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)

Myofibroblasts and cytokines such as transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor (PDGF)-B have been found to play an important role in pancreatitis-associated fibrogenesis. It is still unclear, however, where in the inflamed pancreas and when these fibrogenic cells and cytokines can be detected. In this study we examined pancreatic tissue from patients with alcoholic chronic pancreatitis to determine the localization and distribution of myofibroblasts and the expression of cytokines in relation to the tissue damage and the activity of the inflammatory process. In tissue from pancreatic specimens from 59 patients with alcoholic chronic pancreatitis the inflammatory process was histologically staged. Myofibroblasts and the cytokines latency-associated peptide, a TGF-beta propeptide, TGF-beta receptor II, PDGF-B and the alpha-isoform of the PDGF receptor were immunohistochemically identified in 10 selected cases representing the four defined stages of alcoholic chronic pancreatitis. In stage I, the stage with overt tissue injury, myofibroblasts were numerous and especially associated with macrophages around areas of necrosis. In stage II, the stage with cellular fibrosis, myofibroblasts were the main component of the interlobular tissue. In stage III, the stage with dense fibrosis, myofibroblasts were rare, and in stage IV, when calculi were present, myofibroblasts were only detected adjacent to duct ulcerations caused by calculi. Latency-associated peptide and TGF-beta receptor II as well as PDGF-B and PDGF receptor-alpha were mainly expressed by macrophages, myofibroblasts and epithelial cells in stages I and II. The results suggest that the fibrogenic process in alcoholic chronic pancreatitis is initiated by a cytokine-based interplay of macrophages and myofibroblasts that follows tissue injury.
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PMID:Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. 1668 Jan 57

Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
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PMID:Expression of connective tissue growth factor in pancreatic cancer cell lines. 1778 99

Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.
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PMID:Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma. 1793 47

Pancreatic fibrosis is the hallmark of chronic pancreatitis, currently an incurable disease. Pancreatitis fibrosis is caused by deposition of extracellular matrix (ECM) and the underlying pathological mechanism remains unclear. In addition to its broad biological activities, TGF-beta is a potent pro-fibrotic factor and many in vitro studies using cell systems have implicated a functional role of TGF-beta in the pathogenesis of pancreatic fibrosis. We analyzed the in vivo role of TGF-beta pathway in pancreatic fibrosis in this study. Smad7, an intracellular inhibitory protein that antagonizes TGF-beta signaling, was specifically expressed in the pancreas using a transgenic mouse model. Chronic pancreatitis was induced in the mouse with repeated administration of cerulein. Smad7 expression in the pancreas was able to significantly inhibit cerulein-induced pancreatic fibrosis. Consistently, the protein levels of collagen I and fibronectin were decreased in the Smad7 transgenic mice. In addition, alpha-smooth muscle actin, a marker of activated pancreas stellate cells, was reduced in the transgenic mice. Taken together, these data indicate that inhibition of TGF-beta signaling by Smad7 is able to protect cerulein-induced pancreatic fibrosis in vivo.
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PMID:Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7. 1901 26

The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor (CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-beta, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic beta-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin(+) cells, but becomes down-regulated in beta-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon(+) cells with a concomitant decrease in insulin(+) cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in beta-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon(+) cells, and beta-cell hypertrophy.
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PMID:Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation during embryogenesis. 1913 12

Patients with autoimmune pancreatitis have a striking polyclonal elevation of total IgG4 in serum. This observation has been confirmed and extended to other fibrotic conditions (that are therefore called IgG4-related disease) but as yet remains unexplained. The affected tissue contains many IgG4-producing plasma cells embedded in a fibrotic matrix originating from activated mesenchymal (stellate) cells. We propose that the process results from an unusual interaction between two regulatory systems: the regulatory arm of the immune system (including Bregs) and the tissue repair regulatory components orchestrated by the activated stellate cell. This interaction results in ongoing mutual activation, generating TGFbeta, IL10, and vitamin D. This environment suppresses most immune reactions but stimulates the development of IgG4-producing plasma cells.
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PMID:IgG4-Related Fibrotic Diseases from an Immunological Perspective: Regulators out of Control? 2270 88


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