Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was established in an acute experiment on rats of Wistar line while an acute pancreatitis simulation using the pancreatic tissue freezing that the level of a tumor necrosis factor (TNF) in a blood serum was maximal in 4 hours from the cold action onset, the activity of amylase and trypsin was heightened and trypsin activity inhibitor (TAI) had lowered. Intraperitoneal application of pentoxifylline in 100 mg/kg dose twice daily have promoted the significant lowering of TNF contents, the amylase and trypsin activity as well, and the TAI concentration increase.
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PMID:[Changes in blood enzyme activity and tumor necrosis factor level in the treatment of experimental pancreatitis with pentoxifylline]. 967 Jul 13

Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-alpha and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-alpha but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.
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PMID:The physiologic consequences of macrophage pacification during severe acute pancreatitis. 974 44

Multiple organ failure (MOF) is a critical condition developing in patients with overwhelming bodily injury resulting from major surgical insult, severe trauma, extensive burns, acute pancreatitis, and sepsis. It has recently become evident that the host response to such injury is the main pathogenetic factor contributing to the development of MOF. The proinflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-1 are known to play a pivotal role in the pathogenetic mechanisms of MOF. In response to bodily injury, macrophages produce and release TNF and IL-1, which subsequently induce the production of other cytokines (IL-6, IL-8, etc.) and other endogenous chemical mediators. The resultant systemic inflammation may develop into MOF mainly through neutrophil-endothelial cell interaction when the primary injury is overwhelming or a second inflammatory insult such as sepsis triggers an exacerbated inflammation. It has recently been confirmed that the transcription factor NF-kappaB is involved in the up-regulation of a variety of proinflammatory genes and that cell-mediated immunity is down-regulated in the event of major bodily injury through a shift in the balance between T helper 1 (Th1) and Th2 cytokine response patterns. The molecular immunological mechanisms by which these factors participate in the development of MOF should be characterized.
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PMID:[Mechanism of the development of organ failure]. 978 82

Overproduction of tumor necrosis factor (TNF-), interleukin-1beta (IL-1beta), and nitric oxide (NO) is believed to be detrimental during the progression of acute pancreatitis, yet little is known about the hepatic production of these mediators and their role in mediating pancreatitis-induced hepatic dysfunction. Rats were randomized to receive a single intraperitoneal injection of the macrophage-pacifying compound, CNI-1493 (1.0 mg/kg), or vehicle 1 hour before the induction of retrograde bile salt pancreatitis. Sham-operated animals served as controls. Animals were killed 18 hours later, with serum and livers harvested to determine the degree of hepatocellular injury and the induction of TNF-, IL-1beta, and inducible nitric oxide synthase (iNOS). In addition, serum TNF- and nitrites (end-product of NO breakdown) were determined in each group to assess the mechanism of action of CNI-1493. TNF-, IL-1beta, and iNOS gene expression (by reverse-transcription polymerase chain reaction) as well as aspartate transaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH) (but not alkaline phosphatase [ALP]) increased following the development of pancreatitis (all P < .05). Macrophage pacification significantly prevented the induction of TNF- and IL-1beta mRNA (but not iNOS), resulting in lessened serum AST, ALT, and LDH (all P < .05). Serum TNF- protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and TNF- protein production was significantly attenuated in animals receiving CNI-1493. Hepatocellular, but not bile duct, injury occurs during experimental pancreatitis that is associated with hepatic TNF-, IL-1beta, and iNOS mRNA gene induction, as well as TNF- protein and nitrite production. Preventing the production of TNF- and IL-1beta by macrophage pacification attenuates the hepatocellular damage, suggesting that these mediators play a role in pancreatitis-induced hepatic injury.
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PMID:Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. 979 13

Over the past few years, evidence has accumulated that implicates proinflammatory cytokines as the mediators responsible for the escalation of acute pancreatitis into a multisystem disease. It has been shown that the degree of serum cytokine elevation, particularly the macrophage-derived cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, correlates with the severity and outcome of acute pancreatitis. Interleukin-10 is an anti-inflammatory cytokine that inhibits cytokine production from the macrophage. The aim of this study was to determine whether interleukin-10 would decrease both the severity of acute pancreatitis and the level of circulating proinflammatory cytokines. Ninety female mice were divided into three equal groups. Group 1 (controls) received intraperitoneal saline solution. Groups 2 and 3 received intraperitoneal cerulein (50 mg/kg/hr) for 7 hours. In addition, group 3 was given 1500 units of intraperitoneal interleukin-10, beginning 1 hour after the induction of acute pancreatitis and every 3 hours thereafter. Animals were killed at 3-hour intervals. Blood samples were obtained for serum amylase and cytokine determinations (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha). Pancreata were dissected free and fixed in formalin for blinded histologic scoring. Interleukin-10 reduced the serum levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and amylase in comparison to untreated animals with pancreatitis (P < 0.05). Pancreatic edema, necrosis, and inflammatory cell infiltrate were also reduced in those animals given interleukin-10 (P <0.05). Histologic score, serum cytokines, and amylase levels are elevated during acute pancreatitis. Interleukin-10 given therapeutically, that is, after the onset of acute pancreatitis, lessened the severity of disease, probably through inhibition of the macrophage. This was associated with a decrease in circulating cytokine levels.
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PMID:Interleukin-10 reduces circulating levels of serum cytokines in experimental pancreatitis. 983 43

Inflammation and cell death are critical to pathogenesis of acute pancreatitis. Here we show that transcription factor nuclear factor-kappaB (NF-kappaB), which regulates these processes, is activated and plays a role in rat cerulein pancreatitis. NF-kappaB was strongly activated in the pancreas within 30 min of cerulein infusion; a second phase of NF-kappaB activation was prominent at 3-6 h. This biphasic kinetics could result from observed transient degradation of the inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. The hormone also caused NF-kappaB translocation and IkappaB degradation in vitro in dispersed pancreatic acini. Both p65/p50 and p50/p50, but not c-Rel, NF-kappaB complexes were manifest in pancreatitis and in isolated acini. Coinfusion of CCK JMV-180, which abolishes pancreatitis, prevented cerulein-induced NF-kappaB activation. The second but not early phase of NF-kappaB activation was inhibited by a neutralizing tumor necrosis factor-alpha antibody. Antioxidant N-acetylcysteine (NAC) blocked NF-kappaB activation and significantly improved parameters of pancreatitis. In particular, NAC inhibited intrapancreatic trypsin activation and mRNA expression of cytokines interleukin-6 and KC, which were dramatically induced by cerulein. The results suggest that NF-kappaB activation is an important early event that may contribute to inflammatory and cell death responses in acute pancreatitis.
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PMID:Early NF-kappaB activation is associated with hormone-induced pancreatitis. 984 78

The aim of this study was to assess the significance of peritoneal macrophage in inducing cytotoxicity in ascitic fluid associated with severe acute pancreatitis. The involvement of peritoneal macrophage was examined experimentally in rats by macrophage depletion with peritoneal lavage prior to the development of pancreatitis. More than 94% of the cellular components collected from peritoneal cavities by the lavage are macrophages. Although the ascitic fluid collected from the rats with necrotizing pancreatitis showed cytocidal effects via apoptosis on Madin-Darby canine kidney cells in a dose- and time-dependent manner, cytotoxicity or apoptosis-inducing activity almost disappeared from the ascitic fluid by the preceding peritoneal lavage. The ascitic fluid did not show significant differences by the lavage in osmolarity and in concentrations of albumin, bilirubin, amylase, and lipase. Although a slight reduction of tumor necrosis factor-alpha was noted with the lavage, tumor necrosis factor-alpha failed to induce apoptotic cell death in the cells, and the neutralization by antibody ameliorated neither cell death nor apoptosis. We conclude that peritoneal macrophages secrete apoptosis-inducing factor(s) into pancreatitis-associated ascitic fluid, other than tumor necrosis factor-alpha.
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PMID:Involvement of peritoneal macrophage in the induction of cytotoxicity due to apoptosis in ascitic fluid associated with severe acute pancreatitis. 1009 Aug 25

Bacterial translocation (BT) from the gastrointestinal tract to mesenteric lymph nodes (MLNs) and other extra intestinal organs is an important source of infection in acute pancreatitis (AP). Lexipafant (BB-882) is a potent platelet-activating factor receptor antagonist that has an anti-inflammatory effect. To examine whether BB-882 could affect BT in acute necrotizing pancreatitis, 48 male Sprague Dawley rats (250-350 g) were studied. AP was induced in Group I and Group II by pressure injection of 3% taurocholate and trypsin into the common biliopancreatic duct (1 mL/kg of body weight). Group I rats received BB-882 (10 mg/kg, i.p. qd) and Group II rats received a similar volume of normal saline as a placebo postoperatively for 2 days. Group III and Group IV received BB-882 and placebo, respectively, after an exploratory laparotomy. At 48 hours postoperatively, blood was drawn for culture, serum amylase, and tumor necrosis factor (TNF)-alpha determinations. Specimens from MLNs, spleen, liver, pancreas, and cecum were harvested for culture of gram-positive, gram-negative, and anaerobic bacteria. Quantitative cecal cultures of gram-positive, gram-negative, and anaerobic bacteria were obtained. A point scoring system for five histological features that include interstitial edema, inflammatory cellular infiltration, fat necrosis, parenchymal necrosis, and hemorrhage was used to evaluate the severity of pancreatitis. There was no difference in serum amylase levels (2415 +/- 127 IU/L versus 2476 +/- 170 IU/L), serum TNF-alpha levels (7820 +/- 1396 pg/mL versus 7318 +/- 681 pg/mL), and the mean pancreatic histology score (5.9 +/- 1.2 versus 6.5 +/- 1.1) between Group I and Group II, respectively (P > 0.05). Seven of 12 Group I rats had BT to MLNs, compared with 11 of 12 rats in Group II (P > 0.05). Five of 12 Group I rats had BT to distant sites such as pancreas, spleen, liver, and/or blood, compared with 11 of 12 rats in Group II (P < 0.05). BB-882 treatment decreases bacterial spread to distant sites, but does not reduce serum amylase levels and serum TNF-alpha levels or ameliorate pancreatic damage in rats with AP.
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PMID:The effect of lexipafant on bacterial translocation in acute necrotizing pancreatitis in rats. 1039 68

To clarify the role of cytokines and acinar cell apoptosis in the pathogenesis of acute pancreatitis, we investigated the expression of intrapancreatic cytokines and apoptosis-related molecules in mice after pancreatic duct ligation (PDL). From day 1 or 3 after PDL, the expression of interleukin-1alpha (IL-1alpha), IL-1beta, IL-1 receptor antagonist, IL-6, IL-10, and tumor necrosis factor (TNF-alpha) mRNA were up-regulated in the pancreas, suggesting that these cytokines may be involved in the development of pancreatitis after PDL. Acinar cell apoptosis was observed in the pancreas at rates of 0.13 +/- 0.03, 1.32 +/- 0.38, and 0.86 +/- 0.23% on days 1, 3, and 7 after PDL, respectively. Significant increases in intrapancreatic mRNA levels of TNF-alpha, Fas ligand (FasL), and IL-1beta-converting enzyme (ICE) were observed from day 3 after PDL with the appearance of acinar cell apoptosis. The serum amylase activity peaked on day 1 after PDL and gradually decreased on days 3 and 7 after PDL. These results suggest that acinar cell apoptosis induced after PDL may modulate the progression of acute pancreatitis by reducing the release of digestive enzymes and may therefore be a host defense mechanism, and that acinar cell apoptosis after PDL may be mediated by the TNF-alpha and/or Fas/FasL and ICE system.
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PMID:Cytokine expression and induction of acinar cell apoptosis after pancreatic duct ligation in mice. 1043 65

The pathophysiology of acute pancreatitis accompanied by chronic liver injury, and the therapeutic efficacy of prostaglandin (PG)E1 were studied experimentally in rats. Chronic liver injury was produced by subcutaneous administration of CCl4. Acute pancreatitis was induced by the closed duodenal loop (CDL) method, immediately after which PGE1 (60 ng/kg/min) was infused intravenously via the jugular vein. Serum levels of amylase, alpha2-macroglobulin-trypsin complex (alpha2M-TRY), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) were determined before and at 3 and 6 h after the onset of acute pancreatitis. Rats without administration of CCl4 served as controls. Serum amylase levels were lower in the liver injury (LI) group than in the normal liver (NL) group at 3 and 6 h. PGE1 had no effect on amylase levels in either group. Serum alpha2M-TRY levels were similar in the two groups at 3 h, but significantly higher in LI than in NL at 6 h. PGE1 tended to decrease alpha2M-TRY levels only in LI. Serum CRP levels were significantly more elevated in LI than in NL at 0, 3, and 6 h. PGE1 decreased CRP levels only in LI. Serum TNF-alpha concentrations were higher in LI, especially at 6 h. PGE1 reduced TNF-alpha levels in LI. Pancreatitis severity scores were significantly higher in LI. PGE1 significantly decreased the severity scores only in LI. Fat necrosis scores were significantly lower in LI. Histologically, interstitial edema was much more prominent in NL than in LI, whereas interstitial hemorrhage was more severe in LI at 3 and 6 h. PGE1 lessened the hemorrhage in LI. The extent of both vacuolization and necrosis of acinar cells was similar for both groups and tended to be improved by PGE1. It is concluded that acute pancreatitis becomes much more serious in the presence of chronic liver injury, and that PGE1 can ameliorate the exacerbated lesions, probably by improvements in blood flow through the pancreatic tissue.
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PMID:Exacerbation of acute pancreatitis in the presence of chronic liver injury in rats, with special reference to therapeutic efficacy of prostaglandin E1. 1043 68


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