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Review
, 92 (6), 692-7

The Platelet Activating Factor (PAF) Signaling Cascade in Systemic Inflammatory Responses

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Review

The Platelet Activating Factor (PAF) Signaling Cascade in Systemic Inflammatory Responses

Christian C Yost et al. Biochimie.

Abstract

The platelet-activating factor (PAF) signaling cascade evolved as a component of the repertoire of innate host defenses, but is also an effector pathway in inflammatory and thrombotic diseases. This review focuses on the PAF signaling cascade in systemic inflammatory responses and, specifically, explores its activities in experimental and clinical sepsis and anaphylaxis in the context of the basic biochemistry and biology of signaling via this lipid mediator system.

Figures

Figure 1
Figure 1. The PAF Signaling Cascade
The PAF signaling system includes PAF and PAF-like lipids, which are phospholipid ligands, and a G-protein-coupled receptor, the PAFR, that has restricted distribution on target inflammatory, immune, and hemostatic cells. Engagement of the receptor triggers cellular activation and, via intracellular signaling cascades, alterations in cellular phenotype and function. A variety of regulatory mechanisms have evolved to control the PAF signaling system including PAFR downregulation and desensitization, intracellular biochemical modulation, and activities of a family of enzymes – the PAF acetylhydrolases – that selectively degrade PAF and PAF-LL. Plasma PAF AH, a secreted form, is constitutively present in blood under basal conditions and limits the half life of circulating PAF to minutes. Recombinant PAF AH and competitive PAFR antagonists have been studied as candidate therapies for sepsis in experimental models and clinical trials. Modified from [80] with permission.
Figure 2
Figure 2. PAF induces NET formation by human neutrophils
Neutrophils from healthy adults were activated with nanomolar concentrations of PAF for 60 min. Left panel: NETs were examined using live cell imaging by confocal microscopy after incubation with a cell-impermeable DNA dye (red) or a cell permeable DNA dye (green). Red staining indicates extracellular NET formation, which was further documented by election microscopy (not shown). Right panel: NETs were stained for elastase (magenta fluorescence, white arrows), an intracellular and secreted anti-bacterial enzyme that associates with NETs and is a marker for their formation [19]. Yellow arrows indicate intracellular elastase in neutrophil granules. Reproduced from [19] with permission.
Figure 3
Figure 3. Plasma PAF AH is depressed in some, but not all, patients with sepsis and is dynamically regulated in an experimental model of sepsis
A. Plasma PAF AH activity levels were measured in samples from patients with septic shock or sepsis without shock identified by consensus criteria, and in samples from healthy control subjects. The gray area indicates activity levels below the lowest value in the range of activities in samples from control subjects. B. Mice were subjected to cecal ligation and puncture and plasma PAF AH activity levels were measured in serial fashion in surviving animals. These figures were modified from [37] with permission.
Figure 4
Figure 4. Plasma PAF AH is expressed as human monocytes differentiate into macrophages in vitro
Left: Total PAF AH activity [65]. Right: Secreted and intracellular PAF AH activities [66]. The figures illustrate results from separate experiments using different macrophage cultures, accounting for the differences in total PAF AH activity in the two panels. Additional studies documented expression and synthesis of plasma PAF AH by primary and model human macrophages and by rodent macrophages (reviewed in [7]).

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