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Polymorphonuclear leukocyte dysregulation during the systemic inflammatory response syndrome
1Department of Surgery, Brown University School of Medicine, Rhode Island Hospital, Providence 02903.
Abstract:
Altered polymorphonuclear leukocyte (PMN) function is thought to contribute to organ dysfunction during the systemic inflammatory response syndrome (SIRS). To test this hypothesis, we evaluated whole blood PMN function adherent to fibronectin or laminin in patients with mild or severe acute pancreatitis as a paradigm for sirs. Whole-blood PMN intracellular H2O2 production, expression of CD32w (Fc gamma R II), CD16 (Fc gamma R III), and phagocytosis were performed using dichlorofluorescein diacetate, fluorescein isothiocyanate-labeled anti-CD32w, CD16, and serum-opsonized fluorescent microspheres. Group I (n x 7) represents normal control individuals; group II (n x 11) represents patients with mild acute pancreatitis. Group III (n x 15) represents critically ill patients with severe acute pancreatitis. Adherence of PMN from groups I and II to matrix proteins resulted in a 5% to 20% increase in each PMN function assayed whereas adherence of PMN from group III to matrix proteins resulted in 50% to 75% increases in each PMN function assayed. Pertussis toxin, pentoxifylline, and dibutyryl cyclic adenosine monophosphate (cAMP) each reduced group I-II H2O2 production and phagocytosis. Pentoxifylline and dibutyryl cAMP but not pertussis toxin reduced group III H2O2 production. Both intracellular H2O2 and phagocytosis assays from group III but not groups I-II showed exaggerated upregulation when exposed to NaF (4 mmol/L). Anti-interleukin-6 reduced the increase in intracellular H2O2 production in group III patients and significantly altered the exaggerated oxidative response to NaF. Longitudinal studies of group III whole-blood PMN showed persistent upregulation of intracellular H2O2 production in those patients whose hospital courses were complicated by multiple system organ failure. These results demonstrate abnormal whole blood PMN function during the systemic inflammatory response syndrome in the presence of fibronectin, or laminin and that this is mediated in part via a pertussis toxin insensitive altered guanosine triphosphate-binding protein.
Insights
Polymorphonuclear leukocyte (PMN) dysfunction contributes to organ failure in systemic inflammatory response syndrome (SIRS). In severe SIRS, PMN adherence to fibronectin/laminin significantly increases function, indicating abnormal immune cell behavior.
Area of Science:
- Immunology
- Cellular Biology
- Critical Care Medicine
Background:
- Systemic inflammatory response syndrome (SIRS) can lead to organ dysfunction.
- Altered polymorphonuclear leukocyte (PMN) function is a suspected contributor to SIRS-induced organ dysfunction.
Purpose of the Study:
- To investigate whole blood PMN function in patients with acute pancreatitis, a model for SIRS.
- To assess the impact of fibronectin and laminin adherence on PMN function in mild and severe pancreatitis.
Main Methods:
- Evaluated intracellular hydrogen peroxide (H2O2) production, CD32w/CD16 expression, and phagocytosis in whole blood PMNs.
- Compared PMN function in healthy controls, mild pancreatitis patients, and severe pancreatitis patients.
- Utilized dichlorofluorescein diacetate, fluorescently labeled antibodies, and fluorescent microspheres for assays.
Main Results:
- PMN adherence to fibronectin/laminin increased function by 5-20% in controls and mild pancreatitis, but 50-75% in severe pancreatitis.
- Pertussis toxin, pentoxifylline, and dibutyryl cAMP modulated PMN function differently across groups.
- Severe pancreatitis PMNs showed exaggerated oxidative responses to NaF, partially reduced by anti-interleukin-6.
Conclusions:
- Abnormal whole blood PMN function occurs during SIRS when adhering to fibronectin or laminin.
- This abnormality is partly mediated by a pertussis toxin-insensitive altered guanosine triphosphate-binding protein.
- Persistent PMN dysfunction correlates with multiple system organ failure in severe pancreatitis patients.