Platelet-activating Factor In Inflammation Research Articles

Role of the Platelet-activating Factor in Inflammation

The platelet-activating factor (PAF) is an endogenous lipid mediator derived from membrane phospholipids. PAF was discovered in 1972 as a fluid-phase mediator released from IgE-stimulated basophils that induce the aggregation of rabbit platelets. Biological activity relevant to inflammatory reaction has also been demonstrated, subsequent to identification of the structure of PAF as 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine in 1979. The activity includes activation of leukocytes, increased vascular permeability and contraction of smooth muscle. In the search for antagonists from synthetic analogues of PAF and natural products, a number of antagonists that act on cell surface receptors have been found. A c-DNA for a PAF receptor was cloned first by Shimizu et al. in 1991. PAF is inactivated by the enzyme, PAF-acetylhydrolase, which removes the sn-2 acetyl group of PAF. Discovery of the deficiency of this enzyme, reported by Miwa et al. in 1988, prompted attention to its relationship with diseases such as bronchial asthma. The molecular cloning of intracellular- and plasma-type PAF-acetylhydrolases was achieved in 1994 and 1995, respectively. The isolation of these genes made possible elucidation of the role of PAF in inflammatory reactions on a molecular basis. Recent progress in the study of this factor by a genetical approach is discussed in detail.

Relevance of platelet-activating factor in inflammation and sepsis: Mechanisms and kinetics of removal in extracorporeal treatments

Sepsis can be considered a systemic inflammatory response syndrome (SIRS) caused by infection. When an excessive and/or persistent activation of humoral and cellular mechanisms of host defense is present, an exaggerated and generalized activation of inflammatory mechanisms can lead to a multiple organ dysfunction syndrome. Mediators thought to be involved in this syndrome include the major plasma cascade systems (complement, coagulation, and fibrinolytic systems) and soluble cell-derived mediators (cytokines, reactive oxygen species, platelet-activating factor (PAF), arachidonic acid metabolites, and nitric oxide and related compounds). Several findings indicate that among these mediators, PAF may exert an important role in the pathophysiology of septic shock. Evidence is accumulating that in human sepsis this scenario is far more complicated and that removal of inflammatory mediator excess from plasma, rather than blockade of their potentially beneficial local production, might provide a rationale for the use of continuous renal replacement therapy (CRRT). There is an emerging view that CRRT should be considered in the light of broader concept (ie, the use of blood purification for the treatment of sepsis). Recent studies, performed in an experimental model of continuous arteriovenous hemofiltration with exogenous PAF, demonstrated that polysulfone membranes can adsorb substantial amounts of biologically active PAF. These studies also showed that the removal of this mediator occurs by a two-step process involving early adsorption followed by ultrafiltration. Although the removal of cytokines, such as tumor necrosis factor-α (TNF-α), remains controversial, mainly because of differences in membrane used, operational conditions, and inter- and intra-assay variability, the crucial point is that no evidence has yet been given to show real benefit from CRRT in significantly reducing the plasma concentration of cytokines. The net advantage of CRRT, however, may not only be the removal of cytokines per se, but also the simultaneous elimination of cytokine-inducing substances. Experimental and human studies will be discussed as to whether extracorporeal treatments may remove an excess of circulating cytokines, either by increasing the turnover rate (the so-called high-volume hemofiltration), or by using sorbent systems to regenerate plasma filtrate.

The role of platelet-activating factor in inflammation

Inflammation and hypersensitivity reactions are reactions of vascularized tissue to exogenous or endogenous noxa. Inflammation suggests a protective, immunologically or nonimmunologically mediated response that tends first to localize and then to neutralize noxious material. The inflammatory response is strictly intertwined with a complex series of events that serve to heal and repair the damaged tissue. However, inflammation and repair may be potentially harmful. Hypersensitivity reactions imply an incongruous or sustained activation of the immunologic reactions involved in the inflammatory response, which results not in protection, but in destruction of tissue integrity.