The Rho-related GTPase Rac2 is essential for regulation of neutrophil azurophilic granule release

The eicosanoid lipoxin A4(LXA4) is biosynthesized in vivo by cells present at inflammatory sites and appears to be an endogenous anti-inflammatory mediator. Further, in the presence of aspirin, the 15-epimer of LXA4(15-epi-LXA4) is biosynthesized and may mediate some of aspirin’s desirable bioactions. LXA4, 15-epi-LXA4, and their stable analogs inhibit inflammation in established animal models, indicating that these compounds may be useful for treating inflammatory disease states. To investigate the cellular mechanisms by which these lipid mediators downregulate inflammation, we investigated whether these eicosanoids could influence receptor-mediated degranulation of human neutrophils, an event thought to play a major causative role in several inflammatory disease states. LXA4, 15-epi-LXA4, and their stable analogs potently (IC50< 1 nM) and selectively downregulated neutrophil release of azurophilic granule contents but did not affect other neutrophil secretory functions. Thus the cellular basis of action of these natural off-switches to inflammation appears to involve downregulation of neutrophil azurophilic granule release.

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Tumor-specific regulatory T cells suppress lytic granule release of adoptively transferred cytotoxic effector T cells and inhibit tumor rejection

Zeitschrift für Gastroenterologie ◽

10.1055/s-0029-1241604 ◽

2009 ◽

Vol 47 (09) ◽

Author(s):

C Bauer ◽

F Marangoni ◽

T Murooka ◽

N Elpak ◽

TR Mempel

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Effector T Cells ◽

Tumor Rejection ◽

Lytic Granule ◽

Cytotoxic Effector ◽

Granule Release

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Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647030 ◽

1988 ◽

Vol 60 (02) ◽

pp. 205-208 ◽

Cited By ~ 21

Author(s):

Paul A Kyrle ◽

Felix Stockenhuber ◽

Brigitte Brenner ◽

Heinz Gössinger ◽

Christian Korninger ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Blood Clotting ◽

Normal Subjects ◽

Chronic Uraemia ◽

Wall Interaction ◽

End Stage ◽

Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

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Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651063 ◽

1987 ◽

Vol 57 (01) ◽

pp. 062-066 ◽

Cited By ~ 36

Author(s):

P A Kyrle ◽

J Westwick ◽

M F Scully ◽

V V Kakkar ◽

G P Lewis

Keyword(s):

Platelet Activation ◽

Thrombin Generation ◽

Low Dose ◽

Bleeding Time ◽

Blood Platelets ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Plug Formation ◽

Granule Release

SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

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Different Abilities of Thrombin Receptor Activating Peptide and Thrombin to Induce Platelet Calcium Rise and Full Release Reaction

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649934 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1323-1328 ◽

Cited By ~ 15

Author(s):

Dominique Lasne ◽

José Donato ◽

Hervé Falet ◽

Francine Rendu

Keyword(s):

Essential Role ◽

Calcium Influx ◽

Dense Granule ◽

Receptor Interaction ◽

Thrombin Receptor ◽

Release Reaction ◽

External Calcium ◽

Maximum Rise ◽

Granule Release

SummarySynthetic peptides (TRAP or Thrombin Receptor Activating Peptide) corresponding to at least the first five aminoacids of the new N-terminal tail generated after thrombin proteolysis of its receptor are effective to mimic thrombin. We have studied two different TRAPs (SFLLR, and SFLLRN) in their effectiveness to induce the different platelet responses in comparison with thrombin. Using Indo-1/AM- labelled platelets, the maximum rise in cytoplasmic ionized calcium was lower with TRAPs than with thrombin. At threshold concentrations allowing maximal aggregation (50 μM SFLLR, 5 μM SFLLRN and 1 nM thrombin) the TRAPs-induced release reaction was about the same level as with thrombin, except when external calcium was removed by addition of 1 mM EDTA. In these conditions, the dense granule release induced by TRAPs was reduced by over 60%, that of lysosome release by 75%, compared to only 15% of reduction in the presence of thrombin. Thus calcium influx was more important for TRAPs-induced release than for thrombin-induced release. At strong concentrations giving maximal aggregation and release in the absence of secondary mediators (by pretreatment with ADP scavengers plus aspirin), SFLLRN mobilized less calcium, with a fast return towards the basal level and induced smaller lysosome release than did thrombin. The results further demonstrate the essential role of external calcium in triggering sustained and full platelet responses, and emphasize the major difference between TRAP and thrombin in mobilizing [Ca2+]j. Thus, apart from the proteolysis of the seven transmembrane receptor, another thrombin binding site or thrombin receptor interaction is required to obtain full and complete responses.

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The Effect of Antiplatelet Drugs on Plasma Betathromboglobulin in Coronary Artery Disease

10.1055/s-0038-1665677 ◽

1979 ◽

Cited By ~ 1

Author(s):

P Han ◽

A Turpie ◽

E Genton ◽

M Gent

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Crossover Trial ◽

Specific Protein ◽

Antiplatelet Drugs ◽

Significant Difference ◽

Pre Treatment ◽

Artery Disease ◽

Therapeutic Doses ◽

Granule Release

Platelets play a role in the development and complications of coronary artery disease (CAD) and a number of abnormalities of platelet function which can be corrected by antiplatelet drugs have been described. Betathromboglobulin (BTG), a platelet-specific protein which is released from α-granules during platelet activation is significantly elevated in patients with angiographically demonstrated CAD (51.0 ± 31.0 ng/ml., n = 50) compared to normal (28.0 ± 8.0 ng/ml., n = 70) p < 0.001. The effect of sulphinpyrazone (800 mg.) or aspirin (1200 mg.)/dipyridamole (200 mg.) on plasma BTG in CAD was studied in a blind prospective crossover trial in 25 patients. Mean BTG concentration pre-treatment was 52.3 ng/ml. and after 1 month’s treatment with placebo, sulphinpyrazone or aspirin/dipyridamole mean plasma BTG concentrations were 53.5, 49.6 and 56.7 ng/ml. respectively. Analysis of variance showed no significant difference between the means (p > 0.1) . This study confirms increased plasma BTG concentrations in patients with CAD and indicates that therapeutic doses of these antiplatelet drugs do not significantly effect the BTG level and thus appear not to prevent α-granule release in CAD.

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Detection of Enhanced In Vivo Platelet α-Granule Release in Different Patient Groups - Comparison of β-Thromboglobulin, Platelet Factor 4 and Thrombospondin Assays

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661168 ◽

1984 ◽

Vol 52 (02) ◽

pp. 183-187 ◽

Cited By ~ 31

Author(s):

D A Lane ◽

H Ireland ◽

S Wolff ◽

E Ranasinghe ◽

J Dawes

Keyword(s):

Platelet Factor 4 ◽

Renal Elimination ◽

Elevated Plasma ◽

Platelet Factor ◽

Release Reaction ◽

Heparin Anticoagulation ◽

Patient Groups ◽

Granule Release ◽

Sensitive Marker

SummaryDuring the platelet release reaction β-thromboglobulin (βTG), platelet factor 4 (PF4) and thrombospondin (TSP) are released from the platelet into plasma and assays of these proteins can be used to monitor in vivo platelet activation. We have assessed their relative merits as markers of the in vivo platelet α-granule release reaction in a number of patient groups which have previously been shown to have elevated plasma βTG and/or PF4 levels. It is concluded that in diseases or conditions not complicated by its reduced clearance, βTG is the most sensitive marker of in vivo platelet α-granule release. However, the TSP assay may be the least ambiguous when monitoring the platelet α-granule release reaction in patients with renal failure who are undergoing haemodialysis with heparin anticoagulation. Under these circumstances plasma βTG, but not PF4 or TSP, levels are elevated because of impaired renal catabolism, and the presence of a heparin-releasable reservoir of PF4 on the endothelium complicates the use of the PF4 assay. In liver failure none of these assays may accurately reflect platelet α-granule release because of impaired hepatic or renal elimination of the proteins.

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Progress on the Mechanism for Aspirin’s Anti-tumor Effects

Current Drug Targets ◽

10.2174/1389450121999201013152931 ◽

2020 ◽

Vol 22 (1) ◽

pp. 105-111

Author(s):

Lin Zheng ◽

Weibiao Lv ◽

Yuanqing Zhou ◽

Xu Lin ◽

Jie Yao

Keyword(s):

Platelet Aggregation ◽

Energy Metabolism ◽

Side Effects ◽

Energy Production ◽

Immune Escape ◽

Inflammatory Responses ◽

Mechanisms Of Action ◽

Proliferation And Metastasis ◽

Review Current ◽

Granule Release

: Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review current insights of aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant of aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investi-gations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

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DISTRIBUTION OF NEUROSECRETORY GRANULES AMONG THE ANATOMICAL COMPARTMENTS OF THE NEUROSECRETORY PROCESSES OF THE PITUITARY GLAND: A QUANTITATIVE ULTRASTRUCTURAL APPROACH TO HORMONE STORAGE IN THE NEURAL LOBE

Journal of Endocrinology ◽

10.1677/joe.0.0680225 ◽

1976 ◽

Vol 68 (2) ◽

pp. 225-NP ◽

Cited By ~ 39

Author(s):

J. F. MORRIS

Keyword(s):

Basement Membrane ◽

Pituitary Gland ◽

Neurosecretory Granules ◽

Neural Lobe ◽

Releasable Pool ◽

Readily Releasable Pool ◽

Rat Pituitary ◽

Axonal Swellings ◽

Granule Release

SUMMARY The distribution of neurosecretory granules in various anatomical compartments of neurosecretory axons of the neural lobe of the rat pituitary has been studied. Apart from the most anterior tip of the gland, where granules are largely restricted to undilated axons and a few 'swellings', the proportional compartmental storage of granules is essentially homogeneous for the rest of the gland: 13% of granules are found in undilated axons, 31% in axonal 'endings' (which contain microvesicles and abut the basement membrane) and 55% in axonal 'swellings' (which are devoid of significant numbers of microvesicles). These values indicate that the 'endings' contain a much greater proportion of the total number of granules stored in the neural lobe than would be predicted if the readily releasable pool of hormone were composed of all the granules in the 'endings'. Some further constraint on granule release either physiological or anatomical (e.g. the position of the granule in relation to the plasmalemma of the 'ending') must be operative.

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