Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis

University of Toronto, Toronto, Ontario, Canada
New England Journal of Medicine (Impact Factor: 55.87). 01/2008; 358(1):28-35. DOI: 10.1056/NEJMoa070030
Source: PubMed


Platelet-activating factor (PAF) is an important mediator of anaphylaxis in animals, and interventions that block PAF prevent fatal anaphylaxis. The roles of PAF and PAF acetylhydrolase, the enzyme that inactivates PAF, in anaphylaxis in humans have not been reported.
We measured serum PAF levels and PAF acetylhydrolase activity in 41 patients with anaphylaxis and in 23 control patients. Serum PAF acetylhydrolase activity was also measured in 9 patients with peanut allergy who had fatal anaphylaxis and compared with that in 26 nonallergic pediatric control patients, 49 nonallergic adult control patients, 63 children with mild peanut allergy, 24 patients with nonfatal anaphylaxis, 10 children who died of nonanaphylactic causes, 15 children with life-threatening asthma, and 19 children with non-life-threatening asthma.
Mean (+/-SD) serum PAF levels were significantly higher in patients with anaphylaxis (805+/-595 pg per milliliter) than in patients in the control groups (127+/-104 pg per milliliter, P<0.001 after log transformation) and were correlated with the severity of anaphylaxis. The proportion of subjects with elevated PAF levels increased from 4% in the control groups to 20% in the group with grade 1 anaphylaxis, 71% in the group with grade 2 anaphylaxis, and 100% in the group with grade 3 anaphylaxis (P<0.001). There was an inverse correlation between PAF levels and PAF acetylhydrolase activity (P<0.001). The proportion of patients with low PAF acetylhydrolase values increased with the severity of anaphylaxis (P<0.001 for all comparisons). Serum PAF acetylhydrolase activity was significantly lower in patients with fatal peanut anaphylaxis than in control patients (P values <0.001 for all comparisons).
Serum PAF levels were directly correlated and serum PAF acetylhydrolase activity was inversely correlated with the severity of anaphylaxis. PAF acetylhydrolase activity was significantly lower in patients with fatal anaphylactic reactions to peanuts than in patients in any of the control groups. Failure of PAF acetylhydrolase to inactivate PAF may contribute to the severity of anaphylaxis.

Download full-text


Available from: Peter Vadas, Sep 16, 2015
25 Reads
  • Source
    • "However, some studies have reported that the levels of PAF in serum correlates with the severity of the anaphylactic reaction while histamine or tryptase levels do not, and PAF acetylhydrolase activity, the enzyme responsible of PAF inactivation, inversely correlates with severity scores (Vadas et al., 2008), and thus PAF antagonists, alone or in combination with other drugs, may be a consideration as rescue therapy for acute anaphylaxis reactions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.02.058 · 2.53 Impact Factor
  • Source
    • "Also known as lipoprotein-associated phospholipase A2 (Lp-PLA2), the plasma PAF-AH is a single 45-kilodalton polypeptide composed of 441 amino acids encoded by the PLA2G7 gene [2]. Because PAF-AH hydrolyzes platelet-activating factor (PAF) and oxidizes phospholipids with a modified short fatty acyl chain esterified at the sn-2 position [3], PAF-AH plays an important role in human diseases such as severe anaphylaxis [4], rheumatic diseases [5], acute respiratory distress syndrome [6], necrotizing enterocolitis [7], and atherosclerosis [8]. Previous epidemiologic studies demonstrated that increased PAF-AH activity had a prognostic value and was associated with a high risk of future coronary and cerebrovascular events [9,10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The aim of this study was to investigate the variation of platelet-activating factor acetylhydrolase (PAF-AH) in patients with various stages of hepatitis B infection and evaluate the association between PAF-AH activity and chronic severe hepatitis B (CSHB) and mortality in patients with hepatitis B. Methods Serum PAF-AH activity was measured in 216 patients with hepatitis B and in 152 healthy controls using an automatic biochemical analysis system. Spearman correlation was used to investigate the correlation between PAF-AH activity and other biochemical indicators. The receiver operating characteristic (ROC) curve and multivariable logistic regression analysis were used to evaluate the ability of PAF-AH activity to predict CSHB and mortality in patients with hepatitis B. Results The PAF-AH activities in patients with CSHB (1320 ± 481 U/L) were significantly higher than those in healthy controls and in other hepatitis B groups (all P < 0.01). In patients with hepatitis B, PAF-AH activity correlated with total bilirubin (r = 0.633), total bile acid (r = 0.559), aspartate aminotransferase (r = 0.332), apolipoprotein B (r = 0.348), high-density lipoprotein cholesterol (r = −0.493), and apolipoprotein AI (r = −0.530). The areas under the ROC curves for the ability of PAF-AH activity to predict CSHB and mortality in patients with hepatitis B were 0.881 (95% confidence interval (CI): 0.824–0.937, P < 0.001) and 0.757 (95% CI: 0.677–0.837, P < 0.001), respectively. Multivariate logistic regression analysis showed PAF-AH activity to be an independent factor predicting CSHB with an odds ratio of 1.003 (95% CI: 1.002–1.005, P < 0.001). Conclusion Elevated PAF-AH in patients with hepatitis B was significantly associated with liver damage. Thus, serum PAF-AH could be used as a novel indicator for predicting CSHB and mortality in patients with hepatitis B. Further, PAF-AH activity was an independent factor predicting CSHB.
    Lipids in Health and Disease 06/2014; 13(1):105. DOI:10.1186/1476-511X-13-105 · 2.22 Impact Factor
  • Source
    • "PAF agonists can be produced non-enzymatically in response to various pro-oxidative stressors via free-radical attacks on the sn2 position of cellular membrane, phosphocholine lipids.12–21 PAF exerts its effects via a seven-transmembrane G-protein-coupled receptor, the PAF-receptor (PAF-R), expressed on a variety of cells types.10,11,22,23 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated factor-receptor (PAF-R) agonistic activity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxi-dized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system.
    Cancer Growth and Metastasis 06/2014; 7(4265-CGM-Systemic-Platelet-activating-Factor-Receptor-Activation-Augments-Exper.pdf):27-32. DOI:10.4137/cgm.s14501
Show more