Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis.
ABSTRACT Drotrecogin alfa (activated), the pharmacologic form of activated protein C and the first Food and Drug Administration-approved drug for treatment of severe sepsis, is beneficial in experimental acute pancreatitis (AP).
Male Sprague-Dawley rats.
Mild (intravenous cerulein) or severe (intravenous cerulein plus intraductal glycodeoxycholic acid) AP was induced in 72 rats, and coagulation evaluated. Rats with severe AP were randomized to treatment with drotrecogin alfa (activated), 100 microg/kg per hour, or isotonic sodium chloride.
Histologic scoring of pancreatic necrosis, inflammation of the pancreas and lung (measured by myeloperoxidase concentration), coagulation measures, and 24-hour survival.
Severe consumptive coagulopathy, hemoconcentration, and leukocytosis were observed 6 hours after induction of severe AP, but not in mild AP. Treatment of AP with drotrecogin did not worsen coagulation measures. Although the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, drotrecogin significantly reduced myeloperoxidase levels in the pancreas (P = .009) and lungs (P = .03). The 24-hour survival in severe AP was markedly improved in animals treated with drotrecogin (86% vs 38%; P = .05).
Animals with severe AP have severe consumptive coagulopathy, but administration of drotrecogin alfa (activated), 100 microg/kg per hour, does not worsen coagulation abnormalities. Drotrecogin treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of drotrecogin in the treatment of severe AP.
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ABSTRACT: This study investigated the relationship of Fas and Fas ligand (FasL) expression and apoptosis of lymphocytes in relation to the pathogenic immune response and infectious complications observed in experimental severe acute pancreatitis in mice. Forty male Balb/c mice were randomly divided into control, mild (MAP), and severe acute pancreatitis (SAP) groups. Overexpression of Fas/FasL messenger ribonucleic acid (mRNA) and protein was observed in spleen-derived lymphocytes in SAP (p < 0.01). Apoptosis of these resulted in a depletion of circulating lymphocytes in this group (p < 0.05). A further significant change in the SAP group with infectious complications was observed. A positive relationship was found between the Fas/FasL expression and lymphocyte apoptosis, and negative relationships were observed between Fas/FasL expression and CD4(+) and CD19(+) lymphocytes and the CD4(+)/CD8(+) ratio in SAP mice (p < 0.01). The results suggest that the overexpression of Fas/FasL is associated with infectious complications and severity of experimental severe acute pancreatitis by promoting apoptosis of lymphocytes.Inflammation 02/2014; · 2.46 Impact Factor
- 03/2012; , ISBN: 978-953-51-0109-3
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ABSTRACT: Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP. In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 μg/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor κB (NF-κB) p65/IκB, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury. Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of IκB and reduction of NF-κB p65 and modulation of apoptosis. Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-κB pathways without causing pancreatic hemorrhage.Pancreas 03/2012; 41(4):619-28. · 2.95 Impact Factor