Effects on Peritoneal Proteolysis and Hemodynamics of Prophylactic Infusion with CI Inhibitor in Experimental Acute Pancreatitis

Ruud, T. E.; Aasen, Ansgar O.; Pillgram-Larsen, J; Stadaas, J. O.

doi:10.3109/00365528608996414

Cited by 19 publications

(11 citation statements)

References 26 publications

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“…Likewise, leukocyte sequestration in the lungs, as assessed by MPO activity, was decreased by sCR1. These findings are in agreement with other studies (15,23,34) indicating a possible therapeutic role of complement inhibition in the setting of acute pancreatitis. However, two recent studies (2, 31) that could not confirm these beneficial effects applied the model of mild cerulein-induced pancreatitis.…”

Section: Discussionsupporting

confidence: 83%

“…Complement inhibition by the C1 esterase inhibitor has been proven effective in the treatment of experimental severe pancreatitis (23,34). Supporting these results, complement inhibition by the recombinant soluble complement receptor 1 (sCR1) attenuated leukocyte-endothelium interaction and preserved endothelial barrier function in ischemia-reperfusion injury of the pancreas (28).…”

supporting

confidence: 53%

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Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

Hartwig¹,

Klafs²,

Kirschfink³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention. Am J Physiol Gastrointest Liver Physiol 291: G844 -G850, 2006; doi:10.1152/ajpgi.00016.2006.-In acute pancreatitis, local as well as systemic organ complications are mediated by the activation of various inflammatory cascades. The role of complement in this setting is unclear. The aim of the present study was to determine the level of complement activation in experimental pancreatitis, to evaluate the interaction of complement and leukocyte-endothelium activation, and to assess the effects of complement inhibition by soluble complement receptor 1 (sCR1) in this setting. Necrotizing pancreatitis was induced in Wistar rats by the combination of intravenous cerulein and retrograde infusion of glycodeoxycholic acid into the biliopancreatic duct; edematous pancreatitis was induced by intravenous cerulein only. In control animals, a sham operation (midline laparotomy) was performed. Complement activation, leukocyte sequestration, and pancreatic as well as pulmonary injury were assessed in the presence/ absence of sCR1. Increased levels of C3a were found in necrotizing but not in edematous pancreatitis. When complement activation in necrotizing pancreatitis was blocked by sCR1, levels of C3a and total hemolytic activity (CH50) were decreased. Leukocyte-endothelial interaction, as assessed by intravital microscopy, and pancreatic as well as pulmonary organ injury (wet-to-dry weight ratio, MPO activity, and histology) were ameliorated by sCR1. As a result of the present study, necrotizing but not edematous pancreatitis is characterized by significant and early complement activation. Based on the interaction of complement and leukocytes, complement inhibition by sCR1 may be a valuable option in the treatment of leukocyteassociated organ injury in severe pancreatitis. necrotizing pancreatitis; complement activation; soluble complement receptor 1; leukocyte endothelial interaction; lung injury ACTIVATED COMPLEMENT PROTEINS have long been regarded as possible mediators of organ injury in acute pancreatitis. Evidence of complement activation has been reported by several investigators in the setting of both experimental (13, 25) and human acute pancreatitis (7). Once activated, the complement cascade can initiate organ injury in a variety of ways. For example, the components C5 through C9 assemble to form the membrane attack complexes that destroy plasma cell membranes (29,30). C5a is a potent chemoattractant for neutrophils and monocytes and stimulates the release of leukocyte lysosomal enzymes, cytokines, and reactive oxygen species. The anaphylatoxins C3a and C5a induce mast cell degranulation and are thought to be involved in airway hyperresponsiveness.Complement inhibition by the C1 esterase inhibitor has been proven effective in the treatment of experimental severe pancreatitis (23, 34). Supporting these results, complement inhibition by the recombinant soluble complement receptor 1 (sCR1) attenuated leukocyt...

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Section: Discussionsupporting

confidence: 83%

supporting

confidence: 53%

Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

Hartwig¹,

Klafs²,

Kirschfink³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The ischemic pancreas, being a source of controversial myocardial depressant factor MDF [8,10,11], may cause the cardiac depression and aggravate the state of shock. The present study confirms hemodynamic consequences in experimental pancreatitis, delivered by other authors [2,3,5,12,13] although they are quite different from hemodynamic data obtained in patients in clinical conditions [8,14]. Untreated animals developed a progressive circulatory insufficiency: the decrease of cardiac output, mean artery pressure, and left ventricular stroke volumne.…”

Section: Discussionsupporting

confidence: 57%

“…Similarly, Ruud et al [5], using C1 inhibitor durOffprint requests to: Marek Dobosz, MD ing their studies, demonstrated the improvement of survival rate and hemodynamic performance in experimental acute pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

Effect on hemodynamics of therapeutic infusion of gabexate mesilate (FOY) in experimental acute pancreatitis

et al. 1989

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Acute pancreatitis was induced in ten anesthetized dogs by retrograde injection for bile mixed with trypsin into the pancreatic duct. Five animals were treated with i.v. infusion of gabexate mesilate in a dose of 1 mg/kg per hour. Hemodynamic data were regulary monitored during a 10-h observation period. Cardiac output (CO), mean arterial pressure (MAP), and left ventricular stroke volume (LVSV) decreased rapidly in untreated animals. An increase of systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) was observed in dogs without treatment. Gabexate mesilate given as a therapy significantly improved the hemodynamic parameters. The study demonstrates an advantageous influence of synthetic antiprotease gabexate mesilate on the course of acute experimental pancreatitis.

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“…Recent experimental studies from our laboratory have shown that intravenous ad ministration of both Cl-Inh and aprotinin improves hemodynamics and survival rates in taurocholate-induced pancreatitis [28]. Such effects are also seen after corticosteroid pretreatment in the same experimental model on acute pancreatitis [29].…”

Section: Discussionmentioning

confidence: 56%

Peritoneal Lavage Efficiently Eliminates Protease-Alpha-2-Macroglobulin Complexes and Components of the Contact System from the Peritoneal Cavity in Patients with Severe Acute Pancreatitis

et al. 1989

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Trypsin (Try), plasma kallikrein (KK) and plasmin activities together with coagulation factor XII (F XII, Hageman factor), high-molecular-weight kininogen (HMWK), plasma prekallikrein (PKK), α_2-macroglobulin (cα₂-M), C1 inhibitor (C1Inh), and functional plasma kallikrein inhibition (KKI) values were studied in peritoneal fluid and lavage taps of 9 patients with severe acute pancreatitis treated with peritoneal lavage. Both immunochemical methods and functional techniques based on chromogenic peptide substrate assays were used. In the exudate obtained before peritoneal lavage was performed, F XII was 52%, HMWK was 30%, PKK was 40%, α₂-M was 29% and C1Inh was 57% of standard plasma pool values, determined by immunochemical technique. Functional plasma KKI values were zero, whereas Try activities determined by chromogenic peptide substrate technique were markedly elevated in the exudate. Using a prepacked HR 10/30 Superose Tm 12 column (Pharmacia, Uppsala, Sweden) and chromogenic peptide substrate assays, Try and KK activities were detected in the α₂-M containing fractions of the peritoneal exudate demonstrating KK-α₂-M and Try-α₂-M complex formation. The peritoneal lavage procedure efficiently eliminated components of the contact system and protease activities. In the first lavage tap, Try activities were markedly reduced compared to values found in the exudate and concentrations of F XII, HMWK, PKK, α₂-M and C1Inh were all zero. In consecutive lavage taps Try values were also zero. The study shows that the lavage procedure efficiently clears the peritoneal cavity for protease-α₂-M complexes generated during acute pancreatitis. Also, components of the contact system found in peritoneal exudate, and which might serve as substrates for the protease-α₂-M complexes, are rapidly eliminated by the procedure.

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Effects on Peritoneal Proteolysis and Hemodynamics of Prophylactic Infusion with CI Inhibitor in Experimental Acute Pancreatitis

Cited by 19 publications

References 26 publications

Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

Effect on hemodynamics of therapeutic infusion of gabexate mesilate (FOY) in experimental acute pancreatitis

Peritoneal Lavage Efficiently Eliminates Protease-Alpha-2-Macroglobulin Complexes and Components of the Contact System from the Peritoneal Cavity in Patients with Severe Acute Pancreatitis

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