators of PSCs activation (Fig. 1) [10][11][12][13][14][15][16][17][18]. Potential sources of these activating factors include activated macrophages, platelets, pancreatic acinar cells, and endothelial cells in inflamed pancreas.…”

Section: Activation Of Pscsmentioning

confidence: 99%