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)

Peroxisome proliferator-activated receptor (PPAR)-gamma controls growth, differentiation, and inflammation. PPAR-gamma agonists exert anti-inflammatory effects in vitro and inhibit the activation of pancreas stellate cells, implicated in the formation and progression of fibrosis. We determined the influence of troglitazone, a ligand for PPAR-gamma, on pancreatic damage and fibrosis in experimental chronic pancreatitis. Mice received six hourly intraperitoneal injections with 50 microg/kg of cerulein or saline, three times a week for 6 weeks. One week after the last injection all mice were sacrificed. Untreated mice were compared with mice treated with troglitazone either during weeks 1 to 6 or weeks 4 to 6. All mice that received cerulein injections displayed histopathological signs of chronic pancreatitis at week 7. Troglitazone treatment improved all markers for severity of pancreatitis. Moreover, early and postponed troglitazone treatments were equally effective in diminishing intrapancreatic fibrosis as quantified by Sirius red staining, hydroxyproline content, and laminin staining as well as the increased number of pancreatic stellate cells and pancreas levels of transforming growth factor-beta. Thus, troglitazone attenuated pancreatic damage and inflammation in experimental chronic pancreatitis and remained beneficial in a therapeutic setting when given after initial damage had been established.
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PMID:Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice. 1574 84

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that regulate cellular energy and lipid metabolism. PPAR-gamma agonists also have potent anti-inflammatory properties through down-regulation of early inflammatory response genes. The role of PPAR-gamma in acute pancreatitis has not been adequately examined. In this study, we determined the effect of PPAR-gamma agonists on the severity of pancreatitis and sought to correlate PPAR-gamma expression in pancreatic acinar cells and the severity of acute pancreatitis in vivo. Acute pancreatitis was induced in mice by hyperstimulation with the cholecystokinin analog, cerulein. PPAR-gamma agonists were administered by intraperitoneal injection 15-30 minutes before induction of pancreatitis (pretreatment) or at various times after induction of pancreatitis (treatment). Pancreata and serum were harvested over the course of 24 hours. Serum amylase activity and glucose levels were measured. Pancreata were used for histological evaluation as well as protein and mRNA analysis. Pretreatment of mice with the PPAR-gamma agonists 15-deoxy-Delta12, 14-prostaglandin J(2), or troglitazone significantly reduced the severity of pancreatitis in a dose-dependent manner. This reduction was indicated by reduced serum amylase activity and histological damage (leukocyte infiltration, vacuolization, and necrosis). Although cerulein decreased PPAR-gamma expression in the pancreas, pretreatment with agonists maintained PPAR-gamma expression early in acute pancreatitis. The expression of PPAR-gamma inversely correlated with pancreatitis severity and expression of the proinflammatory cytokines, interleukin-6, and tumor necrosis factor-alpha. Treatment with troglitazone after the induction of pancreatitis reduced serum amylase activity. The results suggest that PPAR-gamma plays a direct role in the inflammatory cascade during the early events of acute pancreatitis. Our data are the first to demonstrate that PPAR-gamma agonists represent a promising therapeutic strategy for acute pancreatitis.
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PMID:Anti-inflammatory effects of PPAR-gamma agonists directly correlate with PPAR-gamma expression during acute pancreatitis. 1696 31

Alcohol abuse is a major cause of pancreatitis, a condition that can manifest as both acute necroinflammation and chronic damage (acinar atrophy and fibrosis). It is generally accepted that alcohol-induced pancreatic injury is a consequence of the metabolism of alcohol by the pancreas (via the oxidative and non-oxidative pathways) producing the toxic metabolites acetaldehyde and fatty acid ethyl esters (FAEEs) respectively. Ethanol oxidation within the pancreas also leads to oxidant stress within the gland. Acetaldehyde, oxidant stress and FAEEs cause numerous molecular changes in pancreatic acinar cells which predispose the gland to autodigestion and necroinflammation. An important recent development relates to the identification of pancreatic stellate cells (PSCs) as the key mediators of alcohol-induced pancreatic fibrosis, when activated by ethanol, acetaldehyde or oxidant stress. Recent studies implicate the mitogen activated protein kinase (MAPK) pathway, a major signalling pathway in mammalian cells, as a critical regulator of the effects of ethanol and acetaldehyde on acinar cells as well as PSCs. Particularly important are the modulatory effects of ethanol and its metabolites on downstream transcription factors NF-kappaB and AP-1 (which regulate inflammatory responses via cytokine production) in acinar cells. In PSCs, additional signalling molecules identified as important to the process of ethanol and acetaldehyde-induced PSC activation include protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and peroxisome proliferator-activated receptor gamma (PPARgamma). Interestingly, cross-talk has been demonstrated between PI3K and MAPK in acetaldehyde-treated PSCs. The above advances in the identification of relevant signalling molecules may enable therapeutic targeting of these pathways so as to prevent/reduce alcohol-induced acute as well as chronic injury of the pancreas.
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PMID:Pancreatic MAP kinase pathways and acetaldehyde. 1759 Sep 96

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

Cancers often arise as the end stage of inflammation in adults, but not in children. As such there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer and limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology. Groups defining staging for neoplasms are strongly encouraged to assess and incorporate measures of the presence of apoptosis, autophagy, and necrosis and also the nature and quality of the immune infiltrate. Both environmental and genetic factors enhance the risk of cigarette smoking, Helicobacter pylori, hepatitis B/C, human papilloma virus, solar irradiation, asbestos, pancreatitis, or other causes of chronic inflammation. Identifying suitable genetic polymorphisms in cytokines, cytokine receptors, and Toll-like receptors among other immune response genes is also seen as high value as genomic sequencing becomes less expensive. Animal models that incorporate and assess not only the genetic anlagen but also the inflammatory cells and the presence of microbial pathogens and damage-associated molecular pattern molecules are necessary. Identifying micro-RNAs involved in regulating the response to damage or injury are seen as highly promising. Although no therapeutic strategies to prevent or treat cancers based on insights into inflammatory pathways are currently approved for the common epithelial malignancies, there remains substantial interest in agents targeting COX2 or PPARgamma, ethyl pyruvate and steroids, and several novel agents on the horizon.
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PMID:Cancer and inflammation: promise for biologic therapy. 2038 72