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

Abstract

. 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...

Overexpression of Fas and FasL Is Associated with Infectious Complications and Severity of Experimental Severe Acute Pancreatitis by Promoting Apoptosis of Lymphocytes

“…The mild acute pancreatitis (MAP) group ( n  = 10) was induced by six hourly intravenous injections of caerulein (5 μg/kg; C9026 Sigma-Aldrich, USA) [25, 26]. The SAP group ( n  = 20) was divided into two subgroups according to the result of bacterial culture: a subgroup with infection complications ( n  = 12) and a subgroup without infectious complication ( n  = 8).…”

Complement in Pancreatic Disease—Perpetrator or Savior?

“…Complement activation seems to happen by both classical and alternative complement pathways, and the extent of changes in complement serum levels shows a correlation with the clinical severity of disease (36, 46, 47). Only severe necrotizing pancreatitis, but not mild edematous AP, in rats was accompanied by early complement activation with increased levels of C3a (48). Similar results linking decreasing complement hemolytic activity (CH50), acinar C3 deposits, and histological tissue damage could be found in a rodent model of AP (49).…”

P-Selectin Inhibition Reduces Severity of Acute Experimental Pancreatitis

“…Leukocyte-endothelium interaction as an early step of the inflammatory response has been characterized as a key step in the pathophysiology of AP [6] . In addition to this cellular factor, activation of the humoral coagulation cascade has also been shown to play an important role in the development of microcirculatory disorders in AP [7,8] . Platelets as cellular elements of hemostasis can functionally link inflammatory cells, and humoral coagulation factors have recently been characterized to play a decisive role in the pathogenesis of AP [9,10] .…”