Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine which modifies tissue stromal matrix synthesis, cell proliferation and immune function. In the present study, we have used a mouse monoclonal antibody to the latent (intracytoplasmic) form of TGF-beta 1 to compare its expression in 144 cases of human chronic pancreatitis (both obstructive and chronic calcifying) with that of 10 control pancreatic specimens. In all the control specimens, and most of those with chronic pancreatitis, cytoplasmic immunoreactivity was identified in pancreatic duct and ductular epithelium, in islet cells and in vascular smooth muscle and endothelium. Two distinct patterns of ductular epithelial staining emerged: in morphologically normal tissues, only individual distal ductular/centroacinar cells stained but in chronic pancreatitis (whether chronic calcifying or chronic obstructive) the staining was panductular. Positive cytoplasmic immunostaining of acinar epithelial cells was found in 3% of pancreatitis specimens but in none of the normal controls. There was no staining of fibroblasts. Synthesis of TGF-beta 1 appears to be normally restricted to a population of epithelial cells located in terminal/centroacinar regions of the ductules (together with occasional ductal cells) whereas in chronic pancreatitis, TGF-beta 1 is expressed in most ductular and ductal epithelial cells.
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PMID:Expression of transforming growth factor-beta 1 in chronic pancreatitis. 765 50

Growth factors such as TGF-beta 1 and EGF are known to modulate the deposition of extracellular matrix components and tissue repair and to affect the cellular growth but their expression in the course of pancreatitis has not been studied. In this study we investigated the gene expression of TGF-beta 1 mRNA and EGF mRNA and other parameters of the pancreas including DNA synthesis, blood flow (PBF), tissue protein content and plasma amylase during the induction of acute pancreatitis. Supramaximal dose of cearulein (10 mg/kg/h s.c.) was infused for 5 h to induce pancreatitis. Animals were killed after 1, 2, 3, 4 and 5 h of infusion. The PBF was measured, blood samples were withdrawn to determine serum amylase concentration, biopsy samples were taken to measure the protein content and DNA synthesis. Expression of TGF-beta 1 and EGF mRNA was studied by reverse-transcription of polymerase chain reaction (RT-PCR). Caerulein infused caused a time-dependent decrease in DNA synthesis accompanied by gradual decrease of PBF and significant increase in pancreatic weight. The pancreatic protein content and plasma amylase showed progressive rise during 5 h of cearulein infusion. Histology revealed tissue edema, cellular vacuolization and prominent leukocyte infiltration after 3 h of cearulein infusion. TGF-beta 1 mRNA was strongly expressed at each time interval beginning from the 1 h after the start of cearulein infusion. In contrast, EGF mRNA was detected only at 5 h after induction of pancreatitis. We conclude that 1) the development of caerulein-induced pancreatitis results in the inhibition of pancreatic growth and the reduction in PBF accompanied by enhanced expression of TGF-beta 1; 2) The expression of EGF that was observed at the end of the induction of pancreatitis may indicate the initiation of pancreatic repair; 3) TGF-beta 1 seems to lead to subsequent induction of EGF that may stimulate the regeneration of injured pancreas.
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PMID:Expression of transforming growth factor-beta 1 and epidermal growth factor in caerulein-induced pancreatitis in rat. 909 26

Regeneration from cerulein-induced pancreatitis is accompanied by a transient synthesis and deposition of extracellular matrix components in the rat pancreas. To study the involvement of transforming growth factor beta1 (TGFbeta1), one of the most potent modulators of the extracellular matrix, in the process of pancreatic regeneration we examined the expression of this gene on the transcript and protein level in pancreata of rats sacrificed 0 hours, 24 hours, 2, 3, 5, 7 days after a 12 hour infusion of maximal doses of cerulein (10 microg kg(-1) h(-1)). TGFbeta1 protein increased twofold after 24 hours and 48 hours and returned to control values 7 days after induction of pancreatitis, while TGFbeta1-mRNA reached maximal values (3-fold over controls) after 2 days. The largest amount of TGFbeta1 mRNA was found in pancreatic acinar cells and in stromal cells. To verify the functional implication of TGFbeta overexpression in regulating extracellular matrix remodeling during regeneration from acute pancreatitis, rats were treated with 3 injections of neutralizing antibody against TGFbeta1 given 30 min before, and 24 hours and 48 hours after the start of infusion. In rats treated with maximal doses of cerulein and TGFbeta antibodies, pancreatic hydroxyproline content and expression of collagens I and III and of TGFbeta1 were significantly reduced. These results provide evidence that transforming growth factor beta1 among other cytokines is involved in the regulation of extracellular matrix remodeling in the rat pancreas during regeneration from cerulein-induced acute pancreatitis. In addition, there is evidence in the literature that application of recombinant TGFbeta after recurrent episodes of acute cerulein-induced pancreatitis promotes pancreatic fibrosis (3). Thus, TGFbeta is a regulator of extracellular matrix remodeling in the pancreas, and may be an important promoting factor in the pathogenesis of chronic pancreatitis. This hypothesis is supported by data in the literature showing enhanced TGFbeta expression in human chronic pancreatitis (2) and development of fibrosis and inflammation in pancreata of transgenic mice overexpressing TGFbeta1 (3).
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PMID:TGFbeta and the extracellular matrix in pancreatitis. 1057 40

Recent observations suggest that immune response is involved in the development of pancreatitis. However, the exact pathogenesis underlying this immune-mediated response is still under debate. TGF-beta has been known to be an important regulating factor in maintaining immune homeostasis. To determine the role of TGF-beta in the initiation or progression of pancreatitis, TGF-beta signaling was inactivated in mouse pancreata by overexpressing a dominant-negative mutant form of TGF-beta type II receptor in the pancreas, under control of the pS2 mouse trefoil peptide promoter. Transgenic mice showed marked increases in MHC class II molecules and matrix metalloproteinase expression in pancreatic acinar cells. These mice also showed increased susceptibility to cerulein-induced pancreatitis. This pancreatitis was characterized by severe pancreatic edema, inflammatory cell infiltration, T- and B-cell hyperactivation, IgG-type autoantibodies against pancreatic acinar cells, and IgM-type autoantibodies against pancreatic ductal epithelial cells. Therefore, TGF-beta signaling seems to be essential either in maintaining the normal immune homeostasis and suppressing autoimmunity or in preserving the integrity of pancreatic acinar cells.
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PMID:Loss of TGF-beta signaling contributes to autoimmune pancreatitis. 1077 50

Although altered cytokine homeostasis has been implicated in the pathogenesis of both alcoholic liver and pancreas diseases, the serum cytokine pattern characteristic of concomitant alcoholic liver cirrhosis and pancreatitis has not been examined. In this paper we examine the serum levels of proinflammatory cytokines, such as IL-6, IL-8, TNF-alpha, and also antiinflammatory ones, such as IL-10 and TGF-beta, in 22 patients with alcoholic liver cirrhosis and 28 patients with chronic pancreatitis and compare them with those detected in the sera of 14 patients with concomitant alcoholic cirrhosis and pancreatitis. All patients were heavy alcohol drinkers, consuming more than 70 g of pure alcohol per day for at least 5 years. The control group consisted of 33 age- and sex-matched healthy subjects receiving an annual health examination. They were not addicted to alcohol and confirmed to be free of major cardiopulmonary, gastrointestinal and hepatobiliary-pancreatic diseases. The results indicated that the cytokine pattern in the sera of patients with concomitant liver cirrhosis and pancreatitis was characterized by increased levels of two proinflammatory cytokines: TNF-alpha, the concentration of which seemed to be influenced by both liver and pancreas injury, and IL-6, which seemed to be rather connected with pancreas injury. Increased levels of IL-8, which were detected in the sera of patients with cirrhosis, pancreatitis and concomitant cirrhosis and pancreatitis, were rather connected with exacerbation of the disease processes which occurred only in some of the patients. No significant changes in the levels of IL-10 or TGF-beta were detected in the sera of patients with chronic pancreatitis and concomitant cirrhosis and pancreatitis, while in patients with cirrhosis significantly decreased levels of IL-10 were found. A significant imbalance between proinflammatory/antiinflammatory signals was especially characteristic of alcoholic cirrhosis and concomitant cirrhosis with pancreatitis.
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PMID:Serum levels of cytokines in alcoholic liver cirrhosis and pancreatitis. 1105 48

The aim of this study was to identify fibrogenic mediators stimulating activation, proliferation, and/or matrix synthesis of rat pancreatic stellate cells (PSC). PSC were isolated from the pancreas of normal Wistar rats and from rats with cerulein pancreatitis. Cell activation was demonstrated by immunofluorescence microscopy of smooth muscle alpha-actin (SMA) and real-time quantitative RT-PCR of SMA, fibronectin, and transforming growth factor (TGF)-beta(1). Proliferation was measured by bromodeoxyuridine incorporation. Matrix synthesis was demonstrated on the protein and mRNA level. Within a few days in primary culture, PSC changed their phenotype from fat-storing to SMA-positive myofibroblast-like cells expressing platelet-derived growth factor (PDGF) alpha- and PDGF beta-receptors. TGF-beta(1) and tumor necrosis factor (TNF)-alpha accelerated the change in the cells' phenotype. Addition of 50 ng/ml PDGF and 5 ng/ml basic fibroblast growth factor (bFGF) to cultured PSC significantly stimulated cell proliferation (4.37 +/- 0.49- and 2.96 +/- 0.39-fold of control). Fibronectin synthesis calculated on the basis of DNA was stimulated by 5 ng/ml bFGF (3.44 +/- 1.13-fold), 5 ng/ml TGF-beta(1) (2.46 +/- 0.89-fold), 20 ng/ml PDGF (2.27 +/- 0.68-fold), and 50 ng/ml TGF-alpha (1.87 +/- 0.19-fold). As shown by RT-PCR, PSC express predominantly the splice variant EIII-A of fibronectin. Immunofluorescence microscopy and Northern blot confirmed that in particular bFGF and TGF-beta(1) stimulated the synthesis of fibronectin and collagens type I and III. In conclusion, our data demonstrate that 1) TGF-beta(1) and TNF-alpha accelerate the change in the cell phenotype, 2) PDGF represents the most effective mitogen, and 3) bFGF, TGF-beta(1), PDGF, and, to a lesser extent, TGF-alpha stimulate extracellular matrix synthesis of cultured rat PSC.
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PMID:Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. 1144 52

Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which eventually form oligomers with SMAD 4 and translocate to the nucleus. Reverse transcriptase-polymerase chain reaction showed that SMADs 1, 2 and 4 are expressed in pancreatic islets. Immunostaining revealed that SMAD 1 and 4 predominantly were expressed by islet insulin and glucagon cells. Since SMAD 1 is known to transduce signals from receptors binding bone morphogenetic protein (BMP) these results indicate a previously unknown role of BMP-like ligands in islet function.
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PMID:Expression of SMAD signal transduction molecules in the pancreas. 1168 56

Acute pancreatitis is a disease of variable severity in which patients can experience mild or severe attacks. Most observers believe that acute pancreatitis results from an early intra-acinar cell activation of inactive zymogens into their active forms. Following this early activation, a trypsin cascade occurs in the gland which leads to the auto-digestion of acinar cells. Recent experimental data indicate that synthesis and release of pro-inflammatory cytokines and chemokines are also responsible for local injury and systemic dispersion of the inflammatory mediators. Experimental studies also provide evidence for the involvement of the immune system in the development of pancreatitis, including lymphocyte and neutrophil activation. However, the factors that will dictate the ultimate severity of the attack are still unknown. Following an attack, the pancreas completely recovers or becomes fibrotic through the action of newly described mediators within the pancreas such as TGF-beta and IGF-1 and the presence of pancreatic stellate cell that is known to play a crucial role in the fibrogenesis.
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PMID:Experimental acute pancreatitis: new insights into the pathophysiology. 1177 94

The objective was to investigate the effects of vitamin E on collagen deposition induced by Cyclosporin A (CsA) administration in rats with caerulein (Cr) pancreatitis. CsA transforms the fully regenerative, self-limited form of Cr pancreatitis into a chroniclike disease in conjunction with increased transforming growth factor (TGF)-beta and myofibroblast proliferation. Vitamin E inhibits TGF-beta release in mesangial cells and reduces CsA cytotoxicity. Wistar rats received CsA daily (20 mg/kg), and CR pancreatitis was induced on days 1 and 8 (Cr + CsA group). In a separate group, vitamin E (600 mg.kg(-1).day(-1)) was administered starting 4 days before CsA. Three other groups received either vehicle, CsA, or Cr alone. Thiobarbituric acid-reactive substance (TBARS), 8-isoprostanes, and hyaluronic acid were measured in plasma obtained on the day the animals were killed (day 15). Pancreases were weighed and processed for light microscopy to assess connective tissue and myofibroblast number. Pancreatic homogenates were also assayed for collagen (hydroxyproline) and TBARS content. TBARS, 8-isoprostane, and TGF-beta were elevated in CsA and Cr + CsA rats. Vitamin E treatment greatly decreased these parameters. Vitamin E also decreased the fall in pancreatic weight observed in Cr + CsA pancreas. Pancreatic hydroxyproline and plasma hyaluronic acid were increased in Cr + CsA rats but were effectively reduced by vitamin E. Morphology showed improvement in fibrosis score and a decreased number of myofibroblasts in vitamin E-treated rats. Vitamin E reduces oxidative stress and collagen deposition during the development of experimental chronic pancreatitis. Adjuvant antioxidants may be of value in the treatment of chronic pancreatitis.
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PMID:Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. 1500 29

Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1beta mRNA and secrete IL-1beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1beta activity secreted from PSCs by IL-1beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1beta in activated PSCs through Smad3- and ERK-dependent pathways.
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PMID:Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells. 1637 39


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