A comparison of the actions of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse

1993 ◽  
Vol 16 (4) ◽  
pp. 477-487 ◽  
Author(s):  
A. P. FOSTER ◽  
F. M. CUNNINGHAM ◽  
M.J. ANDREWS ◽  
P. LEES
Keyword(s):  
Platelet Activating Factor ◽  
Paf Antagonists ◽  
Web 2086

Platelet-activating factor-antagonists reduce implantation in mice at low doses only

1995 ◽  
Vol 7 (1) ◽  
pp. 51 ◽  
Author(s):  
C O'Neill
Keyword(s):  
Early Pregnancy ◽  
Embryo Implantation ◽  
Platelet Activating Factor ◽  
Implantation Rate ◽  
Corpora Lutea ◽  
Detailed Knowledge ◽  
Low Doses ◽  
Paf Antagonists ◽  
Implantation Sites ◽  
Web 2086

The effects of a number of platelet-activating factor (PAF)-antagonists on embryo implantation were investigated. Mice were treated from Day 1 to Day 4 of pregnancy with three defined PAF-antagonists: SRI 63 441, BN 52021, and WEB 2086. Necroscopies were performed on Day 8 and the number of implantation sites, the implantation rate (number of implanted embryos compared with the number of corpora lutea) and the proportion of animals pregnant were determined. Each agent caused a reduction in the number of implantation sites at relatively low doses. The dose that had a maximum contragestational effect was 40 micrograms, 10 micrograms and 10 micrograms (per 30 g bodyweight per day) for SRI 63 441, WEB 2086 and BN 52021 respectively. This contragestational effect was completely lost at twice (SRI 63 441), five times (WEB 2086) and ten times (BN 52021) the most effective dose. Treatment with WEB 2086 on the day of implantation (Day 4) by intraperitoneal injection or instillation into the uterus only did not significantly reduce the implantation rate and neither did treatment after implantation (Days 5-8). The results show that the pharmacology of PAF-antagonists in early pregnancy is not simple. An understanding of the actions of these agents in early pregnancy will require a detailed knowledge of their pharmacokinetics, pharmacodynamics and targets of action in early pregnancy.

PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension

1991 ◽  
Vol 71 (6) ◽  
pp. 2483-2492 ◽  
Author(s):  
S. Ono ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Platelet Activating Factor ◽  
Lipid Mediators ◽  
Right Ventricular Hypertrophy ◽  
Vascular Leak ◽  
Paf Antagonists ◽  
Web 2086

Lung platelet-activating factor (PAF) levels increased in some rats at 1–3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.

Pulmonary vascular reactivity: effect of PAF and PAF antagonists

1992 ◽  
Vol 73 (5) ◽  
pp. 1762-1769 ◽  
Author(s):  
C. R. Chen ◽  
N. F. Voelkel ◽  
S. W. Chang
Keyword(s):  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Platelet Activating Factor ◽  
Lung Edema ◽  
Physiological Salt Solution ◽  
Similar Response ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Paf Antagonists ◽  
Web 2086

We investigated the effects of two different platelet-activating factor (PAF) antagonists, SRI 63–441 and WEB 2086, on PAF-, angiotensin II-, and hypoxia-induced vasoconstrictions in isolated rat lungs perfused with a physiological salt solution. Bolus injection of PAF (0.5 micrograms) increased pulmonary arterial and microvascular pressures and caused lung edema. Both SRI 63–441, a PAF-analogue antagonist, and WEB 2086, a thienotriazolodiazepine structurally unrelated to PAF, completely blocked PAF-induced vasoconstriction and lung edema at 10(-5) M. At a lower concentration (10(-6) M), WEB 2086 was more effective than SRI 63–441. WEB 2086 also blocked the pulmonary vasodilation induced by low-dose PAF (15 ng) in blood-perfused lungs preconstricted with hypoxia. SRI 63–441 and CV 3988 (another PAF analogue antagonist), but not WEB 2086, caused acute pulmonary vasoconstriction at 10(-5) M and severe lung edema at a higher concentration (10(-4) M). PAF-induced but not SRI- or CV-induced pulmonary vasoconstriction and edema were inhibited by WEB 2086. In addition, SRI 63–441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions. This effect of SRI 63-441 is not due to PAF receptor blockade because 1) addition of PAF (1.6 nM) to the perfusate likewise potentiated angiotensin II-induced vasoconstriction and 2) WEB 2086 did not cause a similar response. We conclude that both SRI 63–441 and WEB 2086 are effective inhibitors of PAF actions in the rat pulmonary circulation. However, antagonists with structures analogous to PAF (SRI 63–441 and CV 3988) can have significant pulmonary vasoactive side effects.

The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma.

1994 ◽  
Vol 149 (5) ◽  
pp. 1142-1148 ◽  
Author(s):  
D P Spence ◽  
S L Johnston ◽  
P M Calverley ◽  
P Dhillon ◽  
C Higgins ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Orally Active ◽  
Factor Antagonist ◽  
Web 2086

Platelet-activating factor contributes to acute lung leak in rats given interleukin-1 intratracheally

2000 ◽  
Vol 279 (1) ◽  
pp. L75-L80 ◽  
Author(s):  
Young M. Lee ◽  
Brooks M. Hybertson ◽  
Hyun G. Cho ◽  
Lance S. Terada ◽  
Okyong Cho ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Platelet Activating Factor ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Myeloperoxidase Activity ◽  
Cerium Chloride ◽  
Neutrophil Accumulation ◽  
Web 2086

Lung lavage fluid of patients with acute lung injury (ALI) has increased levels of interleukin-1 (IL-1) and neutrophils, but their relationship to the lung leak that characterizes these patients is unclear. To address this concern, we investigated the role of the neutrophil agonist platelet-activating factor [1- O-alkyl-2-acetyl- sn-glycero-3-phosphocholine (PAF)] in the development of the acute neutrophil-dependent lung leak that is induced by giving IL-1 intratracheally to rats. We found that PAF acetyltransferase and PAF activities increased in lungs of rats given IL-1 intratracheally compared with lungs of sham-treated rats given saline intratracheally. The participation of PAF in the development of lung leak and lung neutrophil accumulation after IL-1 administration was suggested when treatment with WEB-2086, a commonly used PAF-receptor antagonist, decreased lung leak, lung myeloperoxidase activity, and lung lavage fluid neutrophil increases in rats given IL-1 intratracheally. Additionally, neutrophils recovered from the lung lavage fluid of rats given IL-1 intratracheally reduced more nitro blue tetrazolium (NBT) in vitro than neutrophils recovered from control rats or rats that had been given WEB-2086 and then IL-1. Histological examination indicated that the endothelial cell-neutrophil interfaces of cerium chloride-stained lung sections of rats given IL-1 contained increased cerium perhydroxide (the reaction product of cerium chloride with hydrogen peroxide) compared with lungs of control rats or rats treated with WEB-2086 and then given IL-1 intratracheally. These in vivo findings were supported by parallel findings showing that WEB-2086 treatment decreased neutrophil adhesion to IL-1-treated cultured endothelial cells in vitro. We concluded that PAF contributes to neutrophil recruitment and neutrophil activation in lungs of rats given IL-1 intratracheally.

scholarly journals Regulation of Immunoglobulin G2 Production by Prostaglandin E2 and Platelet-Activating Factor

2000 ◽  
Vol 68 (3) ◽  
pp. 1563-1568 ◽  
Author(s):  
Yuichi Ishihara ◽  
Ji-Bo Zhang ◽  
Steve M. Quinn ◽  
Harvey A. Schenkein ◽  
Al M. Best ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Platelet Activating Factor ◽  
Pokeweed Mitogen ◽  
Cell Contact ◽  
Blood Leukocytes ◽  
Secreted Factors ◽  
Paf Antagonists ◽  
Localized Juvenile Periodontitis ◽  
Positive Regulators

ABSTRACT Patients with localized juvenile periodontitis (LJP) have elevated levels of immunoglobulin G2 (IgG2) in their sera. This is also observed in vitro when peripheral blood leukocytes from LJP patients are stimulated with pokeweed mitogen. In previous studies, we showed that lymphocytes from subjects with no periodontitis (NP subjects) produced substantial amounts of IgG2 when they were cultured with monocytes from LJP patients (LJP monocytes). These observations indicate that monocytes or monocyte-derived mediators are positive regulators of the production of IgG2. The present study was initiated to determine if secreted factors from LJP monocytes were capable of enhancing IgG2 production and to determine if prostaglandin E2 (PGE2), which LJP monocytes produce at elevated levels, enhances IgG2 production. Experiments in a transwell system and with monocyte-conditioned media indicated that cell-cell contact was not necessary for LJP monocytes to augment the production of IgG2 by T and B cells from NP subjects. Moreover, the production of IgG2 was selectively induced by the addition of PGE2 or platelet-activating factor (PAF), another lipid cytokine, which can elevate PGE2 synthesis. Furthermore, IgG2 production was abrogated when cells were treated with indomethacin, a cyclooxygenase inhibitor that blocks the synthesis of PGE2, or the PAF antagonists CV3988 and TEPC-15. The effects of indomethacin were completely reversed by PGE2, indicating that this is the only prostanoid that is essential for the production of IgG2. Similarly, PGE2 reversed the effects of a PAF antagonist, suggesting that the effects of PAF are mediated through the induction of PGE2 synthesis. Together, these data indicate that PGE2 and PAF are essential for the production of IgG2.

scholarly journals Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2Catalytic Subunit

2004 ◽  
Vol 279 (50) ◽  
pp. 52425-52436 ◽  
Author(s):  
Fanny Bonin ◽  
Scott D. Ryan ◽  
Lamiaa Migahed ◽  
Fan Mo ◽  
Jessica Lallier ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Platelet Activating Factor ◽  
Cell Loss ◽  
Catalytic Subunits ◽  
Physiological Conditions ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Important Mediator ◽  
Apoptotic Protein ◽  
Paf Antagonists ◽  
Paf Receptor

Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by ∼15 pm/cell for 60 min. Reducing cytosolic PAF to less than 10 pm/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I α1regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I α2expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I α2homodimer activity by reducing PAF-AH I α1expression. These findings identify PAF-AH I α2as a potent anti-apoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.

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