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)

The markers of oxidative stress and inflammation were studied in acute pancreatitis in transgenic rats exhibiting activated polyamine catabolism. In addition, the effect of bismethylspermine (Me(2)Spm) pretreatment, preventing pancreatitis in this model, on these mediators was investigated. Lipid peroxidation was increased at 6 and 24 h after induction of pancreatitis. These changes as well as the markedly decreased superoxide dismutase activity at 24 h were abolished by Me(2)Spm pretreatment. Glutathione level and catalase activity changed transiently, and the effect of Me(2)Spm was clear at 24 h. Serum inflammatory cytokine levels increased already at 4 h whereas NF-kappaB was distinctly activated only at 24 h. Me(2)Spm prevented the increase in TNF-alpha and IL-6 while it had no effect on NF-kappaB activation. These results show that typical inflammatory and, to a lesser degree, some oxidative stress mediators are involved and beneficially affected by the disease-ameliorating polyamine analogue in our pancreatitis model.
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PMID:Oxidative stress and inflammation in the pathogenesis of activated polyamine catabolism-induced acute pancreatitis. 1741 Mar 33

Induction of proinflammatory cytokines IL-6 and TGF-beta1 are the hallmark of human pancreatitis. Cerulein pancreatitis is similar to human edematous pancreatitis involving dysregulation of digestive enzyme production, cytoplasmic vacuolization, and increased cytokine production. We previously showed that cerulein induced IL-1beta expression through the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway in pancreatic acinar cells. Suppressor of cytokine signaling (SOCS) is a negative feedback regulator of JAK/STAT signaling. In this study, we demonstrate that SOCS 3 is induced by cerulein in pancreatic acinar AR42J cells and in the rat pancreas. In both AR42J cells and rat pancreas, cerulein induced expression of IL-6 and TGF-beta1, which is enhanced by transfection or injection of SOCS 3 antisense oligonucleotide (AS ODN). Pre-treating cerulein-stimulated AR42J cells or rats with the peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands, 15d-PGJ2 and troglitazone, induced SOCS 3 expression and inhibited JAK2/STAT3 activation. This treatment regimen also inhibited IL-6 and TGF-beta1 induction, vacuolization, and alpha-smooth muscle actin (alpha-SMA) expression. Thus, SOCS 3 expression is associated with a reduction in IL-6 and TGF-beta1 expression, edema formation, vacuolization, and alpha-SMA expression, possibly by direct regulation of JAK2/STAT3 signaling. 15d-PGJ2 and troglitazone are potentially useful pancreatitis therapies by suppressing the JAK2/STAT3 inflammatory signaling through SOCS 3 induction.
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PMID:SOCS 3 and PPAR-gamma ligands inhibit the expression of IL-6 and TGF-beta1 by regulating JAK2/STAT3 signaling in pancreas. 1803 85

Ulinastatin, a trypsin inhibitor, is useful as a first-line or a second-line treatment regimen including alternative therapy for IVIG-resistant or IVIG nonresponder Kawasaki disease (KD) patients. Mechanisms involving protections against tissue organs and endthelial cell and anti-inflammatory effects by ulinastatin, are dependent on the inhibition of PMN-derived elastase, tumor necrosis factor alpha (TNFalpha), and other proinflammatory cytokines/interleukins(IL-1, IL-6, IL-8). Ulinastatin also suppresses the activation of PMN cells, macrophages, and platelets. Although almost no statistical data related to the definitive effect in acute stage of KD, ulinastatin have shown possible effects, but not always, in a part of KD patients. The indications of clinical use include shock and pancreatitis. Off-label uses of ulinastatin have been reported in hematological, hepatic, renal, OB/Gy diseases and cardiovascular diseases including vasculitis syndromes. The efficacy of ulinastatin in aKD remained to be investigated.
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PMID:[Clinical utility of ulinastatin, urinary protease inhibitor in acute Kawasaki disease]. 1826 58

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.
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PMID:A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. 1858 60

Pancreatitis-associated proteins (PAP) are stress-induced secretory proteins that are implicated in immunoregulation. Previous studies have demonstrated that PAP is up-regulated in acute pancreatitis and that gene knockdown of PAP correlated with worsening severity of pancreatitis, suggesting a protective effect for PAP. In the present study, we investigated the effect of PAP2 in the regulation of macrophage physiology. rPAP2 administration to clonal (NR8383) and primary macrophages were followed by an assessment of cell morphology, inflammatory cytokine expression, and studies of cell-signaling pathways. NR8383 macrophages which were cultured in the presence of PAP2 aggregated and exhibited increased expression of IL-1, IL-6, TNF-alpha, and IL-10; no significant change was observed in IL-12, IL-15, and IL-18 when compared with controls. Chemical inhibition of the NFkappaB pathway abolished cytokine production and PAP facilitated nuclear translocation of NF-kappaB and phosphorylation of IkappaB alpha inhibitory protein suggesting that PAP2 signaling involves this pathway. Cytokine responses were dose dependent. Interestingly, similar findings were observed with primary macrophages derived from lung, peritoneum, and blood but not spleen. Furthermore, PAP2 activity was inhibited by the presence of serum, inhibition which was overcome with increased PAP2. Our results demonstrate a new function for PAP2: it stimulates macrophage activity and likely modulates the inflammatory environment of pancreatitis.
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PMID:Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages. 1864 32

Pancreatitis-associated protein 2 (PAP2) is a member of the Reg3 gene family and is classified as a group 7 C-type lectin-like protein. In rats, each of the three PAP isoforms has independent immunologic functional effects on macrophages. We have previously shown that PAP2 up-regulates inflammatory cytokines in macrophages in a dose-dependent manner and acts through NF-kappaB mechanisms. In this study, we aimed to determine protein domains that are essential for the immunologic function of PAP2 by mutational or chemical analysis. The protein activity for each mutant was determined by measuring TNF-alpha, IL-6, or IL-1 production in macrophages. Truncation of the first 25 residues on the N terminus of PAP2 did not affect protein activity whereas truncation of the last 30 residues of the C terminus of PAP2 completely inactivated the function of PAP2. Additionally, reduction of three disulfide bonds proved to be important for the activity of this protein. Further investigation revealed two invariant disulfide bonds were important for activity of PAP2 while the disulfide bond that is observed in long-form C-type lectin proteins was not essential for activity. Coupling the ability of PAP2 to up-regulate inflammatory cytokines via NF-kappaB with its associated expression in acute pancreatitis, a condition with aberrant concentrations of inflammatory cytokines, we investigated whether PAP2 mutants mechanistically activate the NF-kappaB-signaling pathway and demonstrate that preincubation with select rPAP2 mutant proteins affect translocation of this transcription factor into the nucleus.
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PMID:Mutational characterization of pancreatitis-associated protein 2 domains involved in mediating cytokine secretion in macrophages and the NF-kappaB pathway. 1864 33

Pancreatitis is a severe debilitating disease with high morbidity and mortality. Treatment is mostly supportive, and until now there are no clinically useful strategies for anti-inflammatory therapy. Although omega-3 polyunsaturated fatty acids (n-3 PUFA) are known to have anti-inflammatory effects, the utility of these fatty acids in the alleviation of pancreatitis remained to be investigated. The aim of this study was to examine the effect of n-3 PUFA on both acute and chronic pancreatitis in a well-controlled experimental system. We used the fat-1 transgenic mouse model, characterized by endogenously increased tissue levels of n-3 PUFA, and their wild-type littermates to examine the effect of n-3 PUFA on both acute and chronic cerulein-induced pancreatitis. Disease activity and inflammatory status were assessed by both histology and molecular methods. In acute pancreatitis, fat-1 mice showed a trend towards decreased necrosis and significantly reduced levels of plasma IL-6 levels as well as reduced neutrophil infiltration in the lung. In chronic pancreatitis there was less pancreatic fibrosis and collagen content accompanied by decreased pancreatic stellate cell activation in the fat-1 animals with increased n-3 PUFA tissue levels as compared to wild-type littermates with high levels of omega-6 (n-6) PUFA in their tissues. Our data provide evidence for a reduction of systemic inflammation in acute pancreatitis and of tissue fibrosis in chronic pancreatitis by increasing the tissue content of omega-3 polyunsaturated fatty acids. These results suggest a beneficial potential for n-3 PUFA supplementation in acute and particularly chronic pancreatitis.
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PMID:Reduction of inflammation and chronic tissue damage by omega-3 fatty acids in fat-1 transgenic mice with pancreatitis. 1883 28

In a previous article, we showed that a potent serotonin-, 5-hydroxytryptamine-2A (5-HT(2A)) antagonist, risperidone, ameliorated cerulein-induced edematous pancreatitis in mice. In the present article, young female mice were fed a choline-deficient, ethionine-supplemented diet. All of the mice developed severe necrotic pancreatitis, and approximately 50% of them died within 4 days. Serum levels of proinflammatory interleukin (IL)-6 significantly increased on day 3 and returned toward the control on day 4 of choline-deficient ethionine-supplemented (CDE) diet treatment. The time course of IL-6 levels paralleled those of plasma amylase and lipase activities. On the other hand, platelet counts significantly decreased on day 3, and the change became more marked on day 4, coinciding with mortality and histological alterations of the pancreas (edema, inflammatory cell infiltration, necrosis). Preceding these changes, plasma levels of 5-hydroxyindoleacetic acid (5-HIAA) increased on feeding a CDE diet to reach a peak on day 3 and returned toward the control on day 4. Risperidone (0.1-3.2 mg/kg twice a day) hardly affected the 5-HIAA levels but dose-dependently attenuated the serum IL-6 levels, plasma amylase/lipase levels, platelet counts, histological alterations, and mortality of diet-induced pancreatitis mice. These results are discussed in relation to the pathogenesis of acute pancreatitis. Thus, we speculate that acinar cell injury triggers local inflammatory reactions and, if coincided with enhanced IL-6 release, leads to a systemic inflammatory response syndrome, which is responsible for the mortality. In addition, it is suggested that diet-induced 5-HT release and 5-HT(2A) receptor activation are involved in this whole process of pancreatitis development. Risperidone may provide a new therapy for the disease.
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PMID:Risperidone attenuates local and systemic inflammatory responses to ameliorate diet-induced severe necrotic pancreatitis in mice: it may provide a new therapy for acute pancreatitis. 1883 8

Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase-activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50-G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic beta-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFalpha, IL-1beta, and IL-6) at 12 h with similar magnitude both in wild-type and PACAP-Tg mice. In addition, the mRNA and protein levels of regenerating gene III beta (RegIIIbeta), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIbeta, an anti-inflammatory factor.
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PMID:Over-expression of pancreatic pituitary adenylate cyclase-activating polypeptide (PACAP) aggravates cerulein-induced acute pancreatitis in mice. 1967 38

Oxidative stress is regarded as a major pathogenic factor in acute pancreatitis. Inflammation and apoptosis linked to oxidative stress has been implicated in cerulein-induced pancreatitis as an experimental model of acute pancreatitis. Recently, we found that reactive oxygen species mediate inflammatory cytokine expression and apoptosis of pancreatic acinar cells stimulated with cerulein. Omega-3 fatty acids show antioxidant action in various cells and tissues. In the present study, we investigated whether omega-3 fatty acids inhibit cytokine expression in cerulein-stimulated pancreatic acinar cells and whether omega-3 fatty acids suppress apoptotic cell death in pancreatic acinar cells exposed to hydrogen peroxide. We found that omega-3 fatty acids, such as docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA), suppressed the expression of inflammatory cytokines (IL-1beta, IL-6) and inhibited the activation of transcription factor activator protein-1 in cerulein-stimulated pancreatic acinar cells. DHA and ALA inhibited DNA fragmentation, inhibited the decrease in cell viability, and inhibited the expression of apoptotic genes (p53, Bax, apoptosis-inducing factor) induced by hydrogen peroxide in pancreatic acinar cells. In conclusion, omega-3 fatty acids may be beneficial for preventing oxidative stress-induced pancreatic inflammation and apoptosis by inhibiting inflammatory cytokine and apoptotic gene expression of pancreatic acinar cells.
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PMID:Inhibitory mechanism of omega-3 fatty acids in pancreatic inflammation and apoptosis. 1972 85


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