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Neutrophils, not complement, mediate the mortality of experimental hemorrhagic pancreatitis
C Kyriakides1, J Jasleen, Y Wang
1Department of Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Chemoactivation of the neutrophil (PMN) via the complement system has been observed in many inflammatory conditions and is thought to play a pathogenic role in acute pancreatitis. This study examined the effects of PMN depletion in experimental hemorrhagic pancreatitis and tested the role played by complement. Severe pancreatitis was induced by a choline-deficient, 0.5% ethionine-supplemented diet in female Institute of Cancer Research (ICR) mice weighing 11-13 g. Neutropenia was induced by an antibody injection. Total complement depletion was achieved by tail vein injections of cobra venom factor (CVF). Serum amylase levels and local pancreatic injury were not significantly modulated by either PMN or complement depletion at 72 hours. Systemic and remote organ injury, assessed by the formation of ascites, hematocrit, and serum alanine aminotransferase levels, was significantly reduced in neutropenic mice but failed to be moderated by complement depletion. In addition, liver and lung myeloperoxidase activity was independent of complement depletion. At 5 days, mortality was zero in PMN-depleted mice. There was no improvement in survival in the CVF-treated group. Neutrophils are important in the systemic injury and mortality of severe pancreatitis. PMN chemoactivation involves mechanisms other than complement.
Insights
Neutrophil depletion significantly reduced systemic injury and mortality in experimental pancreatitis, suggesting neutrophils, not complement, drive severe disease progression. This highlights novel therapeutic targets for pancreatitis management.
Area of Science:
- Gastroenterology
- Immunology
- Inflammation Research
Background:
- Neutrophil (PMN) chemoactivation via the complement system is implicated in inflammatory conditions like acute pancreatitis.
- The precise role of neutrophils and complement in the pathogenesis of severe pancreatitis requires further elucidation.
Purpose of the Study:
- To investigate the effects of neutrophil depletion on experimental hemorrhagic pancreatitis.
- To determine the role of the complement system in mediating pancreatitis-induced injury and mortality.
Main Methods:
- Severe pancreatitis was induced in mice using a choline-deficient, ethionine-supplemented diet.
- Neutropenia was achieved via antibody injection; complement depletion was induced using cobra venom factor (CVF).
- Pancreatic injury, systemic organ damage (ascites, hematocrit, ALT), myeloperoxidase activity, and mortality were assessed.
Main Results:
- Neither neutrophil nor complement depletion significantly altered local pancreatic injury or serum amylase levels at 72 hours.
- Neutrophil depletion markedly reduced systemic and remote organ injury, including ascites formation and elevated ALT.
- Complement depletion did not mitigate systemic injury, and myeloperoxidase activity in the liver and lungs was independent of complement levels.
- Mortality was eliminated in neutrophil-depleted mice, while complement depletion offered no survival benefit.
Conclusions:
- Neutrophils play a critical role in the systemic injury and mortality associated with severe acute pancreatitis.
- Complement activation is not the primary mechanism driving neutrophil chemoactivation in this model of pancreatitis.
- These findings suggest that targeting neutrophils, independent of complement, may be a viable therapeutic strategy for severe pancreatitis.