Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1856-1861 ◽  
Author(s):  
Wim K. Bleeker ◽  
Jessica L. Teeling ◽  
Arthur J. Verhoeven ◽  
Gemma M. M. Rigter ◽  
Jacques Agterberg ◽  
...  
Keyword(s):  
Side Effects ◽  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Platelet Activating Factor ◽  
Human Neutrophils ◽  
Ivig Infusion ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Paf Acetylhydrolase ◽  
Immunoglobulin Preparations

Previously, we observed in a rat model that intravenous administration of intramuscular immunoglobulin preparations induced a long-lasting hypotension, which appeared to be associated with the presence of IgG polymers and dimers in the preparations, but unrelated to complement activation. We found evidence that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different manufacturers, in anesthetized rats. Eight of the IVIG preparations showed no hypotensive effects (less than 15% decrease), whereas the other 8 had relatively strong effects (15%-50% decrease). The hypotensive effects correlated with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypotensive reaction on IVIG infusion, and administration after the onset of hypotension resulted in normalization of the blood pressure. We also observed PAF production on in vitro incubation of human neutrophils with IVIG, which could be blocked by anti-Fcγ receptor antibodies. This indicates that induction of PAF generation may also occur in a human system. Our findings support the hypothesis that the clinical side effects of IVIG in patients may be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fcγ receptors. Because phagocyte activation may also lead to the release of other inflammatory mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for the treatment of those adverse reactions.

A Mutation in Plasma Platelet-activating Factor Acetylhydrolase (Val279Phe) Is a Genetic Risk Factor for Cerebral Hemorrhage but not for Hypertension

1998 ◽  
Vol 80 (09) ◽  
pp. 372-375 ◽  
Author(s):  
Hidemi Yoshida ◽  
Tadaatsu Imaizumi ◽  
Koji Fujimoto ◽  
Hiroyuki Itaya ◽  
Makoto Hiramoto ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Platelet Activating Factor ◽  
Vascular Diseases ◽  
Genetic Risk Factor ◽  
Brain Hemorrhage ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Paf Acetylhydrolase ◽  
Polymerase Chain ◽  
The Difference

SummaryPlatelet-activating factor (PAF) acetylhydrolase is an enzyme that inactivates PAF. Deficiency of this enzyme is caused by a missense mutation in the gene. We previously found a higher prevalence of this mutation in patients with ischemic stroke. This fact suggests that the mutation might enhance the risk for stroke through its association with hypertension. We have addressed this hypothesis by analyzing the prevalence of the mutation in hypertension. We studied 138 patients with essential hypertension, 99 patients with brain hemorrhage, and 270 healthy controls. Genomic DNA was analyzed for the mutant allele by the polymerase-chain reaction. The prevalence of the mutation was 29.3% (27.4% heterozygotes and 1.9% homozygotes) in controls and 36.2% in hypertensives and the difference was not significant. The prevalence in patients with brain hemorrhage was significantly higher than the control: 32.6% heterozygotes and 6.1% homozygotes (p <0.05). PAF acetylhydrolase deficiency may be a genetic risk factor for vascular diseases.

scholarly journals Molecular characterization of the constitutive expression of the plasma platelet-activating factor acetylhydrolase gene in macrophages

2003 ◽  
Vol 375 (2) ◽  
pp. 351-363 ◽  
Author(s):  
Xiaoqing WU ◽  
Thomas M. McINTYRE ◽  
Guy A. ZIMMERMAN ◽  
Stephen M. PRESCOTT ◽  
Diana M. STAFFORINI
Keyword(s):  
Platelet Activating Factor ◽  
Constitutive Expression ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Band Shift ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Nuclear Extracts ◽  
Mediators Of Inflammation ◽  
Human And Mouse

Plasma platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase that inactivates platelet-activating factor (PAF) and PAF-like lipids to generate products with little or no biological activity. The levels of circulating PAF-AH correlate with several disease syndromes. We previously reported that mediators of inflammation regulate the expression of the human PAF-AH gene at the transcriptional level. In the present paper, we characterize the constitutive expression of plasma PAF-AH using the mouse gene as a model system, and we report comparative results obtained using human and mouse promoter constructs. We first cloned, sequenced and analysed the promoter region of the murine plasma PAF-AH (mPAF-AH) gene and found that this gene lacks a canonical TATA box. We demonstrated that the cis-elements required for basal transcription are localized within the −316 to −68 bp region. In vitro band-shift and supershift assays showed that Sp1 and Sp3 transcription factors from RAW264.7 and J774A.1 macrophage nuclear extracts bound strongly to a distal GC-rich site within −278/−243 [specificity protein (Sp-A)] and to a proximal TC-rich motif within −150/−114 (Sp-B). In addition, we observed weak binding to a GA-rich site within −110/−82 (Sp-C). The regions containing Sp-B and Sp-C are highly conserved between the human and mouse genes. Forced expression of Sp1 or Sp3 in Sp-lacking Drosophila SL2 cells induced markedly the activity of the exogenous mPAF-AH promoter in a dose-dependent manner, and this induction was dependent on the presence of intact Sp-A and Sp-B. Interestingly, we found that the Sp1- and Sp3-associated DNA-binding activities increased during the maturation of primary human monocytes into macrophages in cell culture. These results demonstrate that Sp1 and Sp3 are key factors that contribute to the basal, constitutive transcription of the plasma PAF-AH gene in macrophages.

Human Plasma Gelsolin Inhibits Cellular Responses to Platelet Activating Factor (PAF).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3568-3568
Author(s):  
Teresia A. Magnuson-Osborn ◽  
Claes Dahlgren ◽  
John H. Hartwig ◽  
Thomas P. Stossel
Keyword(s):  
Platelet Activating Factor ◽  
Actin Binding ◽  
Major Surgery ◽  
Human Neutrophils ◽  
Dependent Manner ◽  
Cellular Activation ◽  
Blood Concentrations ◽  
Plasma Gelsolin ◽  
Molar Excess

Abstract Gelsolin is a highly conserved intracellular actin-binding protein with an extracellular isoform named plasma gelsolin (pGSN). Relatively high (250 mg /L) blood concentrations of pGSN decrease in response to trauma, major surgery, sepsis, burns, ionizing radiation, and hyperoxia. Depletion of pGSN to a critical (~20%) level precedes and predicts complications of primary injuries such as lung permeability changes, ARDS, assisted ventilation and death. Administration of recombinant pGSN ameliorates such complications and reduces mortality in animal models. A proposed mechanism for pGSN’s protective effects is that it inhibits inflammatory mediators generated during primary injuries, since pGSN binds bioactive mediators, including lysophospatidic acid (LPA) and endotoxin in vitro. Because of its structural similarity we hypothesized that plasma gelsolin binds also to the potent lipid mediator platelet activating factor (PAF) and report here on the inhibition of PAF-induced cellular activation. Recombinant pGSN inhibited PAF-induced P-selectin up-regulation by human platelets as measured by flow cytometry. A ten- to 40-fold molar excess (0.5–20 μM) of pGSN over PAF inhibits P-selectin expression by 40 to 80%. The concentrations of plasma gelsolin used approximate the ~2–3 μM concentrations in plasma, and the molar excess of pGSN over PAF is probably greater in biological systems, where PAF has nanomolar affinity for its receptor. pGSN also inhibited PAF-induced superoxide anion (O2-) production (measured by chemiluminescence) of human neutrophils (PMN) in a concentration-dependent manner. The inhibition was up to 80% at a concentration of 10 μM (tenfold molar excess over PAF). A phospholipid-binding peptide derived from pGSN (QRLFQVKGRR) also inhibited PAF-mediated O2- generation by PMN. The inhibition was 65% at a 1:1 molar ratio (1 μM). In conclusion pGSN interferes with PAF-induced cellular activation in vitro, suggesting a mechanism for the protective role of plasma gelsolin that has been observed in vivo.

scholarly journals Intravenous immunoglobulin preparations induce mild activation of neutrophils in vivo via triggering of macrophages - studies in a rat model

2001 ◽  
Vol 112 (4) ◽  
pp. 1031-1040 ◽  
Author(s):  
Jessica L. Teeling ◽  
Wim K. Bleeker ◽  
Gemma M. M. Rigter ◽  
Nico Van Rooijen ◽  
Taco W. Kuijpers ◽  
...  
Keyword(s):  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Immunoglobulin Preparations

scholarly journals Potential cardioprotective peptides generated in Spanish dry-cured ham

2019 ◽  
Vol 6 ◽  
Author(s):  
Marta Gallego ◽  
Leticia Mora ◽  
Fidel Toldrá
Keyword(s):  
Cardiovascular Health ◽  
Platelet Activating Factor ◽  
Developed Countries ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Angiotensin I Converting Enzyme ◽  
Lipoxygenase Inhibition ◽  
Dry Cured Ham ◽  
Anti Inflammatory

Food-derived bioactive peptides are promising compounds for the prevention and treatment of cardiovascular diseases, the main cause of mortality in developed countries. The aim of this work was to determine the in vitro anti-inflammatory, antioxidant, and angiotensin I-converting enzyme (ACE-I) inhibitory activities of twenty-four peptides that were identified in Spanish dry-cured hams. For the first time, some peptides such as PSNPP, HCNKKYRSEM and FNMPLTIRITPGSKA showed anti-inflammatory activity expressed as platelet-activating factor-acetylhydrolase, autotaxin, and lipoxygenase inhibition. Peptides MDPKYR and TKYRVP were the strongest antioxidants, whereas GGVPGG, TKYRVP, and HCNKKYRSEM showed the highest ACE-I inhibitory activity. Additionally, several peptides such as KPVAAP, MDPKYR, TKYRVP, and HCNKKYRSEM presented more than one of the assayed activities, increasing their health-enhancing potential. More studies are needed to evaluate the bioavailability of such peptides and their in vivo effect. This would contribute to consider dry-cured ham as a source of peptides beneficial for cardiovascular health.

scholarly journals Identification and characterization of specific receptors for monocyte-derived neutrophil chemotactic factor (MDNCF) on human neutrophils.

1989 ◽  
Vol 169 (3) ◽  
pp. 1185-1189 ◽  
Author(s):  
A K Samanta ◽  
J J Oppenheim ◽  
K Matsushima
Keyword(s):  
Human Peripheral Blood ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Chemotactic Factor ◽  
Single Type ◽  
Human Neutrophils ◽  
Scatchard Analysis ◽  
Specific Receptors ◽  
Neutrophil Chemotactic Factor

Specific receptors for a recently purified and cloned monocyte-derived neutrophil chemotactic factor (MDNCF) have been identified on the surface of normal human peripheral blood neutrophils using 125I-labeled recombinant human MDNCF (125I-MDNCF). Competitive binding of 125I-MDNCF to human neutrophils reached a maximal level at 1-3 h at 4 degrees C. The Scatchard analysis showed that there are approximately 20,000 receptors per cell with a single type of high affinity binding (Kd, 8 x 10(-10) M). The receptors for MDNCF are clearly distinct from the receptors for other cytokines and chemotactic agents, e.g., IL-1 alpha, TNF-alpha, and FMLP, C5a, leukotriene B4, and platelet activating factor. Based on the SDS-PAGE analysis of chemically crosslinked 125I-MDNCF receptor complex, there are two polypeptides that bind MDNCF; the molecular weight of these two MDNCF receptors were estimated to be 67,000 and 59,000. Treatment of a promyelocytic cell line, HL60, with 1.25% DMSO for 5 d in vitro increased the number of receptors up to 7,000 receptors/cell with a Kd of 1.2 x 10(-9) M.

scholarly journals The effect of intravenous immunoglobulin on the in vitro function of human neutrophils

1989 ◽  
Vol 18 (2) ◽  
pp. 97-105
Author(s):  
John W.M. Lawton ◽  
J.Paul Robinson ◽  
Gerd O. Till
Keyword(s):  
Intravenous Immunoglobulin ◽  
Human Neutrophils

scholarly journals Protection against Oxidative Stress-induced Hepatic Injury by Intracellular Type II Platelet-activating Factor Acetylhydrolase by Metabolism of Oxidized Phospholipids in Vivo

2007 ◽  
Vol 283 (3) ◽  
pp. 1628-1636 ◽  
Author(s):  
Nozomu Kono ◽  
Takao Inoue ◽  
Yasukazu Yoshida ◽  
Hiroyuki Sato ◽  
Tomokazu Matsusue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatic Injury ◽  
Platelet Activating Factor ◽  
Type Ii ◽  
Oxidized Phospholipids ◽  
Wild Type ◽  
Membrane Phospholipids ◽  
Platelet Activating Factor Acetylhydrolase

Membrane phospholipids are susceptible to oxidation, which is involved in various pathological processes such as inflammation, atherogenesis, neurodegeneration, and aging. One enzyme that may help to remove oxidized phospholipids from cells is intracellular type II platelet-activating factor acetylhydrolase (PAF-AH (II)), which hydrolyzes oxidatively fragmented fatty acyl chains attached to phospholipids. Overexpression of PAF-AH (II) in cells or tissues was previously shown to suppress oxidative stress-induced cell death. In this study we investigated the functions of PAF-AH (II) by generating PAF-AH (II)-deficient (Pafah2-/-) mice. PAF-AH (II) was predominantly expressed in epithelial cells such as kidney proximal and distal tubules, intestinal column epithelium, and hepatocytes. Although PAF-AH activity was almost abolished in the liver and kidney of Pafah2-/- mice, Pafah2-/- mice developed normally and were phenotypically indistinguishable from wild-type mice. However, mouse embryonic fibroblasts derived from Pafah2-/- mice were more sensitive to tert-butylhydroperoxide treatment than those derived from wild-type mice. When carbon tetrachloride (CCl4) was injected into mice, Pafah2-/- mice showed a delay in hepatic injury recovery. Moreover, after CCl4 administration, liver levels of the esterified form of 8-iso-PGF2α, a known in vitro substrate of PAF-AH (II), were higher in Pafah2-/- mice than in wild-type mice. These results indicate that PAF-AH (II) is involved in the metabolism of esterified 8-isoprostaglandin F2α and protects tissue from oxidative stress-induced injury.

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