scholarly journals Interleukin 3-dependent mediator release in basophils triggered by C5a.

1989 ◽  
Vol 170 (2) ◽  
pp. 467-479 ◽  
Author(s):  
Y Kurimoto ◽  
A L de Weck ◽  
C A Dahinden
Keyword(s):  
Time Course ◽  
Lipid Mediators ◽  
Mediator Release ◽  
Lipid Mediator ◽  
Cell Fractionation ◽  
Leukotriene C4 ◽  
Bioactive Lipids ◽  
Anaphylatoxin C5a ◽  
Dose Dependent

The anaphylatoxin C5a is a potent trigger for basophil degranulations, but in contrast to IgE-dependent basophil activation, it does not result in the synthesis of sulfidoleukotrienes (leukotriene C4/D4/E4). Thus, degranulation and the generation of lipid mediators are separately regulated cellular responses. Exposure of human blood basophils to the cytokine IL-3 alone does not induce the release of histamine in cells from most donors and never leads to the generation of LTC4, indicating that IL-3 is not a direct agonist for basophil mediator release. However, preincubation of basophils with IL-3 enhances the degranulation response to C5a. Most importantly, IL-3 "primes" basophils to release large amounts of leukotriene C4 after challenge with C5a (mean of 50 gp LTC4 per nanograms cellular histamine), while neither peptide alone is capable of inducing the formation of bioactive lipids. This effect is dose dependent, occurring at IL-3 concentrations considerably lower than are required to stimulate the growth of bone marrow progenitor cells. IL-3 affects the extent but not the time course of basophil degranulation, and leukotriene release of cells sequentially exposed to IL-3 and C5a occurs very rapidly concomitant with degranulation. A preincubation of the basophils with IL-3 is strictly required for C5a-induced LTC4 synthesis, but not for an enhancement of degranulation. Priming for C5a-induced lipid mediator generation occurs rapidly after exposure of the cells to IL-3, starting at 1 min and reaching maximal effects at 5 min, but this altered state of responsiveness is relatively long lasting. Cell fractionation studies indicate that the basophil is the source of lipid mediators and that IL-3 affects the basophil response directly. This study demonstrates that IL-3 is a potent modifier of effector functions of mature basophils; this is possibly of greater in vivo significance than its growth factor properties. The large amounts of LTC4 formed after triggering of IL-3-primed basophils may not only enhance but also qualitatively change the pathophysiological consequences of complement activation, and this might be important in the pathogenesis of immediate type hypersensitivity reactions, shock syndromes, and inflammation.

Metabolism and cardiovascular effects of leukotrienes in warm- and cold-acclimated American bullfrogs (Rana catesbeiana)

1991 ◽  
Vol 260 (5) ◽  
pp. R834-R838
Author(s):  
C. A. Herman ◽  
G. A. Charlton ◽  
R. L. Cranfill
Keyword(s):  
Time Course ◽  
Rana Catesbeiana ◽  
Cardiovascular Effects ◽  
Leukotriene C4 ◽  
Gamma Glutamyl Transpeptidase ◽  
Leukotriene D4 ◽  
Inactivation Mechanism ◽  
Glutamyl Transpeptidase

Sulfidopeptide leukotrienes are important mediators in mammals, but much less is known of their metabolism and action in nonmammalian vertebrates. This study examines the cardiovascular effects of leukotrienes on blood pressure and heart rate and compares the metabolism of leukotrienes in vivo and in vitro in warm- and cold-acclimated bullfrogs. Leukotriene C4 (LTC4) is more potent than leukotriene D4 (LTD4) and leukotriene E4 (LTE4) in eliciting hypotension. The leukotrienes are more potent in warm-acclimated animals. Conversion of [3H]LTC4 to [3H]LTD4 occurs rapidly in warm-acclimated bullfrogs, with 15.2 +/- 1.7% of the [3H]LTC4 remaining at 1.5 min. Conversion is slower in vivo in cold-acclimated frogs, with 20.2 +/- 1.7% of the [3H]LTC4 remaining by 6 min. In blood taken from warm-acclimated frogs, conversion of [3H]LTC4 to [3H]LTD4 occurs more rapidly at 22 than at 5 degrees C. This pattern is similar in blood taken from cold-acclimated frogs, suggesting that no modification of gamma-glutamyl transpeptidase occurs at low temperature. [3H]LTE4 production is not observed in vivo or in vitro during the time course of the experiments. The rapid metabolism of LTC4 to LTD4 may represent an inactivation mechanism in amphibians. The cardiovascular effects of LTC4 in vivo may be much greater than current measurements indicate because of rapid conversion of LTC4 to the less potent LTD4.

scholarly journals Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 141
Author(s):  
Anne-Sophie Archambault ◽  
Julyanne Brassard ◽  
Émilie Bernatchez ◽  
Cyril Martin ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Biosynthetic Pathway ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
Eosinophilic Asthma ◽  
Asthmatic Response ◽  
Pharmacological Targets ◽  
Arachidonoyl Glycerol ◽  
Human And Mouse

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

2016 ◽  
Vol 36 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Devyani Swami ◽  
Hitendra N Karade ◽  
Jyotiranjan Acharya ◽  
Pravin Kumar
Keyword(s):  
Time Course ◽  
Lethal Dose ◽  
Nerve Agent ◽  
Ache Inhibition ◽  
Inhibition Concentration ◽  
Time Course Study ◽  
Dose Dependent ◽  
Protection Index ◽  
Lethal Doses

In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)- N-(pyridin-3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 µg/kg) and 0.48 LD50 (77.23 µg/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE ( p < 0.05) at 2× IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo.

Regional differences in constitutive and induced ICAM-1 expression in vivo

1995 ◽  
Vol 269 (6) ◽  
pp. H1955-H1964 ◽  
Author(s):  
J. Panes ◽  
M. A. Perry ◽  
D. C. Anderson ◽  
A. Manning ◽  
B. Leone ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Regional Differences ◽  
Time Course ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Fourfold Increase ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

The aim of the present study was to characterize and compare the expression of intercellular adhesion molecule 1 (ICAM-1) on unstimulated and endotoxin-challenged endothelial cells in different tissues of the rat. ICAM-1 expression was measured using 125I-labeled anti-rat ICAM-1 monoclonal antibody (MAb) and an isotype-matched control MAb labeled with 131I (to correct for nonspecific accumulation of the binding MAb). Under baseline conditions, ICAM-1 MAb binding was observed in all organs. The binding of 125I-ICAM-1 MAb varied widely among organs, with the largest accumulation (per g tissue) in the lung, followed by heart (1/30th of lung activity), splanchnic organs (1/50th of lung activity), thymus (1/100th of lung activity), testes (1/300th of lung activity), and skeletal muscle (1/800th of lung activity). Endotoxin induced an increase in ICAM-1 MAb binding in all organs except the spleen. Endotoxin-induced upregulation of ICAM-1 was greatest in heart and skeletal muscle (5- to 10-fold), whereas the remaining organs exhibited a two- to fourfold increase in ICAM-1 expression. Maximal upregulation of ICAM-1 occurred at 9-12 h after endotoxin administration. A dose-dependent increase in ICAM-1 expression was elicited by 0.1-10 microgram/kg, with higher doses (up to 5 mg/kg) producing no further increment. Induction of ICAM-1 mRNA after endotoxin was observed in all tissues examined (lung, heart, intestine), peaked at 3 h, and then rapidly returned to control levels. These findings indicate that ICAM-1 is constitutively expressed on vascular endothelium in all organs of the rat and that there are significant regional differences in the magnitude and time course of endotoxin-induced ICAM-1 expression.

Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ivan Hartling ◽  
Alessio Cremonesi ◽  
Ester Osuna ◽  
Phing-How Lou ◽  
Eliana Lucchinetti ◽  
...  
Keyword(s):  
Human Plasma ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Reference Ranges ◽  
Good Precision ◽  
Plasma Samples ◽  
Omega 3 ◽  
Bioactive Lipids ◽  
Blood Draw

Abstract Objectives Lipid mediators are bioactive lipids which help regulate inflammation. We aimed to develop an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify 58 pro-inflammatory and pro-resolving lipid mediators in plasma, determine preliminary reference ranges for adolescents, and investigate how total parenteral nutrition (TPN) containing omega-3 polyunsaturated fatty acid (n-3 PUFA) or n-6 PUFA based lipid emulsions influence lipid mediator concentrations in plasma. Methods Lipid mediators were extracted from plasma using SPE and measured using UHPLC-MS/MS. EDTA plasma was collected from healthy adolescents between 13 and 17 years of age to determine preliminary reference ranges and from mice given intravenous TPN for seven days containing either an n-3 PUFA or n-6 PUFA based lipid emulsion. Results We successfully quantified 43 lipid mediators in human plasma with good precision and recovery including several leukotrienes, prostaglandins, resolvins, protectins, maresins, and lipoxins. We found that the addition of methanol to human plasma after blood separation reduces post blood draw increases in 12-hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE), 12S-hydroxyeicosatrienoic acid (12S-HETrE), 14-hydroxydocosahexaenoic acid (14-HDHA) and thromboxane B2 (TXB2). Compared to the n-6 PUFA based TPN, the n-3 PUFA based TPN increased specialized pro-resolving mediators such as maresin 1 (MaR1), MaR2, protectin D1 (PD1), PDX, and resolvin D5 (RvD5), and decreased inflammatory lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2). Conclusions Our method provides an accurate and sensitive quantification of 58 lipid mediators from plasma samples, which we used to establish a preliminary reference range for lipid mediators in plasma samples of adolescents; and to show that n-3 PUFA, compared to n-6 PUFA rich TPN, leads to a less inflammatory lipid mediator profile in mice.

Time course and dose-dependent in vivo effect of ethyl-lfptophos on hen brain neurotoxic esterase activity

1983 ◽  
Vol 18 ◽  
pp. 111 ◽  
Author(s):  
N.S. Ahmed ◽  
K.S. El-Gendy ◽  
J.D. Farmer ◽  
R. Novak ◽  
N. Bakry ◽  
...  
Keyword(s):  
Esterase Activity ◽  
Time Course ◽  
Dose Dependent ◽  
Neurotoxic Esterase

scholarly journals Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

2019 ◽  
Vol 116 (5) ◽  
pp. 1698-1703 ◽  
Author(s):  
Allison Gartung ◽  
Jun Yang ◽  
Vikas P. Sukhatme ◽  
Diane R. Bielenberg ◽  
Djanira Fernandes ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Ovarian Tumor ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
First Line ◽  
Proinflammatory Mediators ◽  
Dual Inhibition ◽  
Cox 2

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived “surge” of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.

Potential Usefulness of Leukotriene B4 (LTB4) on Mobilization of Hematopoietic Progenitor Cells (HPC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5271-5271
Author(s):  
Yeung-Chul Mun ◽  
Seung-Eun Lee ◽  
Kyung-Eun Lee ◽  
Eun-Sun Yoo ◽  
Eun Suk Kang ◽  
...  
Keyword(s):  
Side Effects ◽  
Synergistic Effects ◽  
Leukotriene B4 ◽  
Lipid Mediator ◽  
Control Group ◽  
Optimal Timing ◽  
Dependent Manner ◽  
Dose Dependent

Abstract The mechanisms on HPC mobilization seem to be multifactorial processes. Many cell adhesion molecules (VLA-4, ICAM-1, VCAM-1 etc), SDF-1/CXCR4, and proteases (ie, MMP-9) may be important players for this mobilization processes. However, finding more mechanisms on HPC mobilization is under intense scrutiny. So far, G-CSF is the best known cytokine for this purpose. Meanwhile, its limitation on using G-CSF is to take 4–6 days for the optimal mobilization at clinic and its side effects (ie; bone pain, high WBC counts) are not negligible. LTB4 is lipid mediator during the process of inflammation, having many roles (ie; inducer of chemotaxis, the production of nitric oxide, transepithelial migration of neutrophil). In present study, we focused on the roles of LTB4 on HPC mobilization and its feasibility on mobilization in vivo. Samples were collected from the peripheral blood via heart puncture and the bone marrow on time dependent manner (1hr, 4hr, 6hr, 12hr, 24hr, 48hr) after LTB4 injection which was given via intravenously and the dose dependent manner of LTB4 (0.5μg, 1μg, 2μg, 3μg). These data were compared with two other groups after G-CSF injection and normal saline injection. Collected total nucleated cells were analyzed for Sca-1+/Lin- using flow cytometry and CFU studies. There were definite increase of Sca-1+/Lin- cells after 1μg of LTB4 injection group (TNC: 29.55(±0.92)×105/ml and HPC: 3.72(±0.09) %). Its control group showed as follows: TNC: 14.55(±0.21)×105/ml, HPC: 0.41(±0.04) %, (p&lt;0.05). Mobilization was optimal only after 4hours of LTB4 injection (TNC: 36.25(±2.90)×105/ml & HPC: 3.50(±0.37) %). After 4hours of LTB4 injection, there was a obvious down pattern. In terms of quantity, more than 20 fold of HPC mobilization after one LTB4 injection was observed. There were no immediate toxicity in the cohort, though long term potential side effects are under investigations. In conclusion, we showed the rapid mobilization of HPC with LTB4 at only 4 hours post-injection. This finding with LTB4 could be significant in terms of shortening the optimal period of mobilization comparing to that by G-CSF, which takes at least 4–6 days by repetitive injection to reach the optimal timing for collection. The possible synergistic effects of G-CSF with LTB4 for larger quantity of HPC and the cellular and molecular mechanism(s) of mobilization by LTB4 are being investigated in our lab.

Involvement of 5-Hydroxytryptamine in Platelet Aggregation In Vivo in Rats and Guinea Pigs

1989 ◽  
Vol 61 (03) ◽  
pp. 463-467 ◽  
Author(s):  
G M Smith
Keyword(s):  
Platelet Count ◽  
Guinea Pigs ◽  
Platelet Adhesion ◽  
Adenosine Diphosphate ◽  
Rate Of Return ◽  
Low Doses ◽  
Dose Dependent ◽  
Higher Doses ◽  
Rat Platelets

SummaryIn this study, 5-hydroxytryptamine (5-HT) caused a dose- dependent fall in the circulating platelet count suggesting that 5-HT receptors are activated in rat platelets to cause platelet adhesion and aggregation. When low doses of adenosine diphosphate (ADP) were simultaneously injected with 5-HT, there was a significant potentiation of the responses to ADR Ketanserin significantly reduced the potentiated responses. When higher doses of ADP were infused with bolus injections of 5-HT there was no potentiation and ketanserin did not reduce these responses. Ketanserin did not inhibit the collagen-induced fall in circulating platelet count, but did significantly increase the rate of return to the basal platelet count compared with control. 5-HT did not cause a fall in platelet count in guinea-pigs

Comparison of High Purity Factor IX Concentrates and a Prothrombin Complex Concentrate in a Canine Model of Thrombogenicity

1991 ◽  
Vol 66 (05) ◽  
pp. 609-613 ◽  
Author(s):  
I R MacGregor ◽  
J M Ferguson ◽  
L F McLaughlin ◽  
T Burnouf ◽  
C V Prowse
Keyword(s):  
High Purity ◽  
Time Course ◽  
Prothrombin Complex Concentrate ◽  
Degradation Products ◽  
Canine Model ◽  
Factor Ix ◽  
In Vitro Tests ◽  
Albumin Infusion

SummaryA non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.

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