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

Increased lipid peroxidation, enhanced nuclear factor kappa-B (NF-kappaB) activation and augmented tumor necrosis factor-alpha (TNF-alpha) production have been implicated in cerulein-induced pancreatitis. We investigated whether lipid peroxidation inhibition might reduce NF-kappaB activation and the inflammatory response in cerulein-induced pancreatitis. Male Sprague-Dawley rats of 230-250g body weight received administration of cerulein (80 microg/kg s.c. for each of four injections at hourly intervals). A control group received four s.c. injections of 0.9% saline at hourly intervals. Animals were randomized to receive either raxofelast, an inhibitor of lipid peroxidation (20 mg/kg i.p. administered with the first cerulein injection) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). All these rats were sacrificed 2 h after the last injection of either cerulein or its vehicle. Raxofelast administration (20 mg/kg i.p. with the first cerulein) significantly reduced malondialdehyde (MDA) levels, an index of lipid peroxidation (CER + DMSO = 3.075 +/- 0.54 micromol/g; CER + raxofelast = 0.693 +/- 0.18 micromol/g; p < 0.001), decreased myeloperoxidase (MPO) activity (CER + DMSO = 22.2 +/- 3.54 mU/g; CER + raxofelast = 9.07 +/- 2.05 mU/g, p < 0.01), increased glutathione levels (GSH) (CER + DMSO = 5.21 +/- 1.79 micromol/g; CER + raxofelast = 15.71 +/- 2.14 micronol/g; p < 0.001), and reduced acinar cell damage evaluated by means of histology and serum levels of both amylase (CER + DMSO = 4063 +/- 707.9 U/l; CER + raxofelast = 1198 +/- 214.4 U/l; p < 0.001), and lipase (CER + DMSO = 1654 +/- 330 U/l; CER + raxofelast = 386 +/- 118.2 U/l; p < 0.001), Furthermore, raxofelast reduced pancreatic NF-kappaB activation and the TNF-alpha mRNA levels and tissue content of mature protein in the pancreas. Indeed, lipid peroxidation inhibition might be considered a potential therapeutic approach to prevent the severe damage in acute pancreatitis.
 ...
PMID:Lipid peroxidation inhibition reduces NF-kappaB activation and attenuates cerulein-induced pancreatitis. 1274 37

Here we compare the degree of pancreatitis caused by cerulein in mice lacking 5-lipoxygenase (5-LO) and in the corresponding wild-type mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for intracellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin in the pancreas and lung of cerulein-treated mice. In contrast, the degree of (1) pancreatic inflammation and tissue injury (histological score), (2) up-regulation/expression of P-selectin, E-selectin and ICAM-1, and (3) neutrophil infiltration was markedly reduced in pancreatic and lung tissue obtained from cerulein-treated 5-LO-deficient mice. These findings support the view that 5-LO plays an important, pro-inflammatory role in the acute pancreatitis caused by cerulein in mice.
 ...
PMID:5-lipoxygenase knockout mice exhibit a resistance to acute pancreatitis induced by cerulein. 1294 Nov 49

p8 is a transcription cofactor whose expression is strongly and rapidly activated in pancreatic acinar cells during the acute phase of pancreatitis. A p8-deficient mouse strain was generated as a tool to investigate its function. Upon induction of acute pancreatitis, myeloperoxidase activity in pancreas and serum concentrations of amylase and lipase were much higher and pancreatic lesions more severe in p8-deficient mice than in wild-type, indicating that p8 expression decreased pancreatic sensitivity to pancreatitis induction. The protective mechanism might involve the pancreatitis-associated protein (PAP I), whose strong induction during pancreatitis is p8-dependent, because administration of anti-PAP I antibodies to rats increased pancreatic inflammation during pancreatitis. In addition, 100 ng/ml PAP I in the culture medium of macrophages prevented their activation by tumor necrosis factor alpha, strongly suggesting that PAP I was an anti-inflammatory factor. Finally, PAP I was able to inhibit NFkappaB activation by tumor necrosis factor alpha, in macrophages and in the AR42J pancreatic acinar cell line. In conclusion, p8 improves pancreatic resistance to inducers of acute pancreatitis by a mechanism implicating the expression of the anti-inflammatory protein PAP I.
 ...
PMID:p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I. 1466 Jun 81

Nuclear factor (NF)-kappaB plays a central role in acute pancreatitis. We studied cerulein (CER)-induced pancreatitis in NF-kappaB knockout (KO) mice. NF-kappaB KO mice and normal control littermate wild-type (WT) mice were given four hyperstimulating doses of cerulein every hour to elicit secreatagogue-induced pancreatitis. Malonildialdehyde activity, glutathione levels, myeloperoxidase activity, TNF-alpha, and NF-kappaB binding activity and its inhibitory protein IkappaBalpha were studied in the pancreas. Furthermore, we measured plasma lipase and amylase and the histological damage. KO mice had reduced malonildialdehyde levels (WT + CER = 4.083 +/- 0.95 micromol/g; KO + CER = 1.513 +/- 0.63 microol/g), decreased myeloperoxidase activity (WT + CER = 19.3 +/- 2.39 mU/g; KO + CER = 10.21 +/- 2.05 mU/g), increased glutathione levels (WT + CER 6.22 +/- 2.46 micromol/g; KO + CER = 15. 516 +/- 2.92 micromol/g), and reduced serum levels of amylase (WT + CER = 2519 +/- 656.9 U/L; KO + CER = 916 +/- 280.4 U/L) and lipase (WT + CER = 1420 +/- 170 U/L; KO + CER = 861 +/- 172. 3 U/L). KO mice showed reduced pancreatic NF-kappaB activation, decreased TNF-alpha tissue content, and reduced histologic alterations. Our data suggest that KO mice have an attenuated cerulein-induced pancreatitis and help to define the possible interaction between NF-kappaB activation and oxidative stress in this deleterious event.
 ...
PMID:Attenuated cerulein-induced pancreatitis in nuclear factor-kappaB-deficient mice. 1469 Dec 90

In a patient with an undiagnosed pleural effusion, the first question to answer is whether the fluid is an exudate or a transudate. This is usually determined by means of Light's criteria, which differentiate transudative effusions from exudative effusions by measuring the levels of total protein and lactate dehydrogenase in the pleural fluid (PF) and serum. In patients under diuretic treatment, Light's criteria misclassify transudates as exudates, but the serum to pleural fluid albumin gradient usually remains above 12 g/L. When tests are done only in PF, protein concentration >30 g/L performs at least as well as the other individual markers. To diagnose tuberculous pleuritis among exudates, PF adenosine deaminase and PF interferon-g exhibit high diagnostic accuracy. When malignancy is suspected the addition of tumour markers to the results of cytologic analysis increases the rate of detection. Other biochemical markers are useful in specific circumstances involving pleural effusion, such as amylase in effusions due to pancreatitis, or oesophageal rupture, and triglycerides in chylothorax. Several PF markers are associated with complicated parapneumonic effusion - e.g. low PF pH and glucose, and high PF LDH activity -- although PF pH appears to be the best biochemical aid in decisions regarding chest tube drainage. Recent reports suggest that neutrophil-derived enzymes (polymorphonuclear elastase and myeloperoxidase) can be useful as early indicators of the need of chest tube insertion; however these findings must be confirmed in large series. This review discusses the clinical usefulness of biochemical markers in the diagnosis and management of pleural effusions. The vast majority of prospective studies in this field have been conducted in adults and, although the mechanisms of pleural effusion production do not differ in children and adults, the prevalence of each etiologic cause does. Therefore it seems advisable to confirm or recalculate the predictive values of each marker in the paediatric population.
 ...
PMID:Useful clinical biological markers in diagnosis of pleural effusions in children. 1498 Feb 72

Mechanisms of pain transduction in acute pancreatitis are poorly understood. Increased Fos expression in the spinal cord is a marker of activation of nociceptive neurons. We hypothesized that cerulein pancreatitis leads to increased Fos expression at T9 and T10, which receive sensory input from the pancreas. Rats were injected with cerulein (100 microg/kg, s.c.) or saline carrier (NS). Endpoints at 4, 6, and 10 h were serum amylase, myeloperoxidase activity (MPO), and spinal cord Fos expression (number of immunoreactive nuclei/section dorsal gray matter). Fos-like immunoreactivity (FLI) at T9-T10 was compared to internal controls (T6, T12). An average of 20 spinal cord histologic sections were evaluated per rat. Some animals were injected with the mu-opioid receptor agonist, buprenorphine (90 microg/kg, s.c.), 3 h after cerulein, and their endpoints were measured at 6 h. Analysis of variance and t tests were used for statistical analysis. Results are means +/- SEM. As expected, cerulein induced edematous pancreatitis, with a 4-fold increase in serum amylase at 6 h [cer (n = 8): 14,000 +/- 1,300 U/ml versus NS (n = 10): 3,700 +/- 300, P < 0.005)] and a 2-fold increase in MPO activity (0.25 +/- 0.05) activity units/dry wt versus 0.13 +/- 0.02, P < 0.05). Cerulein induced nearly a 2-fold increase in FLI at T9 and T10 [n = 10 (cer) and n = 13 (NS): T9, 14 +/- 1.5 versus 7.8 +/- 0.88; T10, 15 +/- 1.7 versus 8.3 +/- 0.70; P < 0.05]. Peak effects of cerulein on FLI occurred at 6 h and were greatest at T9/T10 with relative sparing of T6/T12. T6/T12 expression was similar in experimental and control groups. Buprenorphine significantly reduced both serum amylase and FLI and T9/T10. Cerulein-induced acute pancreatitis in rat increases visceral nociceptive signaling at spinal cord levels T9 and T10, with a peak at 6 h. Blockade of this effect by the mu-opioid receptor agonist buprenorphine could occur either by direct activation of central opioid receptors and/or an anti-inflammatory mechanism. FLI is a useful tool for studying the pathophysiology of pain in experimental acute pancreatitis.
 ...
PMID:Activation of nociceptive neurons in T9 and T10 in cerulein pancreatitis. 1504 23

Severe impairment of exocrine pancreatic secretion has recently been demonstrated in a clinical study in sepsis and septic shock patients. The purpose of this study was to further evaluate involvement of the pancreas in the acute phase reaction in sepsis. Using a normotensive rat model of Pseudomonas pneumonia-induced sepsis, we assessed the expression of PAP-I, amylase and trypsinogen mRNA, PAPI protein levels, and cytokine expression in the pancreas by Northern and Western blot analysis and RT-M PCR, respectively. Presence of several well-established features of pancreatitis in sepsis-induced animals were examined by biochemical and histopathological methods as well as by a determination of both water and myeloperoxidase content. Sepsis resulted in an up-regulation of PAP-I gene expression and increase in its protein level in pancreas while the mRNA levels of amylase and trypsinogen were down-regulated. Differences in the pancreatic cytokine expression, serum amylase and serum lipase levels, the occurrence of pancreatic edema as well as the severity of inflammatory infiltration and necrosis were not significantly different between sham and pneumonia groups. Acinar cells showed increased vacuolization in pneumonia animals 24 hours after the treatment. These findings demonstrate that the pancreas is actively involved in the acute phase reaction in sepsis of remote origin. This involvement occurs without concomitant biochemical and histopathologic alterations observed in pancreatitis. Taken all together, these features are indicative of a sepsis-specific dysfunction of the pancreas.
 ...
PMID:Pseudomonas pneumonia-mediated sepsis induces expression of pancreatitis-associated protein-I in rat pancreas. 1521 Nov 9

The aim of this study was to investigate the influence of melatonin on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increases in mortality rate, pancreatic necrosis and increased serum activity of amylase, alanine aspartate transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO (2). Melatonin inhibited the changes in blood pressure, urine output, pO (2), serum concentration of urea, and calcium, tissue activity of MPO and MDA in the pancreas and lung, LDH level in BAL fluid, and partially reduced serum activity of IL-6. Melatonin did not change serum activity of amylase, ALT, pancreatic damage and the mortality rate. The use of melatonin has a limited value on the course of ANP. It may be useful as a supportive treatment during ANP.
 ...
PMID:Effects of melatonin on acute necrotizing pancreatitis in rats. 1545 65

Hydrogen sulfide (H2S) is a naturally occurring gas with potent vasodilator activity. Cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS) utilize L-cysteine as substrate to form H2S. Of these two enzymes, cystathionine-gamma-lyase (CSE) is believed to be the key enzyme that forms H2S in the cardiovascular system. Whilst H2S has been reported to relax precontracted rat arteries in vitro and to lower blood pressure in the rat, its effect in an inflammatory condition such as acute pancreatitis has not previously been reported. In this paper, we report the presence of H2S synthesizing enzyme activity and CSE (as determined by mRNA signal) in the pancreas. Also, prophylactic, as well as therapeutic, treatment with the CSE inhibitor, DL-propargylglycine (PAG), significantly reduced the severity of caerulein-induced pancreatitis and associated lung injury, as determined by 1) hyperamylasemia [plasma amylase (U/L) (control, 1204+/-59); prophylactic treatment: placebo, 10635+/-305; PAG, 7904+/-495; therapeutic treatment: placebo, 10427+/-470; PAG, 7811+/-428; P<0.05 PAG c.f. placebo; n=24 animals in each group]; 2) neutrophil sequestration in the pancreas [pancreatic myeloperoxidase oxidase (MPO) activity (fold increase over control) (prophylactic treatment: placebo, 5.78+/-0.63; PAG, 2.97+/-0.39; therapeutic treatment: placebo, 5.48+/-0.52; PAG, 3.03+/-0.47; P<0.05 PAG c.f. placebo; n=24 animals in each group)]; 3) pancreatic acinar cell injury/necrosis; 4) lung MPO activity (fold increase over control) [prophylactic treatment: placebo, 1.99+/-0.16; PAG, 1.34+/-0.14; therapeutic treatment: placebo, 2.03+/-0.12; PAG, 1.41+/-0.97; P<0.05 PAG c.f. placebo; n=24 animals in each group]; and 5) histological evidence of lung injury. These effects of CSE blockade suggest an important proinflammatory role of H2S in regulating the severity of pancreatitis and associated lung injury and raise the possibility that H2S may exert similar activity in other forms of inflammation.
 ...
PMID:Role of hydrogen sulfide in acute pancreatitis and associated lung injury. 1567 Nov 55

The aim of the present study was to investigate the potential effect of treatment with a platelet-activating factor (PAF) antagonist, lexipafant (BB-882), on gut endothelial and epithelial barrier dysfunction and leukocyte recruitment in rats with acute pancreatitis. Severe acute pancreatitis was induced by the intraductal administration of 5% sodium taurodeoxycholate and pancreatitis-associated gut barrier dysfunction was characterized by increased exudation of radiolabelled albumin into the interstitium and alterations in bidirectional (over both the endothelial and epithelial barrier components) permeability of the intestine at the early stage of bile salt-induced acute pancreatitis. Levels of interleukin 1beta and 6, ileal and colonic myeloperoxidase (MPO) content, clearance of radiolabelled albumin from blood to the gut lumen or gut lumen to blood, and leakage of radiolabelled albumin to the ileum or colon were measured 3 and 12h after induction of acute pancreatitis. Treatment with lexipafant 30 min and 6h after pancreatitis reduced severity of pancreatitis-associated intestinal dysfunction, associated with a diminish in systemic concentrations of IL-1 and local leukocyte recruitment. The findings imply that PAF plays a critical role in the development of pancreatitis-associated gut barrier dysfunction and that PAF antagonist in some forms may represent potential candidates for future therapeutic intervention.
 ...
PMID:Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant. 1582 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>