Role of thromboxane A2 in airway microvascular leakage induced by inhaled platelet-activating factor

1991 ◽  
Vol 71 (5) ◽  
pp. 1729-1734 ◽  
Author(s):  
K. Tokuyama ◽  
J. O. Lotvall ◽  
A. Morikawa ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airflow Obstruction ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Blue Dye ◽  
Dependent Manner ◽  
Thromboxane A2 Receptor ◽  
Microvascular Leakage ◽  
Thromboxane Synthase Inhibitor ◽  
Synthase Inhibitor

We studied the effects of OKY-046 (1, 10, and 30 mg/kg iv), a selective thromboxane synthase inhibitor, and of ICI 192605 (0.5 mg/kg), a selective thromboxane A2 receptor antagonist, on airflow obstruction and airway microvascular leakage induced by inhaled platelet-activating factor (PAF). Extravasated Evans blue dye content was measured as a reflection of airway microvascular leakage. In control animals, PAF caused a significantly higher increase in extravasation of dye and significantly less increase in lung resistance (RL) than histamine. OKY-046 significantly inhibited both changes in RL and airway microvascular leakage after PAF in a dose-dependent manner, whereas it inhibited histamine-induced airway microvascular leakage only at main bronchi, without any significant effect on RL. ICI 192605 significantly inhibited both RL and airway microvascular leakage induced by PAF, but not after histamine. After both PAF and histamine, changes in RL correlated significantly with the degree of microvascular leakage. Airway microvascular leakage and airflow obstruction after PAF, but not after histamine, may be dependent on thromboxane A2 generation.

The Endocannabinoid 2-Arachidonoylglycerol Regulates Platelet Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3904-3904
Author(s):  
Samantha Baldassarri ◽  
Alessandra Bertoni ◽  
Paolo Lova ◽  
Stefania Reineri ◽  
Chiara Sarasso ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Cannabinoid Receptors ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
Dependent Manner ◽  
Cb2 Receptor ◽  
Thromboxane A2 Receptor

Abstract 2-Arachidonoylglycerol (2-AG) is a naturally occurring monoglyceride that activates cannabinoid receptors and meets several key requisites of an endogenous cannabinoid substance. It is present in the brain and hematopoietic cells, including macrophages, lymphocytes and platelets. 2-AG is released from cells in a stimulus-dependent manner and is rapidly eliminated by uptake into cells and enzymatic hydrolysis in arachidonic acid and glycerol. 2-AG might exert a very fine control on platelet function either through mechanisms intertwining with the signal transduction pathways used by platelet agonists or through mechanisms modulating specific receptors. The aim of this study was to define the role of 2-AG in human platelets and characterize the mechanisms by which it performs its action. Platelets from healthy donors were isolated from plasma by differential centrifugations and gel-filtration on Sepharose 2B. The samples were incubated with 2-AG (10–100 μM) under constant stirring in the presence or absence of various inhibitors. Platelet aggregation was measured by Born technique. We have found that stimulation of human platelets with 2-AG induced irreversible aggregation, which was significantly enhanced by co-stimulation with ADP (1–10 μM). Furthermore, 2-AG-dependent platelet aggregation was completely inhibited by ADP scavengers, aspirin, and Rho kinase inhibitor, as well as by antagonists of the 2-AG receptor (CB2), of the ADP P2Y12 receptor, and of the thromboxane A2 receptor. We further investigated the role of endocannabinoids on calcium mobilization. Intracellular [Ca2+] was measured using FURA-2-loaded platelets prewarmed at 37°C under gentle stirring in a spectrofluorimeter. 2-AG induced rapid increase of cytosolic [Ca2+] in a dose-dependent manner. This effect was partially blocked by ADP scavengers and CB2 receptor antagonists. Furthermore, 2-AG-induced [Ca2+] mobilization was totally suppressed by aspirin or the thromboxane A2 receptor antagonist. These results suggest that 2-AG is able to trigger platelet activation, and that this action is partially mediated by CB2 receptor and ADP. Furthmore, 2-AG-dependent platelet activation is totally dependent on thromboxane A2 generation.

Acute effects of prostaglandin D2 to induce airflow obstruction and airway microvascular leakage in guinea pigs: role of thromboxane A2 receptors

2001 ◽  
Vol 66 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Hideko Nishimura ◽  
Kenichi Tokuyama ◽  
Yoshinari Inoue ◽  
Hirokazu Arakawa ◽  
Masahiko Kato ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Airflow Obstruction ◽  
Thromboxane A2 ◽  
Prostaglandin D2 ◽  
Acute Effects ◽  
Microvascular Leakage ◽  
A2 Receptors

Platelet Aggregation in Whole Blood: The Role of Thromboxane A2 and Adenosine Diphosphate

1985 ◽  
Vol 54 (03) ◽  
pp. 612-616 ◽  
Author(s):  
A J Carter ◽  
S Heptinstall
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Adenosine Diphosphate ◽  
Blood Platelet ◽  
Thromboxane B2 ◽  
Lipoxygenase Inhibitor ◽  
Thromboxane Synthase Inhibitor ◽  
Synthase Inhibitor

SummaryThe platelet aggregation that occurred in whole blood in response to several aggregating agents (collagen, arachidonic acid, adenosine diphosphate, adrenaline and thrombin) was measured using an Ultra-Flo 100 Whole Blood Platelet Counter. The amounts of thromboxane B2 produced were measured by radioimmunoassay. The effects of various inhibitors of thromboxane synthesis and the effects of apyrase, an enzyme that destroys adenosine diphosphate, were determined.Platelet aggregation was always accompanied by the production of thromboxane B2, and the amounts produced depended on the nature and concentration of the aggregating agent used. The various inhibitors of thromboxane synthesis - aspirin and flurbiprofen (cyclo-oxygenase inhibitors), BW755C (a cyclo-oxygenase and lipoxygenase inhibitor) and dazoxiben (a selective thromboxane synthase inhibitor) - did not markedly inhibit aggregation. Results obtained using apyrase showed that adenosine diphosphate contributed to the aggregation process, and that its role must be acknowledged when devising means of inhibiting platelet aggregation in vivo.

CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling

2021 ◽  
Author(s):  
Lingfeng Qin ◽  
Haifeng Zhang ◽  
Busu Li ◽  
Quan Jiang ◽  
Francesc Lopez ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Fluorescein Isothiocyanate ◽  
The Body ◽  
Blue Dye ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Cavernous Malformations ◽  
Morphological Alterations ◽  
The Brain

Objective: Cerebral cavernous malformations (CCMs) can happen anywhere in the body, although they most commonly produce symptoms in the brain. The role of CCM genes in other vascular beds outside the brain and retina is not well-examined, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in lymphatics. Approach and Results: Mice with an inducible pan–endothelial cell (EC) or lymphatic EC deletion of Ccm3 ( Pdcd10 ECKO or Pdcd10 LECKO ) exhibit dilated lymphatic capillaries and collecting vessels with abnormal valve structure. Morphological alterations were correlated with lymphatic dysfunction in Pdcd10 LECKO mice as determined by Evans blue dye and fluorescein isothiocyanate(FITC)-dextran transport assays. Pdcd10 LECKO lymphatics had increased VEGFR3 (vascular endothelial growth factor receptor-3)-ERK1/2 signaling with lymphatic hyperplasia. Mechanistic studies suggested that VEGFR3 is primarily regulated at a transcriptional level in Ccm3-deficient lymphatic ECs, in an NF-κB (nuclear factor κB)–dependent manner. CCM3 binds to importin alpha 2/KPNA2 (karyopherin subunit alpha 2), and a CCM3 deletion releases KPNA2 to activate NF-κB P65 by facilitating its nuclear translocation and P65-dependent VEGFR3 transcription. Moreover, increased VEGFR3 in lymphatic EC preferentially activates ERK1/2 signaling, which is critical for lymphatic EC proliferation. Importantly, inhibition of VEGFR3 or ERK1/2 rescued the lymphatic defects in structure and function. Conclusions: Our data demonstrate that CCM3 deletion augments the VEGFR3-ERK1/2 signaling in lymphatic EC that drives lymphatic hyperplasia and malformation and warrant further investigation on the potential clinical relevance of lymphatic dysfunction in patients with CCM.

EFFECTIVENESS AND TOLERABILITY OF CV-3988, A SELECTIVE PAF ANTAGONIST, AFTER INTRAVENOUS ADMINISTRATION TO MAN

1987 ◽  
Author(s):  
J Arnout ◽  
A Van Hecken ◽  
I Delepeleire ◽  
Y Miyamoto ◽  
I Holmes ◽  
...  
Keyword(s):  
Light Transmission ◽  
Platelet Rich Plasma ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Platelet Activating Factor ◽  
Controlled Study ◽  
Dependent Manner ◽  
Double Blind ◽  
Health And Disease

Platelet activating factor (PAF) is a naturally occurring phospholipid with a wide spectrum of biological activities. Although PAF has been ascribed a potential role in various conditions including inflammation, asthma, glomerulonephritis and thrombosis, its precise function in physiologic/pathophysiologic processes remains unclear. The introduction of selective PAF receptor antagonists could represent a useful tool to extend our knowledge of the role of this mediator in health and disease.We have investigated the efficacy and tolerability of (RS)-2-methoxy-3-(octadecylcarbomoyloxy)propy1 2-(3-thiazolio)-ethyIphosphate (CV-3988, Takeda Chem. Ind), a selective PAF antagonist with structural analogies with PAF, after intravenous infusion in man in a double-blind, placebo-controlled study. The compound, in doses from 750 to 2,000 pg/kg, significantly reduced platelet sensitivity to PAF. The threshold aggregating concentration (TAC) of PAF was defined as the minimal concentration causing an irreversible aggregation with a maximal amplitude of at least 50% of the difference in light transmission between platelet rich plasma and platelet poor plasma. It increased in a dose-dependent manner reaching 3.6 times the basal TAC (p<0.0005) at the end and 2.60 times the basal TAC (p<0.0005) 4 hours after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 hours after the end of the infusion.CV-3988 did not cause major side effects nor changes in blood pressure, pulse or respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and four hours after the end of the infusion, indicating a slight haemolysis probably by high local concentrations at the infusion site.Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can be safely administered to man and should be useful in elucidating the role of PAF in health and disease.

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