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Endotoxin-induced macrophage gene expression depends on platelet-activating factor
1Department of Surgery, University of California, Los Angeles 90095-6904, USA. clo@surgery.medsch.ucla.edu
Archives of Surgery (Chicago, Ill. : 1960)
|December 24, 1997
Summary
Platelet-activating factor (PAF) drives macrophage gene expression in sepsis. Inhibiting PAF or its receptor reduces inflammatory responses, suggesting PAF modulation as a sepsis treatment.
Area of Science:
- Immunology
- Molecular Biology
- Sepsis Pathophysiology
Background:
- Sepsis-induced multiple organ failure stems from systemic inflammation orchestrated by macrophages.
- Macrophage activation in sepsis is a critical factor for patient survival.
- Early macrophage activation involves phospholipase A2 (PLA2) and platelet-activating factor (PAF) generation.
Purpose of the Study:
- To investigate the hypothesis that macrophage gene expression is dependent on PAF.
- To elucidate the role of PAF in lipopolysaccharide (LPS)-induced macrophage activation.
Main Methods:
- Rabbit alveolar macrophages were stimulated with LPS, PAF, PAF receptor antagonist (CV3988), or PLA2 inhibitors (AACOCF3, manoalide).
- Tumor necrosis factor (TNF) mRNA expression was assessed via Northern blot.
- TNF production was quantified using L929 bioassays.
Main Results:
- LPS stimulation significantly increased TNF mRNA and TNF production in macrophages.
- PAF receptor antagonist CV3988 inhibited LPS-induced TNF mRNA expression.
- PLA2 inhibitors (AACOCF3, manoalide) also inhibited LPS-induced TNF mRNA, indicating PAF's role in its production.
- PAF's effects were linked to intracellular calcium concentration changes, as calcium flux inhibitors attenuated LPS-induced responses.
Conclusions:
- LPS-induced macrophage gene expression is mediated by PAF.
- Modulating PAF production or activity could be a therapeutic strategy to reduce macrophage overactivity in sepsis.