Interactions between platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs

The effects of platelet activating factor (PAF) on eicosanoid release during endotoxic shock was investigated in anaesthetized pigs receiving 5 μg kg−1Escherichia coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period, by measuring plasma levels of a variety of mediators. Fifteen of the 31 animals infused with LPS and not treated with BN 52021, a PAF receptor antagonist, died within 30 min after the commencement of LPS infusion (non-survivors), while the other 16 survived the experimental period of 3 h, though in a state of shock (survivors). No alterations were observed in plasma concentrations of eicosanoids in the non-survivors. A significant, though transient, increase in eicosanoid concentrations occurred only in the survivors. Treatment with BN 52021 (4 mg kg-1, i.v.) injected 5 min prior to LPS infusion, failed to exert any effect on the survival rate. However, pretreatment with BN 52021 prevented circulatory collapse in the survivors and reduced the concentration of cyclooxygenase enzyme products, without affecting LTB4release. Exogenous administration of PAF (0.01 μg kg−1) caused hypotension and increased TXB2levels although 6-keto PGF1αand LTB4concentrations were unchanged. The data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by LPS infusion in survivors, and give further support to the suggestion that PAF prostanoid interaction is important during endotoxic shock. However, their role in early death seems to be negligible, indicating the importance of other mediators.

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Platelet-activating factor: an endogenous mediator of mesenteric ischemia-reperfusion-induced shock

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.257.4.r872 ◽

1989 ◽

Vol 257 (4) ◽

pp. R872-R877 ◽

Cited By ~ 2

Author(s):

T. Mozes ◽

P. Braquet ◽

J. Filep

Keyword(s):

Receptor Antagonist ◽

Mesenteric Artery ◽

Superior Mesenteric Vein ◽

Platelet Activating Factor ◽

Artery Occlusion ◽

Circulatory Collapse ◽

Mesenteric Vein ◽

Paf Receptor ◽

Mesenteric Artery Occlusion ◽

Paf Receptor Antagonist

The role of platelet-activating factor (PAF) in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring PAF levels in the superior mesenteric vein during reperfusion after 2-h occlusion of the superior mesenteric artery; by monitoring the effects of BN 52021, a specific PAF receptor antagonist; and by studying the circulatory effects of exogenous PAF injected into the superior mesenteric vein. PAF was measured by a platelet-aggregation assay. Identity of PAF-like bioactivity was ascertained by thin-layer chromatography, high-pressure liquid chromatography, and alkaline treatment. Removal of the superior mesenteric artery occlusion caused an immediate dramatic decrease in mean arterial blood pressure with concomitant increase in mean portal venous pressure and hematocrit values. PAF concentration in the superior mesenteric vein increased from 0.2 +/- 0.1 to 2.8 +/- 0.4 ng/ml (n = 4, P less than 0.05) within the first 5 min of reperfusion. Administration of exogenous PAF (0.1 microgram/kg) injected into the superior mesenteric vein produced similar hemodynamical effects. Pretreatment of the animals with BN 52021 (4 mg/kg), a specific PAF receptor antagonist, prevented the circulatory collapse. The present results suggest that PAF release during intestinal ischemia may play an important role in the development of circulatory collapse caused by mesenteric artery occlusion.

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Role of platelet-activating factor and eicosanoids during endotoxin-induced lung injury in pigs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.258.6.h1674 ◽

1990 ◽

Vol 258 (6) ◽

pp. H1674-H1686 ◽

Cited By ~ 2

Author(s):

N. C. Olson ◽

P. B. Joyce ◽

L. N. Fleisher

Keyword(s):

Lung Injury ◽

Phase I ◽

Receptor Antagonist ◽

Ex Vivo ◽

Plasma Concentrations ◽

Platelet Activating Factor ◽

Calcium Ionophore ◽

Paf Receptor ◽

Paf Receptor Antagonist

We hypothesized that platelet-activating factor (PAF) and eicosanoids might be important mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h, followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. During phase I (i.e., 0-2 h), endotoxin caused pulmonary hypertension and hypoxemia, decreased cardiac index, increased pulmonary vascular resistance, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin (PG)F2 alpha, and 6-keto-PGF1 alpha. These phase I effects were attenuated or blocked by SRI 63-675 (10 mg/kg before endotoxin + 3 mg.kg-1.h-1 during endotoxemia). During phase II endotoxemia (i.e., 2-4 h), the PAF receptor antagonist blocked endotoxin-induced pulmonary edema and hypoxemia and increased relative permeability index of the alveolar-capillary membrane. SRI 63-675 also blocked the endotoxin-induced increases in plasma and bronchoalveolar lavage fluid concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2 and LTB4. These increases were not significantly modified in blood derived from pigs treated with SRI 63-675, indicating no inhibition of cyclooxygenase or 5-lipoxygenase and suggesting that the in vivo effects were PAF receptor mediated. We conclude that PAF plays an important role in the release of eicosanoids during endotoxemia and in mediating, either directly or indirectly, endotoxin-induced lung injury in anesthetized pigs.

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Effects of L-652,731, a platelet activating factor (PAF) receptor antagonist, in splanchnic artery occlusion (SAO) shock in rats

Pharmacological Research ◽

10.1016/1043-6618(90)90804-m ◽

1990 ◽

Vol 22 ◽

pp. 53-54

Author(s):

F SQUADRITO

Keyword(s):

Receptor Antagonist ◽

Platelet Activating Factor ◽

Artery Occlusion ◽

Splanchnic Artery ◽

Paf Receptor ◽

Paf Receptor Antagonist

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Exogenous xanthine promotes neutrophil adherence to cultured endothelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.2.g342 ◽

1997 ◽

Vol 273 (2) ◽

pp. G342-G347

Author(s):

H. Ichikawa ◽

R. E. Wolf ◽

T. Y. Aw ◽

N. Ohno ◽

L. Coe ◽

...

Keyword(s):

Endothelial Cells ◽

Tissue Injury ◽

Umbilical Vein ◽

Platelet Activating Factor ◽

Adhesion Assay ◽

Neutrophil Adherence ◽

Paf Receptor ◽

Umbilical Vein Endothelial Cells ◽

Adhesive Effect ◽

Paf Receptor Antagonist

Oxidants generated by endothelial xanthine oxidase (XO) can help trigger free radical-mediated tissue injury. An important event in oxidant-mediated tissue injury is neutrophil-endothelial adhesion. Although activation of endothelial XO increases adhesion, little is known about xanthine in the adhesive effect of XO. This study examined administered xanthine on the adhesion of neutrophils. Endothelial [human umbilical vein endothelial cells (HUVEC)] monolayers were exposed to xanthine (15 min), and neutrophils were allowed to adhere to HUVEC in an adhesion assay. Adhesion was dose dependently increased by xanthine (3-100 microM). Either catalase (1,000 U/ml), oxypurinol (XO inhibitor; 100 microM), or platelet-activating factor (PAF) receptor antagonist (WEB 2086; 10 microM) reduced neutrophil adhesion. Superoxide dismutase (1,000 U/ml) had no effect. Pretreatment of HUVEC with 50 microM tungsten also blocked xanthine-induced adherence. Adhesion was also inhibited by preincubation with 100 U/ml heparin. Finally, anti-P-selectin antibody (PB1.3; 20 micrograms/ml) attenuated adhesion. Our results indicate that xanthine may promote neutrophil-endothelial adhesion via a hydrogen peroxide- and PAF-mediated P-selectin expression.

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Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Clinical Science ◽

10.1042/cs1000601 ◽

2001 ◽

Vol 100 (6) ◽

pp. 601-607 ◽

Cited By ~ 1

Author(s):

Roger TAYLOR ◽

Daniel FATOVICH ◽

Thomas HITCHCOCK ◽

Catherine MORRISON ◽

Lloyd CURTIS

Keyword(s):

Myocardial Infarction ◽

Blood Pressure ◽

Acute Myocardial Infarction ◽

Receptor Antagonist ◽

Platelet Activating Factor ◽

Systolic Pressure ◽

Induced Hypotension ◽

Paf Receptor ◽

Double Blinded ◽

Paf Receptor Antagonist

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n = 35), or matching placebo (n = 36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5×106 units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43±28 mmHg (mean±S.D.) and 40±26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to < 90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3±17.5 and 40.2±13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

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Effect of PAF receptor antagonism on cardiopulmonary alterations during coinfusion of TNF-alpha and IL-1 alpha in pigs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.264.2.l175 ◽

1993 ◽

Vol 264 (2) ◽

pp. L175-L182 ◽

Cited By ~ 1

Author(s):

K. T. Kruse-Elliott ◽

M. V. Pino ◽

N. C. Olson

Keyword(s):

Vascular Resistance ◽

Interleukin 1 ◽

Plasma Concentrations ◽

Platelet Activating Factor ◽

Physiological Role ◽

Systemic Hypertension ◽

Tnf Alpha ◽

Pulmonary Hemodynamics ◽

Paf Receptor ◽

Web 2086

We examined the possibility that platelet-activating factor (PAF) might be a mediator of cardiopulmonary alterations induced by a 6-h coinfusion of human recombinant tumor necrosis factor (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) in anesthetized pigs. Our hypothesis was tested by pretreating TNF-alpha + IL-1 alpha-infused pigs with WEB 2086 (3 mg/kg from -0.5 to 0 h + 0.75 mg.kg-1.h-1 from 0–6 h), a specific PAF receptor antagonist. Each cytokine was infused intravenously at 0.5 microgram/kg from 0-0.5 h + 5 ng.kg-1.min-1 from 0.5-6 h. WEB 2086 attenuated the early (0.25 h) cytokine-induced increases in mean pulmonary arterial pressure and pulmonary vascular resistance and blocked or markedly attenuated the later occurring (4–6 h) systemic hypertension and increased systemic vascular resistance. WEB 2086 lessened the severity of TNF-alpha + IL-1 alpha-induced hemoconcentration and airway constriction, but did not modify leukopenia, granulocytopenia, or the cytokine-induced increases in plasma concentrations of thromboxane B2, prostaglandin F2 alpha, and 6-ketoprostaglandin F1 alpha. Microscopically, WEB 2086 did not modify the increased number of granulocytes present in lung tissue derived from pigs infused with TNF-alpha + IL-1 alpha. We conclude that PAF occupies a physiological role in modulating TNF-alpha + IL-1 alpha-induced hemoconcentration, the early changes in pulmonary hemodynamics, and the later alterations in systemic hemodynamics.

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Invasion of Human Vascular Endothelial Cells byActinobacillus actinomycetemcomitans via the Receptor for Platelet-Activating Factor

Infection and Immunity ◽

10.1128/iai.68.9.5416-5419.2000 ◽

2000 ◽

Vol 68 (9) ◽

pp. 5416-5419 ◽

Cited By ~ 67

Author(s):

Harvey A. Schenkein ◽

Suzanne E. Barbour ◽

C. R. Berry ◽

Barbara Kipps ◽

John G. Tew

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Platelet Activating Factor ◽

Systemic Circulation ◽

Oral Bacteria ◽

Periodontal Pathogen ◽

Vascular Endothelial ◽

Transmission Electron ◽

Paf Receptor ◽

Paf Receptor Antagonist

ABSTRACT Strains of the periodontal pathogen Actinobacillus actinomycetemcomitans are variable with respect to display of phosphorylcholine (PC)-bearing antigens. We have examined strains ofA. actinomycetemcomitans with and without PC to assess their ability to invade endothelial cells via the receptor for platelet-activating factor (PAF). Results of antibiotic protection assays indicate that PC-bearing A. actinomycetemcomitansinvade human vascular endothelial cells by a mechanism inhibitable by CV3988, a PAF receptor antagonist, and by PAF itself. The invasive phenotype was verified by transmission electron microscopy. A PC-deficient strain of this organism was not invasive. This property, in addition to the established ability of A. actinomycetemcomitans to invade epithelial cells, may provide this organism with access to the systemic circulation. The ability of PC-bearing oral bacteria to access the circulation may also explain the elevated levels of anti-PC antibody in serum found in patients with periodontitis.

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Receptor mechanisms of PAF mediated lymphatic constriction in the canine forelimb

Mediators of Inflammation ◽

10.1155/s0962935192000590 ◽

1992 ◽

Vol 1 (6) ◽

pp. 391-395 ◽

Cited By ~ 3

Author(s):

D. E. Dobbins

Keyword(s):

Smooth Muscle ◽

Receptor Antagonist ◽

Lymphatic Vessel ◽

Perfusion Pressure ◽

Muscle Tone ◽

Platelet Activating Factor ◽

Arterial Infusion ◽

Paf Receptor ◽

Transport Fluid ◽

Paf Receptor Antagonist

Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 × 10−6, 7.47 × 10−5and 7.47 × 10−4M) increased lymphatic perfusion pressure at the two highest infusion rates. PAF mediated lymphatic constriction was not altered by the intra-arterial infusion of phentolamine but was blocked by the intra-arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF's effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by α-receptors but rather through PAF receptor mediated mechanism.

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