Mechanisms contributing to gastric motility changes induced by PAF-acether and endotoxin in rats

1989 ◽  
Vol 256 (2) ◽  
pp. G275-G282
Author(s):  
J. V. Esplugues ◽  
B. J. Whittle
Keyword(s):  
Gastric Motility ◽  
Platelet Activating Factor ◽  
Mucosal Damage ◽  
Serotonin Release ◽  
Initial Increase ◽  
Intragastric Pressure ◽  
Paf Receptor ◽  
Endogenous Release ◽  
Gastric Contractions

Platelet-activating factor (PAF) may be involved in the pathophysiology of gastrointestinal damage and motility changes. The effects of PAF in inducing gastric contractions in vivo have now been determined in pentobarbital sodium-anesthetized rats. Local intra-arterial infusion of PAF (5-50 ng.kg-1.min-1 for 10 min) induced a maintained rise in intragastric pressure followed by a further postinfusion increase. Inhibitors of eicosanoid biosynthesis had no effect on these gastric motility changes. However, pretreatment with cimetidine or methysergide decreased by 50% the initial increase in intragastric pressure, whereas mepyramine, adrenergic alpha- and beta-receptor blockade, atropine, hexamethonium, or vagotomy had no effect. During the local infusion of tetrodotoxin, the initial increase in intragastric pressure was not maintained, and the postinfusion increase was abolished. With these inhibitors and antagonists, there was no consistent correlation between the extent of PAF-induced mucosal damage and increase in intragastric pressure. Tetrodotoxin had no effect on the changes in intragastric pressure induced by the thromboxane mimetic U-46619. Administration of Escherichia coli and Salmonella typhosa endotoxin (50 mg/kg iv) also increased intragastric pressure, which peaked after 10 min and slowly declined thereafter. These effects were inhibited by the specific PAF-receptor antagonist L652,731, suggesting that the endogenous release of PAF may contribute to the endotoxin-induced increases in gastric motility. The present study suggests that PAF initially acts directly on smooth muscle and through histamine and serotonin release with a secondary motility response due to activation of nonadrenergic noncholinergic, neuronal activity.

Duodenal acid-induced gastric relaxation is mediated by multiple pathways

1999 ◽  
Vol 276 (6) ◽  
pp. G1501-G1506 ◽  
Author(s):  
Yuan-Xu Lu ◽  
Chung Owyang
Keyword(s):  
Gastric Motility ◽  
No Reduction ◽  
Direct Action ◽  
Intragastric Pressure ◽  
Afferent Pathways ◽  
Serotonin Antagonist ◽  
Intraduodenal Infusion ◽  
Rate Dependent ◽  
Vagal Afferent

In this study, we used an in vivo anesthetized rat model to investigate the mechanisms responsible for duodenal acid-induced inhibition of gastric motility. Intraduodenal infusion of HCl produced a rate-dependent decrease in intragastric pressure. Infusion of HCl at 2 ml/h produced a physiological plasma secretin level and elicited a decrease in intragastric pressure of 3.0 ± 0.2 cmH20. Infusion of rabbit secretin antiserum reduced the acid-induced inhibition of gastric motility by 85 ± 5%, suggesting mediation mainly by endogenous secretin. Administration of the cholecystokinin (CCK)-A antagonist MK-329 caused only a modest 10 ± 3% reduction in gastric relaxation, whereas the serotonin antagonist ICS-205930 had no effect. In contrast, immunoneutralization with the secretin antibody caused only a 15% reduction in the relaxation evoked by a higher rate of HCl infusion (3 ml/h), whereas MK-329 and ICS-205930 caused a 20 ± 4% reduction and no reduction, respectively. Bilateral truncal vagotomy or perivagal application of capsaicin completely abolished gastric relaxation in response to low rates (1–2 ml/h) of 0.1 N HCl infusion but only partially affected gastric relaxation in response to a higher infusion rate (3 ml/h). These observations indicate that multiple pathways mediate the duodenal acid-induced inhibition of gastric motility. At low rates of HCl infusion, gastric relaxation is mediated primarily by endogenous secretin, which acts through vagal afferent pathways. At higher rates of HCl infusion, gastric relaxation is mediated by endogenous secretin, CCK, and possibly by the direct action of HCl on vagal afferent pathways or yet unidentified neuropathways.

scholarly journals Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2553-2558 ◽  
Author(s):  
S Nourshargh ◽  
SW Larkin ◽  
A Das ◽  
TJ Williams
Keyword(s):  
Vessel Wall ◽  
Interleukin 1 ◽  
Platelet Activating Factor ◽  
Micron Diameter ◽  
Paf Receptor ◽  
Leukocyte Extravasation ◽  
Mesenteric Microvessels ◽  
Adherent Leukocytes

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK-74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.

Platelet-activating factor antagonists increase vascular reactivity in perfused rat lungs

1988 ◽  
Vol 65 (5) ◽  
pp. 1921-1928 ◽  
Author(s):  
J. Haynes ◽  
S. W. Chang ◽  
K. G. Morris ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Circulation ◽  
Vascular Reactivity ◽  
Platelet Activating Factor ◽  
Base Line ◽  
Ang Ii ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Paf Receptor ◽  
Blood Elements

Platelet-activating factor (PAF) administered to the pulmonary circulation in low dose (nanogram) has vasodilatory properties. Therefore, we investigated whether endogenous PAF plays a role in the control of tone in the pulmonary circulation. The PAF receptor antagonists, SRI 63-441 (2.6 X 10(-4) M) and L659,989 (1 X 10(-5) M), were the major investigative tools. In isolated perfused rat lungs, both agents caused a persistent increase in base-line perfusion pressure (Ppa), potentiated angiotensin II (ANG II) vasoconstriction, and potentiated hypoxic vasoconstriction (HPV). This potentiation of ANG II and HPV was found to be independent of circulating blood elements. Vasodilation in the presence of PAF blockade was also impaired. The combination of cyclooxygenase inhibition and PAF receptor blockade had an additive effect on ANG II vasoconstriction but did not cause more potentiation of HPV than achieved with PAF antagonism alone. In vivo, SRI 63-441 (10 mg/kg) caused only a transient increase in base-line Ppa without altering ANG II and hypoxic vasoconstriction. These findings support a vasodilatory role for endogenous PAF in the pulmonary circulation.

scholarly journals Kupffer Cell Release of Platelet Activating Factor Drives Dose Limiting Toxicities of Nucleic Acid Nanocarriers

2020 ◽  
Author(s):  
Meredith A. Jackson ◽  
Shrusti S. Patel ◽  
Fang Yu ◽  
Matthew A. Cottam ◽  
Evan B. Glass ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Adverse Events ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Platelet Activating Factor ◽  
Toxicity Mechanism ◽  
Lipid Nanoparticle ◽  
Cell Release ◽  
Paf Receptor

AbstractIn vivo nanocarrier-associated toxicity is a significant and poorly understood hurdle to clinical translation of siRNA nanomedicines. In this work, we demonstrate that platelet activating factor (PAF), an inflammatory lipid mediator, plays a key role in nanocarrier-associated toxicities, and that prophylactic inhibition of the PAF receptor (PAFR) completely prevents these toxicities. High-dose intravenous injection of siRNA-polymer nano-complexes (si-NPs) elicited acute, shock-like symptoms (vasodilation and vascular leak) in mice and caused a three-fold increase in blood PAF levels. PAFR inhibition completely prevented these toxicities, indicating PAF activity is a primary driver of systemic si-NP toxicity. Pre-treatment with clodronate liposomes fully abrogated si-NP-associated increases in blood PAF and consequent toxicities, suggesting that nanoparticle uptake by Kupffer macrophages is the source of PAF. Assessment of varied si-NP chemistries further confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on the endosome disruptive function of the carrier. Finally, the PAF toxicity mechanism was shown to be generalizable to commercial delivery reagent in vivo-jetPEI® and an MC3 lipid nanoparticle formulated to match an FDA-approved siRNA nanomedicine. Greater sensitivity to the PAF mechanism occurs in 4T1 tumor-bearing mice, a mammary tumor model known to exhibit increased circulating leukocytes and potential to respond to inflammatory insult. These results establish Kupffer cell release of PAF as a key mediator of in vivo nucleic acid nanocarrier toxicity and identify PAFR inhibition as an effective prophylactic strategy to increase maximum tolerated dose and reduce nanocarrier-associated adverse events.SignificanceNon-viral nucleic acid nanocarriers can enable in vivo gene therapy, but their potential interaction with innate immune cells can cause dose-limiting toxicities. Nanoparticle toxicities are currently poorly understood, making it difficult to identify relevant design criteria for maximizing nanoparticle safety. This work connects nanoparticle-associated toxicities to the release of platelet activating factor (PAF) by liver Kupffer cells. Small molecule inhibition of the PAF receptor (PAFR) completely prevents severe adverse events associated with high doses of multiple polymer-based formulations and a lipid nanoparticle matching the composition of the first clinically-approved siRNA nanomedicine. This study identifies PAF as a toxicity biomarker for future nanomedicine discovery programs. Further, PAFR inhibition should be explored as a strategy to expand the therapeutic index of nanomedicines.

Molecular mechanisms involved in superoxide-induced leukocyte-endothelial cell interactions in vivo

1994 ◽  
Vol 266 (2) ◽  
pp. H637-H642 ◽  
Author(s):  
J. P. Gaboury ◽  
D. C. Anderson ◽  
P. Kubes
Keyword(s):  
Molecular Mechanisms ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Leukocyte Rolling ◽  
Rolling Velocity ◽  
Paf Receptor ◽  
Rolling Leukocytes ◽  
Adherent Leukocytes ◽  
Web 2086

Intravital microscopy was used to monitor leukocyte adherence, flux, rolling velocity, and number of rolling leukocytes (flux/velocity) in venules 25–40 microns in diameter. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX/XO), was infused into the mesenteric circulation in untreated animals or in animals pretreated with either catalase (a hydrogen peroxide scavenger), WEB-2086 [a platelet-activating factor (PAF) receptor antagonist], or monoclonal antibodies directed against adhesion molecules CD18 (CL26) or P-selectin (PB1.3). HX/XO infusion caused a decrease in leukocyte rolling velocity and an increase in the number of rolling and adherent leukocytes. WEB-2086 prevented the increase in leukocyte adhesion and markedly increased leukocyte rolling velocity. PB1.3 abolished the HX/XO-associated rise in the flux of rolling leukocytes and proportionally decreased the number of adherent leukocytes. CL26 abolished HX/XO-induced leukocyte adhesion and also reduced the number of rolling leukocytes. In conclusion, P-selectin mediates the increased leukocyte flux induced by superoxide, whereas PAF and CD18 modulate leukocyte adhesion. PAF also reduces leukocyte rolling velocity, possibly as a result of CD18, but not P-selectin.

scholarly journals Metabolic effects of platelet-activating factor in rats in vivo. Stimulation of hepatic glycogenolysis and lipogenesis

1990 ◽  
Vol 269 (1) ◽  
pp. 269-272 ◽  
Author(s):  
R D Evans ◽  
V Ilic ◽  
D H Williamson
Keyword(s):  
Platelet Activating Factor ◽  
Hepatic Metabolism ◽  
Isolated Hepatocytes ◽  
Metabolic Effects ◽  
Hepatic Glycogen ◽  
Dose Dependent Fashion ◽  
Paf Receptor ◽  
High Doses ◽  
Stimulation Of

1. The effects of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphocholine; PAF) on hepatic metabolism in vivo in rats were studied. 2. PAF stimulated synthesis of hepatic lipid (saponified and non-saponified) in a dose-dependent fashion and caused hypertriglyceridaemia. There was no effect of PAF on lipogenesis in isolated hepatocytes. 3. High doses of PAF also decreased hepatic glycogen. 4. All doses of PAF decreased plasma insulin, and this was accompanied by hyperglycaemia, except at the lowest dose. 5. The selective PAF-receptor antagonist L659.989 prevented the stimulation of lipogenesis, but indomethacin did not.

Platelet-activating factor stimulates lung pericyte growth in vitro

1996 ◽  
Vol 270 (2) ◽  
pp. L298-L304 ◽  
Author(s):  
J. Khoury ◽  
D. Langleben
Keyword(s):  
Distress Syndrome ◽  
Thymidine Incorporation ◽  
Platelet Activating Factor ◽  
In Vitro Growth ◽  
Rat Lung ◽  
Pulmonary Vessel ◽  
Control Growth ◽  
Paf Receptor

Platelet-activating factor (PAF) is released from activated leukocytes and endothelial cells in sepsis, lung injury, and the adult respiratory distress syndrome. With these disorders, pulmonary hypertension develops, partly due to muscularization of the microvasculature by proliferation of pericytes. PAF may be a mediator of this process. Therefore, we examined the effects of PAF on in vitro growth of rat lung pericytes. Compared with control growth, semisynthetic PAF (10(-9) M) stimulated the 7-day mean growth of proliferating pericytes by 31% in medium with serum and 29% without serum and of previously growth-arrested pericytes by 12% with serum and 23% without serum. These effects were blocked by the PAF-receptor blocker CV-3988. PAF also increased [3H]thymidine incorporation into pericytes by 79%. Synthetic 16:0 PAF stimulated pericyte growth, but 18:0 PAF did not. PAF exposure did not induce apoptosis in pericytes. Thus PAF compounds, similar to those found in vivo, stimulate lung pericyte growth in vitro. PAF may act as a direct cytokine on cells involved in muscularization of the pulmonary vessel walls.

PAF receptor antagonist modulates neutrophil responses with thermal injury in vivo

2001 ◽  
Vol 281 (4) ◽  
pp. C1310-C1317 ◽  
Author(s):  
Nadeem Fazal ◽  
Walid M. Al-Ghoul ◽  
Mashkoor A. Choudhry ◽  
Mohammed M. Sayeed
Keyword(s):  
Receptor Antagonist ◽  
Burn Injury ◽  
Total Body Surface Area ◽  
Platelet Activating Factor ◽  
Skin Thickness ◽  
Reactive Oxygen Intermediate ◽  
Paf Receptor ◽  
Paf Receptor Antagonist

The role of platelet-activating factor (PAF) in Ca2+signaling and Ca2+-related enhancement of reactive oxygen intermediate (ROI) generation in neutrophils of burn-injured rats was ascertained by evaluating the effect of treatment of the rats with a PAF receptor antagonist. The treatment of rats with the antagonist also allowed us to evaluate the role of PAF in the priming of neutrophil ROI response with burn in vivo. A full skin thickness burn injury was produced in anesthetized rats by exposing 30% of total body surface area to 98°C water for 10 s. Sham and burn rats were killed 1 day later, and their blood was collected to obtain neutrophils. Fluorescence-activated cell sorter analysis was used to quantify ROI production by the neutrophils. Cytosolic-free Ca2+concentration ([Ca2+]i) imaging technique was employed to measure neutrophil [Ca2+]iin individual cells and microfluorometry for the assessment of [Ca2+]iresponses in suspensions of neutrophils. There was an overt enhancement of ROI generation by burn rat neutrophils. ROI release was accompanied by a marked elevation of [Ca2+]isignaling. The treatment of rats with PAF receptor antagonist before burn prevented the upregulation of both [Ca2+]iand ROI generation in neutrophils. These studies indicate that enhanced ROI production in neutrophils in the early stages after burn injury results from a PAF-mediated priming of the [Ca2+]isignaling pathways in vivo.

scholarly journals A Novel Platelet Activating Factor Receptor Antagonist Reduces Cell Infiltration and Expression of Inflammatory Mediators in Mice Exposed to Desiccating Conditions after PRK

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Salomon Esquenazi ◽  
Jiucheng He ◽  
Na Li ◽  
Nicolas G. Bazan ◽  
Isi Esquenazi ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Receptor Antagonist ◽  
Turnover Rate ◽  
Inflammatory Cell ◽  
Platelet Activating Factor ◽  
The Other ◽  
Cell Infiltration ◽  
Paf Receptor ◽  
Arginase I

Purpose. To study the contribution of a novel PAF receptor antagonist LAU-0901 in the modulation of the increased inflammatory response in mice exposed to dessicating conditions (DE) after PRK.Methods. Eighty 13-14 week old female Balb/C mice were used. They were divided into two groups: One group was treated with LAU-0901 topical drops. The other group was treated with vehicle. In each group ten mice served as controls and ten were placed in DE. The other twenty mice underwent bilateral PRK and were divided in two additional groups: ten mice remained under normal conditions (NC) and the other ten were exposed to DE. After 1 week all animals underwent in vivo confocal microscopy, immunostaining and western blotting analysis.Results. Confocal microscopy showed an increased number of reflective structures in the corneal epithelium after PRK and exposure to DE in eyes treated with vehicle as compared to eyes treated with LAU-0901. Significant decrease of COX-2 and Arginase I expression and reduced alpha SMA cells was observed after PRK and exposure to DE in eyes treated with LAU-0901. Discussion: Exposure of mice to a DE after PRK increases the epithelial turnover rate. PAF is involved in the inflammatory cell infiltration and expression of inflammatory cytokines that follow PRK under DE.

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