Polymorphonuclear leukocyte dysfunction syndrome in patients with increasing sepsis severity

Area of Science:

• Immunology
• Cellular Biology
• Pathophysiology

Background:

• Granulocytes, including polymorphonuclear leukocytes (PMNs), produce oxygen radicals essential for microbicidal and tissue-damaging functions.
• The role of PMNs in sepsis is complex, with potential for both beneficial and detrimental effects.
• Understanding PMN responses to various stimuli is crucial for managing sepsis severity.

Purpose of the Study:

• To investigate hydrogen peroxide (H2O2) production by PMNs in patients with varying sepsis severity.
• To compare PMN H2O2 production in response to different particulate (zymosan) and soluble stimuli.
• To identify potential defects in PMN signaling pathways during sepsis progression.

Main Methods:

• Prospective study of patients with sepsis, severe sepsis, and septic shock, compared to healthy controls.
• Assessed PMN adhesion, phagocytosis, and H2O2 production using unopsonized and opsonized zymosan particles.
• Evaluated H2O2 production stimulated by soluble agents like fMLP, TNF-alpha, A23187, and phorbol myristate acetate, bypassing or activating specific signaling pathways.

Main Results:

• PMN H2O2 production varied significantly with sepsis severity and stimulus type.
• Phagocytosis of zymosan and associated H2O2 production were decreased in septic patients.
• Spontaneous and stimulated H2O2 production by soluble stimuli were markedly increased, particularly in septic shock.
• PMN surface binding of zymosan remained unchanged, suggesting defects in lectin-binding site (CD11b) or dectin-1 signaling.

Conclusions:

• Septic patients develop a PMN dysfunction syndrome characterized by impaired response to particulate stimuli and heightened response to soluble stimuli.
• These functional changes correlate with sepsis severity and may stem from defects in specific pathogen recognition receptor signaling.
• Findings highlight the complex and altered behavior of PMNs in sepsis, impacting their effector functions.