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

Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) gene was identified because of its increased expression in 25% of human hepatocellular carcinoma. HIP/PAP protein, a C-type lectin, binds laminin, acts as an adhesion molecule for hepatocytes, and has also been described as an acute phase secretory protein during acute pancreatitis in humans and rats. We investigated HIP/PAP protein expression in patients with various liver diseases associated with ductular reaction. At the same time, we analyzed patients with hepatocellular carcinoma and cholangiocarcinoma, and tested HIP/PAP protein levels in sera to establish the pattern of secretion. Our data show that HIP/PAP expression was not restricted to hepatocellular carcinoma, but was also detected in cholangiocarcinoma cells as well as in reactive non-malignant bile ductules. In contrast, HIP/PAP protein expression was undetectable in normal mature hepatocytes, but some ductular cells localized at the interface of portal tracts with parenchyma were HIP/PAP immunoreactive in normal liver. Finally, we present evidence that HIP/PAP serum levels were increased in 21/28 (75%) patients with hepatocellular carcinoma, and in 25/51 (49%) patients with nonmalignant cirrhosis. Altogether, these results suggest that HIP/PAP protein may be implicated in hepatocytic and cholangiolar differentiation and proliferation.
 ...
PMID:Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) is expressed and secreted by proliferating ductules as well as by hepatocarcinoma and cholangiocarcinoma cells. 1055 Mar 9

This article reviews the recent changes in the understanding of acute pancreatitis pathophysiology emphasizing results deriving from the more detailed comprehension of the local and systemic aspects of the inflammatory process. The authors briefly discuss those theories that have been influencing the basic philosophies of treatment efforts. The role of premature digestive enzyme activation as the principal determinant of the pathoetiology and mortality of this disease has been questioned lately, and the inflammatory explosion has been placed into the center of attention. Simultaneously with the enzyme activation, the pancreatitogenic noxious event rapidly induces the formation of oxygen derived free radicals, activation of the transcription factor NF kappa-B, with consequent citokine production, cellular adhesion molecule upregulation and leukocyte hyperstimulation. Numerous other mediator cascades are activated in parallel, the uncontrolled surge of proinflammatory stimuli, and activity of the effector cells lead to multiple organ failure in severe cases. A genetically determined catastrophe management program is set forth in the acinar cell with pancreatitis associated protein expression and activation of the apoptosis machinery. Therapeutic approaches based on these recent findings are briefly touched upon.
 ...
PMID:[Acute pancreatitis: recent advances in understanding its pathophysiology]. 1069 50

Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. The pathogenesis of these microcirculatory disorders is multifactorial and involves various vasoactive mediators. Thus questions arise as to which vasoactive mediators are most important and how long after the onset of disease vasoactive mediator blockade may be effective. The present study compares the effect of delayed therapy with two vasoactive mediator antagonists, previously tested with promising results in other studies in a well-established rodent model of severe acute pancreatitis. Twelve hours after induction of acute pancreatitis, rats were randomized to therapy with intracellular adhesion molecule-1 (ICAM-1) antibody (2 mg/kg IA-29), endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution (volume equivalent). After 12 hours of fluid resuscitation, animals underwent repeat laparotomy for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment, both ICAM antibody and ET-RA significantly enhanced capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. These beneficial effects on microcirculation were associated with decreased fluid loss into the third space and improved renal function and survival. Although both antagonists likewise enhanced capillary blood flow and reduced leukocyte rolling, ET-RA was significantly more effective than ICAM antibody in counteracting capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of endothelin and ICAM antagonists in severe acute pancreatitis, even with delayed therapy, suggesting that both compounds are candidates for further clinical testing. Selective endothelin A receptor blockade appears to be especially attractive for clinical use not only because it was superior to ICAM antibody in the present study but also because of its favorable pharmacologic properties and (preliminary) positive results in clinical phase 2 studies currently underway for other diseases.
 ...
PMID:Therapy for microcirculatory disorders in severe acute pancreatitis: comparison of delayed therapy with ICAM-1 antibodies and a specific endothelin A receptor antagonist. 1076 86

Lung injury is a major cause of patient morbidity in acute pancreatitis. The purpose of this study was to examine the mechanism of pulmonary infiltration and lung injury in acute pancreatitis. Mice were fed a choline-deficient/ethionine-supplemented (CDE) diet for 144 hours to induce severe acute pancreatitis. Serum samples were collected for measurement of biochemical markers of disease and for the detection of tumor necrosis factor-alpha (TNF-alpha). Cell surface adhesion molecule expression was quantified by the sensitive radiolabeled dual monoclonal antibody technique. Neutrophil sequestration in lung tissue was measured by the myeloperoxidase assay. Lung injury was determined histologically and lung edema was assessed by wet/dry ratios. Pancreatic injury was demonstrated to occur in all CDE-fed mice, which developed significant hyperamylasemia and hypoglycemia by 48 hours (P <0.0001). Serum TNF-alpha levels increased significantly by 48 hours over baseline values (P <0.02). Expression of intracellular adhesion molecule (ICAM-1) in pulmonary endothelia was significantly increased above baseline by 30% at 48 hours (P <0.02) and peaked at 120 hours by 100% (P <0.0001). Vascular cellular adhesion molecule (VCAM-1) was constitutively expressed at baseline and was upregulated threefold by 48 hours (P <0.0001). Neutrophil infiltration increased gradually 24 hours after ICAM-1 and VCAM-1 were upregulated with significant elevation of myeloperoxidase activity over baseline at 72 hours (7.2 +/- 1.2 vs. 18.1 +/- 2.2 activity units/gram tissue; P <0.05). Neutrophil infiltration peaked at 144 hours (26.24 +/- 10.49 activity units/gram tissue P <0.0001), and its kinetics correlated with the onset and progression of morphologic injury as well as increased lung edema. These results show that acute pancreatitis is associated with a systemic release of inflammatory cytokines, followed by increased expression of pulmonary ICAM-1 and VCAM-1, neutrophil infiltration, and histologic lung injury. The adhesion molecule axis may be a potential target for practical intervention to ameliorate lung injury and morbidity in acute pancreatitis.
 ...
PMID:Temporal correlation of tumor necrosis factor-alpha release, upregulation of pulmonary ICAM-1 and VCAM-1, neutrophil sequestration, and lung injury in diet-induced pancreatitis. 1076 87

Reperfusion injury is defined as the enhancement of the damage that occurs in ischaemic cells during the reperfusion period. Cellular damage to the brain occurs not only during the ischaemic period, but also during the reperfusion period. Such injury occurs when blood flow is restored to heart, brain or other tissue after flow has been blocked. Several mechanisms appear to play a role in the generation of reperfusion injury. To a greater or lesser extent, most involve neutrophils. The infiltration of neutrophils into the previously ischaemic area has been implicated as playing major role following reperfusion. Microscopic examination of tissue has shown a direct correlation between the duration of oxygen deprivation with the amount of damage, and the extent of activated neutrophil recruitment. Activated neutrophils are responsible for the release of serine proteases, which directly lead to tissue damage. Activated neutrophils also contain a newly assembled enzyme that produces tissue damaging free radicals. However, a preliminary and necessary step is to attach the activated neutrophil on to the lining of the blood vessels, a process requiring proteolytic activity. Administration of a drug that prevents neutrophil transmigration would reduce reperfusion injury. SuperGen is developing a drug, LEX 032, with a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface by blocking this proteolytic activity. In addition, this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine proteases. Therefore, LEX 032 is expected to prevent or minimise neutrophil mediated reperfusion injury. Blockade of all three destructive inflammatory responses should limit the amount of damaged tissue and save viable tissue. A drug with these capabilities might find use in the treatment of myocardial infarction, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation. Since LEX 032 has no inhibitory activity against thrombin and plasmin, it represents an ideal drug for use in the treatment of ischaemic stroke. Recently, data have been published demonstrating that ischaemic stroke patients given the thrombolytic drug tPA were at least 30% more likely to have minimal or no disability at three months, as measured by outcome scales, when compared to placebo-treated patients. Presumably, this action was because of the hastening of brain reperfusion, and may have been limited due to reperfusion injury. The FDA approved the use of tPA for the limited treatment of acute ischaemic stroke. Since LEX 032 has been shown to limit neutrophil mediated reperfusion damage, it may find use either alone, to ameliorate damage occurring spontaneously during ischaemic stroke, or in combination therapy with tPA to reduce reperfusion injury secondary to thrombolytic therapy. This unique approach may have broad therapeutic potential in the treatment of neutrophil mediated diseases since, unlike a monoclonal antibody for example, it is independent of the specific adhesion molecule(s). These diseases include inflammatory diseases which are, at least in part, caused or exacerbated by excessive neutrophil proteases, such as acute pancreatitis, arthritis, allograft rejection, sepsis, meningitis, acute pulmonary inflammation, psoriasis and damage caused by burns. This is in addition to reperfusion-related diseases such as myocardial infarction, stroke, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation.
 ...
PMID:LEX 032: a novel recombinant human protein for the treatment of ischaemic reperfusion injury. 1113 33

During the past decade, a considerable number of experimental studies have confirmed the hypothesis that microcirculatory derangements play a pivotal role in the pathogenesis of acute pancreatitis, including the process of conversion from edematous to necrotizing injury. Predominant microcirculatory disorders are nutritive capillary perfusion failure, with the consequence of prolonged focal hypoxia or anoxia, and inflammation-associated microvascular leukocyte recruitment, CD11b- and intercellular adhesion molecule (ICAM)-1-mediated leukocyte-endothelial cell interaction and loss of endothelial integrity, which may result in both edema formation and necrosis. A variety of proinflammatory mediators, such as oxygen radicals, leukotrienes, platelet-activating factor, and interleukins, but also bradykinin and endothelins, seem to be involved in triggering the manifestations of these microcirculatory disorders. In contrast, the anti-inflammatory interleukin-10, as well as nitric oxide, are thought to be capable of protecting from these pancreatitis-associated microvascular injuries. This knowledge may be encouraging for the development of novel therapeutic strategies, aiming at the attenuation of microcirculatory disorders, and, thus, preventing tissue injury in acute pancreatitis.
 ...
PMID:Microcirculatory derangements in acute pancreatitis. 1145 78

Patients with acute pancreatitis may develop acute lung injury, manifest clinically as the adult respiratory distress syndrome. Most patients who die during the early stages of severe acute pancreatitis die either with or as a result of this lung injury. To explore the events which couple acute pancreatitis to lung injury, a number of recent studies have been performed in the author's laboratory using a variety of experimental models and interventions including gene-targeted deletion of chemokines, cytokines, specific receptors, and adhesion molecules. These studies have indicated that adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), neutrophils, platelet activating factor (PAF), substance P, and chemokines acting via the CCR-1 chemokine receptor play a pro-inflammatory role while complement factor C5a plays an anti-inflammatory role in pancreatitis and lung injury. Future studies will build on these observations to expand the list of pro- and anti-inflammatory coupling factors and explore the mechanisms by which they act to cause or prevent lung injury in acute pancreatitis.
 ...
PMID:Relationship between pancreatitis and lung diseases. 1153 57

Necrotizing acute pancreatitis is associated with an inflammatory explosion involving numerous pro-inflammatory mediator cascades and oxidative stress. Acinar oxygen free radical production aggravates pancreatic tissue damage, and promotes cellular adhesion molecule upregulation resulting in leukocyte adherence and activation. The cerium capture oxygen free radical histochemistry combined with reflectance confocal laser scanning microscopy allows the "in situ" histological demonstration of oxygen free radical formation in live tissues. Here we present a case report, where oxidative stress is demonstrated on a histological level for the first time in human acute pancreatitis. A 44-year-old male patient suffering from acute exacerbation of his chronic pancreatitis developed a pancreato-pleural fistula with amylase-rich left pleural exudate causing respiratory compromise. Subsequent to an urgent thoracic decompression a distal pancreatectomy and splenectomy was performed with the closure of abdomino-thoracic fistula. The postoperative course was uneventful, except for a transient pancreatico-cutaneous fistula, which healed after conservative treatment. To carry out cerium capture oxygen free radical histochemistry the resected pancreas specimen was readily perfused with cerium-chloride solution through the arteries on the resection surface. Frozen sections were cut, E-, P-selectin, ICAM and VCAM were labeled by immunofluorescence. The tumor-free margin of an identically treated pancreas carcinoma specimen served as a control. Intrapancreatic oxidative stress and cellular adhesion molecule expression were detected by confocal laser scanning microscopy. Numerous pancreatic acini and neighboring capillaries showed oxygen free radical-derived cerium-perhy-droxide depositions corresponding to strong local oxidative stress. Acinar cytoplasmic reflectance signals suggested xanthine-oxidase as a source of oxygen free radicals. These areas presented considerably increased endothelial P-selectin expression with adherent, oxygen free radical-producing polymorphonuclear leukocytes displaying pericellular cerium-reflectance. Modest ICAM upregulation was noted, E-selectin and VCAM expression was negligible. The control pancreas specimen showed minimal oxidative stress with weak, focal P-selectin expression. The development of deleterious pancreatic oxidative stress was based on indirect evidence in human acute pancreatitis. To the best of our knowledge this is the first report demonstrating persistent intrapancreatic oxidative stress histologically in human acute pancreatitis. We have noted P-selectin overexpression with a preponderance in the areas of acinar oxidative stress.
 ...
PMID:The first histological demonstration of pancreatic oxidative stress in human acute pancreatitis. 1167 40

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

The nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a pivotal role in the induction of genes involved in the response to injury and inflammation. Dithiocarbamates are antioxidants that are potent inhibitors of NF-kappaB. This study tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration, tissue hemorrhage 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 nitrotyrosine and intracellular adhesion molecule-1 in the pancreas and lung of cerulein-treated mice. In contrast, the degree of 1) pancreas and lung injury, 2) upregulation/expression of intracellular adhesion molecule-1, 3) staining for nitrotyrosine, and 4) lipid peroxidation was markedly reduced by pretreatment with PDTC. This study demonstrates that prevention of the activation of NF-kappaB by PDTC ameliorates the tissue injury associated with experimental murine acute pancreatitis and provides an important insight into the molecular biology of acute pancreatitis.
 ...
PMID:Pyrrolidine dithiocarbamate reduces the severity of cerulein-induced murine acute pancreatitis. 1462 79


1 2 3 Next >>