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; 37(4). DOI:10.1007/s10753-014-9847-8 · 1.92 Impact Factor
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ABSTRACT: Acute pancreatitis (AP) is a common emergency condition. In the majority of cases, it presents in a mild and self-limited form. However, about 20% of patients develop severe disease with local pancreatic complications (including necrosis, abscess, or pseudocysts), systemic organ dysfunction, or both. A modern classification of AP severity has recently been proposed based on the factors that are causally associated with severity of AP. These factors are both local (peripancreatic necrosis) and systemic (organ failure). In AP, inflammation is initiated by intracellular activation of pancreatic proenzymes and/or nuclear factor-κB. Activated leukocytes infiltrate into and around the pancreas and play a central role in determining AP severity. Inflammatory reaction is first local, but may amplify leading to systemic overwhelming production of inflammatory mediators and early organ failure. Concomitantly, anti-inflammatory cytokines and specific cytokine inhibitors are produced. This anti-inflammatory reaction may overcompensate and inhibit the immune response, rendering the host at risk for systemic infection. Currently, there is no specific treatment for AP. However, there are several early supportive treatments and interventions which are beneficial. Also, increasing the understanding of the pathogenesis of systemic inflammation and the development of organ dysfunction may provide us with future treatment modalities.12/2012; 2012:360685. DOI:10.1155/2012/360685
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ABSTRACT: Sepsis is a systemic illness caused by invasion of tissues by pathogens. It is highly lethal, causing circulatory failure and death. There has been extensive research trying to identify possible therapies for sepsis. Apart from source control, and antibiotic and supportive therapy, glucocorticoids, anticoagulant agents, and immunoglobulins have been tried in both the experimental setting and in septic patients. Newer strategies include novel anticoagulant agents like ethyl pyruvate, statins, insulin receptor modulators and Toll-like receptor modulators. This review article summarizes both the current therapies and endeavors for future treatment in sepsis. Özet: Sepsis, dokuların patojen organizmalar tarafından işgal edilmesi sonucu ortaya çıkan sistemik bir hastalıktır. Dolaşım bozukluğu ve ölümle sonuçlanabilir. Sepsis tedavisi alanında birçok araştırma yapılmıştır. Kaynak kontrolü, antibiyotik ve destek tedavisi dışında glukokortikoidler, immunoglobulinler, antikoagülan ajanlar da hem deneysel hem de klinikte kullanılan tedavi yöntemleridir. Yeni tedavi stratejileri etil pirüvat gibi antikoagülanları, statinleri, insülin ve toll-like reseptör modülatörlerini içermektedir. Bu makalede sepsisin hem güncel tedavisi hem de gelecekte uygulanabilecek olası tedavi yaklaşımları tartışılmıştır.