Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats

Vaquero, Eva C.; Molero, Xavier; Tian, Xinggui; Salas, Antonio; Malagelada, Juan–R.

doi:10.1136/gut.45.2.269

Cited by 41 publications

(42 citation statements)

References 49 publications

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“…To test the potential benefits of tocotrienols on chronic pancreatitis, we discarded the model we had previously described because we found that cyclosporin A inhibits tocotrienol-induced cell death in vitro (38,48). Some other experimental models induce the development of chronic-like pancreatitis after surgical manipulations (35), after administration of toxic compounds that also affect other organs (43), or under specific genetic backgrounds (29).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

González

García

Samper

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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González AM, Garcia T, Samper E, Rickmann M, Vaquero EC, Molero X. Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis. Am J Physiol Gastrointest Liver Physiol 301: G846 -G855, 2011. First published August 18, 2011 doi:10.1152/ajpgi.00485.2010.-Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chroniclike pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, ␣-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-␤1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-␤1 (185 Ϯ 40 vs. 15 Ϯ 2 ng/ml; P Ͻ0.01) that was blunted by TRF (53 Ϯ 19; P Ͻ 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. ␣-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 Ϯ 0.3% vs. 0.2 Ϯ 0.2%), collagen network complexity (fractal dimension 1.52 Ϯ 0.03 vs. 1.42 Ϯ 0.01; P Ͻ 0.001), and inhomogeneity (lacunarity 0.63 Ϯ 0.03 vs. 0.40 Ϯ 0.02; P Ͻ 0.001), which were all reduced by TRF (1.3 Ϯ 0.4%, 1.43 Ϯ 0.02%, and 0.51 Ϯ 0.03%, respectively; P Ͻ 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r ϭ 0.88) and both parameters with pancreatic weight (r ϭ Ϫ0.91 and Ϫ0

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Section: Discussionmentioning

confidence: 99%

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

González

García

Samper

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In vivo, cyclosporine interferes with the reparative process activated after experimental pancreatitis, at least in part, by inhibiting acinar cell proliferation (31). Because of the short lifetime of dispersed nonimmortalized pancreatic acinar cells, we used AR42J cells, an established model system, to investigate the biology of isolated pancreatic acinar cells (32).…”

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confidence: 99%

Cyclosporine Inhibits Growth through the Activating Transcription Factor/cAMP-responsive Element-binding Protein Binding Site in the Cyclin D1 Promoter

Schneider¹,

Oswald²,

Wahl

et al. 2002

Journal of Biological Chemistry

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The immunosuppressive agent cyclosporine affects proliferation depending on the cellular system used. In an attempt to study the inhibitory effect of cyclosporine on proliferation of pancreatic acinar cells, we used AR42J cells as a model system. Here we demonstrate that cyclosporine inhibits growth of these cells by inducing G 1 cell cycle arrest. This effect is mediated by the 5 regulatory region of the cyclin D1 gene and leads to a reduction of cyclin D1 mRNA expression and protein abundance. We show that in AR42J cells the proximal cyclin D1 promoter contains a cis-regulated element, which is important for the maintenance of basal transcriptional activity. This element overlaps the described cAMP-responsive element (CRE) and confers cyclosporine sensitivity to the cyclin D1 promoter. Furthermore, the DNA binding activity of the CRE-binding protein (CREB) decreases through cyclosporine treatment and this is mediated by cyclosporine-induced reduction of CREB steady-state levels. These results demonstrate that cyclosporine can inhibit proliferation of acinar cells by targeting the cyclin D1 promoter at the proximal CRE via a reduction of CREB protein abundance.Mammalian cell proliferation is regulated in mid-to late G 1 phase of the cell cycle. The D-type cyclins and the associated cyclin-dependent kinases (CDKs) 1 are thought to be the key regulatory components for progression through G 1 phase and for the commitment of cells to enter S phase. Cyclin D1 and its catalytic partners CDK4 and CDK6 phosphorylate the retinoblastoma tumor suppressor gene product (RB), resulting in the release of E2F transcription factors, which are required for the activation of S phase-specific genes (1, 2). Inhibition of cyclin D1 expression prevents transition of cells from G 1 to S phase, whereas ectopic expression of cyclin D1 shortens the G 1 interval in many cell types, suggesting that cyclin D1 may be ratelimiting for G 1 progression (2, 3). The abundance of cyclin D1 is regulated transcriptionally and through the ubiquitin-proteasome pathway via protein degradation (4). The promoter region of the cyclin D1 gene contains multiple cis-acting elements, including binding sites for activator protein-1 (AP-1), for nuclear factor B (NF-B), for signal transducers and activators of transcription, for SP1, and for activating transcription factor (ATF)/cAMP-responsive element-binding protein (CREB). The ATF/CREB-binding site is implicated in the activation of the cyclin D1 gene by pp60 v-src (5). Furthermore, the estrogeninduced activation of the cyclin D1 promoter depends on the ATF/CREB site in which ATF-2 and c-Jun form heterodimers (6). Moreover, the integrin-linked kinase-dependent induction of the cyclin D1 promoter requires an intact ATF/CREB site, which is important for the maintenance of the basal transcriptional activity, but not for the induction of the cyclin D1 promoter activity in vascular endothelial cells (7,8).The basic leucine zipper transcription factor CREB is ubiquitously expressed and activated by phosphorylatio...

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“…Recent studies have indicated that pancreatic stellate cells also undergo a similar transformation to a myofibroblast phenotype during pancreatic fibrosis (Bachem et al, 1998). When activated, the pancreatic myofibroblasts proliferate and generate a large amount of extracellular matrix materials including fibril-forming collagens, fibronectin, and ␣-SMA (Vaquero et al, 1999;Masamune et al, 2003). TGF-␤ plays a dominant role in the development of fibrosis in a number of organs and directly stimulates myofibroblast transformation (e.g., Overall et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Angiotensin II to Alcohol-Induced Pancreatic Fibrosis in Rats

Uesugi

Froh²,

Gäbele³

et al. 2004

J Pharmacol Exp Ther

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The mechanisms by which alcohol causes pancreatic fibrosis remain unknown. Recent studies have demonstrated that angiotensin II contributes to the development of fibrosis in liver, kidney, and heart injury. Here, the effects of angiotensin-converting enzyme inhibitor (captopril) and angiotensin II receptor antagonist (losartan) on alcohol-induced pancreatic fibrosis were examined in an intragastric ethanol-feeding model. Male rats were fed a high-fat liquid diet with either ethanol (16 -20 g/kg/day) or isocaloric maltose-dextrin (control) for 4 weeks. Subgroups daily received captopril (60 mg/kg/day), losartan (3 mg/kg/day), or no additional agent included in liquid diets. Mean urine alcohol concentrations in all groups fed ethanol were more than 270 mg/dl and not significantly different. Dietary alcohol caused diffuse gland atrophy and interlobular and intralobular fibrosis with mild structural distortion in the pancreas, an effect that was blunted by captopril or losartan treatment. Alcohol also increased the number of ␣-smooth muscle actin-positive cells and transforming growth factor-␤ mRNA expression in the pancreas. These increases were blunted significantly by captopril or losartan treatment. These data suggest that angiotensin II contributes to the development of chronic alcohol-induced pancreatic fibrosis through its stimulation of transforming growth factor-␤ expression.

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Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats

Cited by 41 publications

References 49 publications

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

Cyclosporine Inhibits Growth through the Activating Transcription Factor/cAMP-responsive Element-binding Protein Binding Site in the Cyclin D1 Promoter

Contribution of Angiotensin II to Alcohol-Induced Pancreatic Fibrosis in Rats

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