ReviewThe platelet activating factor (PAF) signaling cascade in systemic inflammatory responses
Introduction
The platelet-activating factor (PAF) signaling cascade consists of PAF and PAF-like lipids (PAF-LL) that are specific, structurally-defined ligands for a G-protein-coupled receptor, the PAF receptor (PAFR), which has restricted expression on key target cells of the inflammatory, immune, and hemostatic systems. Engagement of the PAFR by PAF or PAF-LL triggers a variety of intracellular signaling cascades and, via these biochemical mechanisms, induces functional responses of PAFR-bearing cells that then initiate or amplify inflammatory and thrombotic events (Fig. 1). Under physiologic circumstances, receptor desensitization and other regulatory mechanisms control responses of cells activated by binding of phospholipid ligands to the PAFR. In addition, the synthesis of PAF is tightly regulated, and a family of intracellular and extracellular phospholipases A2 termed PAF acetylhydrolases (PAF AH) control and terminate signals in this cascade by selectively degrading PAF and PAF-LL, thereby determining their concentrations and half lives and regulating engagement of the PAFR (Fig. 1). Molecular and biochemical features of the PAF signaling cascade, and its known roles in health and disease, have been extensively reviewed [1], [2], [3], [4], [5], [6], [7].
This focused review will emphasize features of the PAF signaling cascade in systemic inflammatory responses. It will draw heavily on translational studies that link basic inquiries into the biochemistry and biology of PAF signaling to clinical trials and analysis of activities of the PAF signaling cascade in human cells and surrogate models of systemic inflammatory syndromes.1
Inflammation and hemostasis can be localized, occurring at restricted anatomic sites, or systemic, with manifestations in multiple tissues and organ systems. Systemic inflammatory responses are frequently pathologic and uncontrolled, and often are lethal in humans and experimental animals. Sepsis and anaphylaxis are important examples of systemic inflammatory responses. In each case, there is extensive clinical and investigational evidence indicating that the PAF signaling cascade is involved. While this article examines some of these pathologic issues, it should be remembered that the PAF signaling system (Fig. 1) likely evolved as a protective and physiologic cascade that is part of the intricate and extensive innate host defense repertoire [8].
Section snippets
The PAF signaling cascade in sepsis
Sepsis is a syndrome of pathologic systemic inflammation and dysregulated hemostasis that involves activation of myeloid leukocytes, platelets, and endothelial cells, microvascular injury and thrombosis, and damage or dysfunction of many organs, including the lungs [9], [10], [11]. Sepsis is induced by intravascular or extravascular microbial invasion, or challenge to the host with microbial toxins and products, and is common and frequently lethal. A systemic inflammatory response with
The PAF signaling system in anaphylaxis
Anaphylaxis is a complex hypersensitivity reaction characterized by systemic hypotension, vascular leakage, and laryngeal and airway obstruction that is rapid and potentially fatal [73]. Mast cells, which are pivotal cells in inflammatory regulation, and systemically-released mediators including histamine and PAF are key factors in the pathogenesis of human and experimental anaphylactic syndromes [73], [74]. Interestingly, histamine is a potent agonist for PAF synthesis by human endothelial
Acknowledgements
The authors thank Jenny Pierce for preparation of the manuscript, Diana Lim for creating the figures, and our colleagues, students, and technical associates for many contributions to work cited. Studies mentioned in this review were supported by NIH K08 HD049699 (CYY), individual grants from the NIH to ASW and GAZ, and an NIH Special Center of Research in ARDS.
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