Hereditary pancreatitis-associated mutation asn(21) --> ile stabilizes rat trypsinogen in vitro.
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Mutations Arg(117) --> His and Asn(21) --> Ile in human trypsinogen-I have been recently associated with hereditary pancreatitis (HP). The Arg(117) --> His substitution is believed to cause pancreatitis by stabilizing trypsin against autolytic degradation, while the mechanism of action of Asn(21) --> Ile has been unknown. In an effort to understand the effect(s) of this mutation, Thr(21) in the highly homologous rat trypsinogen-II was replaced with Asn or Ile, and the recombinant zymogens and their active trypsin forms were studied. Kinetic parameters of all three trypsins were comparable, and the active enzymes suffered autolysis at similar rates, indicating that neither catalytic properties nor proteolytic stability of trypsin are influenced by mutations at position 21. When incubated at pH 8.0, 37 degrees C, pure zymogens underwent autoactivation with concomitant trypsinolytic degradation in a Ca(2+)-dependent fashion. Thus, in the presence of 5 mM Ca(2+), autoactivation and digestion of the zymogens after Arg(117) and Lys(188) were observed, while in the presence of 1 mM EDTA autoactivation and cleavage at Lys(188) were reduced, and zymogenolysis at the Arg(117) site was enhanced. Overall rates of zymogen degradation in [Asn(21)]- and [Ile(21)]trypsinogens were higher in Ca(2+) than in EDTA, while [Thr(21)]trypsinogen demonstrated inverse characteristics. Remarkably, both in the presence and absence of Ca(2+), [Ile(21)]trypsinogen exhibited significantly higher stability against autoactivation and proteolysis than zymogens with Asn(21) or Thr(21). The observations suggest that autocatalytic trypsinogen degradation may be an important defense mechanism against excessive trypsin generation in the pancreas, and trypsinogen stabilization by the Asn(21) --> Ile mutation plays a role in the pathogenesis of HP. (+info)
Adjuvant treatment of severe acute pancreatitis with C1 esterase inhibitor concentrate after haematopoietic stem cell transplantation.
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BACKGROUND: With an incidence of 4%, acute pancreatitis is a common complication of bone marrow or peripheral haematopoietic stem cell transplantation, which contributes significantly to morbidity and mortality in these patients. In most cases, the pathogenesis of acute pancreatitis cannot be attributed to a single pathogenetic factor, as treatment toxicity, acute graft versus host disease, infection, and cholestasis may all contribute. Acute pancreatitis is characterised by inflammation and activation of digestive proenzymes leading to autodigestive destruction of the pancreas and systemic activation of protease cascades including the complement system. AIM: To describe the effects of human C1 esterase inhibitor in two children, who developed severe acute pancreatitis with considerable complement activation after allogeneic haematopoietic stem cell transplantation. METHODS: Both children showed clinical features resembling those observed in capillary leakage syndrome. In both patients, treatment with C1 esterase inhibitor concentrate contributed to a rapid clinical stabilisation. CONCLUSIONS: These observations strongly support the proposed pathophysiological concept that early treatment with C1 esterase inhibitor interferes with the activation of the complement system in acute pancreatitis. Inhibition of complement activation prevents its adverse effects on vascular function and permeability, and thus stabilises intravascular fluid status and prevents multiorgan failure in acute pancreatitis. (+info)
Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience.
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OBJECTIVE: To present preoperative and early postoperative data for 504 patients who underwent duodenum-preserving pancreatic head resection (DPPHR) for severe chronic pancreatitis (CP). BACKGROUND: The pancreatic head is considered to be the pacemaker of the disease in alcohol-induced CP. Indications for surgery in CP are intractable pain and local complications. DPPHR offers the advantage of treating the complications related to the inflammatory process in the head, relieving the pain syndrome, and preserving the bilioduodenal anatomy, and it may have the potential to change the natural course of chronic pancreatitis. METHODS: Between November 1972 and December 1998, 504 patients with chronic pancreatitis and an inflammatory mass in the pancreatic head were treated surgically after medical pain treatment for a median of 3.6 years. The procedure resulted in a hospital mortality rate of 0.8%. A continuous follow-up investigation lasting up to 26 years was conducted, during which the patients were reevaluated four times (1983, 1987, 1994, 1996). Between November 1982 and October 1996, 388 patients treated surgically were reinvestigated to evaluate the late outcome; the follow-up rate was 94% (25 patients were lost to follow-up). The reinvestigation evaluation included glucose tolerance test, exocrine pancreatic function test, pain status, physical status, professional and social rehabilitation, and quality of life. RESULTS: After an observation period of up to 14 years, 78.8% of the patients were completely pain-free and 12.5% had (yearly) pain. 91.3% were considered as pain-free; 8.7% had continuing abdominal pain; 12% had abdominal complaints. During the 14 years of follow-up, only 9% were admitted to the hospital for acute episodes of chronic pancreatitis. Endocrine function was improved in 11%; in 21%, diabetes developed de novo. The rate of hospital admission for acute episodes decreased from 69% before surgery to 9% after surgery. In the clinical management period of 9 years (median), the frequency of hospital admission dropped from 5.4 per patient before surgery to 2.7 after surgery. Fourteen years after surgery, 69% of the patients were professionally rehabilitated; in 72%, the quality of life index (Karnofsky criteria) was 90 to 100 and in 18%, it was <80. CONCLUSION: In patients with alcoholic chronic pancreatitis in whom an inflammatory mass has developed in the pancreatic head, DPPHR results in a change in the natural course of the disease in terms of pain status, frequency of acute episodes, need for further hospital admission, late death, and quality of life. (+info)
Inducible nitric oxide synthase protection against coxsackievirus pancreatitis.
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Coxsackievirus infection causes myocarditis and pancreatitis in humans. In certain strains of mice, Coxsackievirus causes a severe pancreatitis. We explored the role of NO in the host immune response to viral pancreatitis. Coxsackievirus replicates to higher titers in mice lacking NO synthase 2 (NOS2) than in wild-type mice, with particularly high viral titers and viral RNA levels in the pancreas. Mice lacking NOS have a severe, necrotizing pancreatitis, with elevated pancreatic enzymes in the blood and necrotic acinar cells. Lack of NOS2 leads to a rapid increase in the mortality of infected mice. Thus, NOS2 is a critical component in the immune response to Coxsackievirus infection. (+info)
Nerve growth factor and its high-affinity receptor in chronic pancreatitis.
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OBJECTIVE: To study the mechanisms that are involved in nerve growth and contribute to pain generation in chronic pancreatitis (CP). SUMMARY BACKGROUND DATA: Chronic pancreatitis is a painful disease associated with characteristic nerve changes, including an increase in nerve number and diameter. The mechanisms that influence nerve growth are not known. Nerve growth factor (NGF) and its high-affinity tyrosine kinase receptor A (TrkA) are involved in neural development and survival and growth of central and peripheral nerves. METHODS: Nerve growth factor and TrkA were investigated by Northern blot analysis, in situ hybridization, and immunohistochemical staining in the pancreases of 24 patients with CP, and the findings were correlated with clinical parameters. RESULTS: By Northern blot analysis, NGF and TrkA mRNA expression were increased in 42% (13.1-fold) and 54% (5.5-fold) of the CP samples (p < 0.01), respectively. In situ hybridization revealed that in CP, enhanced NGF mRNA expression was present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells dedifferentiating into tubular structures. TrkA mRNA was intensely present in the perineurium. Further, enhanced NGF and TrkA mRNA signals were also present in intrapancreatic ganglia cells in CP samples. Immunohistochemistry confirmed the in situ hybridization findings. Analysis of the molecular findings with clinical parameters revealed a significant relation (p < 0.05) between NGF mRNA levels and pancreatic fibrosis (r = 0.64) and acinar cell damage (r = 0.74) and between TrkA mRNA and pain intensity (r = 0.84). CONCLUSION: Activation of the NGF/TrkA pathway occurs in CP. It might influence neural morphologic changes and the pain syndrome in this disorder. (+info)
Effect of pancreaticojejunostomy on fibrosis, pancreatic blood flow, and interstitial pH in chronic pancreatitis: a feline model.
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OBJECTIVE: To study the relation between fibrosis, pancreatic blood flow (PMBF), interstitial pH (pHi), and the effects of pancreaticojejunostomy (PJ) in chronic pancreatitis. BACKGROUND: Chronic pancreatitis is associated with low PMBF and pHi, suggesting the existence of underlying ischemia. METHODS: In cats, the main pancreatic duct was partially obstructed and the animals were studied 2, 4, 6, and 8 weeks later. PJ was performed after 2 and 4 weeks of ductal obstruction and studied 4 weeks later. PMBF and pH were measured before and after stimulation with secretin and cholecystokinin. pHi was measured with microelectrodes, PMBF by hydrogen gas clearance. Histologic analysis of the pancreas with Sirius red (collagen stain) and fast green FCF (noncollagen protein) stains allowed semiquantitative analysis of the ratio between collagen and total protein (C/TP). RESULTS: With the evolution of chronic pancreatitis, there is a progressive increase in the collagen content and C/TP ratio, a reduction in basal PMBF and pHi, and loss of the normal response to stimulation. Early PJ restores collagen content, C/TP ratio, and basal and stimulated PMBF and pHi to normal. PJ performed in established CP returns the C/TP ratio to normal, improves basal PMBF, and restores the normal hyperemic response to secretion. Basal pHi is improved and the "acid tide" associated with secretin returns, but there is still no response to cholecystokinin. CONCLUSIONS: Pancreaticojejunostomy restores the elevated collagen and C/TP ratio to normal and reverses the ischemia present in CP. The authors speculate that restoration of PMBF and its normal response to stimulation allows "regeneration" and restoration of secretory function. (+info)
Serum interleukin 10 and interleukin 11 in patients with acute pancreatitis.
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BACKGROUND: Proinflammatory and anti-inflammatory cytokines are involved in the pathogenesis of acute pancreatitis. AIMS: To measure the serial serum levels of interleukin 10 and interleukin 11 in patients with acute pancreatitis and analyse the relation of these anti-inflammatory cytokines to disease severity. METHODS: In 50 patients with acute pancreatitis, the serum concentrations of interleukin 10 and interleukin 11 were determined on days one, two, three, four, and seven after admission. Serum C reactive protein levels were evaluated on days one and two. Severity of pancreatitis was determined according to the Atlanta criteria. RESULTS: Serum concentrations of interleukin 10 on days one to seven were significantly higher in patients with severe pancreatitis than in those with mild pancreatitis. Patients with severe attacks had significantly elevated serum interleukin 11 concentrations on days two to four compared with those with mild attacks, but not on days one and seven. With cut off levels of 30 pg/ml for interleukin 10, 10.5 pg/ml for interleukin 11, and 115 mg/l for C reactive protein, the accuracy rates for detecting severe pancreatitis were 84%, 64%, and 78% respectively on day one and 82%, 74%, and 84% respectively on day two. CONCLUSIONS: Serum interleukin 10 and interleukin 11 concentrations reflect the severity of acute pancreatitis. Interleukin 10 is a useful variable for early prediction of the prognosis of acute pancreatitis. (+info)
Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury.
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Pancreatic proteases are secreted in acute pancreatitis, but their contribution to associated lung injury is unclear. Applying models of mild edematous (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycholic acid) pancreatitis in rats, we showed that both trypsinogen and trypsin concentrations in peripheral blood, as well as lung injury, correlate with the severity of the disease. To isolate the potential contribution of proteases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intravenous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activation worsened lung injury in mild pancreatitis. In vitro incubation of leukocytes with trypsinogen showed that stimulated leukocytes can convert trypsinogen to trypsin. In conclusion, this study demonstrates that the occurrence and severity of pancreatitis-associated lung injury (PALI) corresponds to the levels of circulating trypsinogen and its activation to trypsin. Neutrophils are involved in both protease activation and development of pulmonary injury. (+info)