Nitric oxide prevents leukocyte adherence: role of superoxide

1993 ◽  
Vol 265 (3) ◽  
pp. H862-H867 ◽  
Author(s):  
J. Gaboury ◽  
R. C. Woodman ◽  
D. N. Granger ◽  
P. Reinhardt ◽  
P. Kubes
Keyword(s):  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Leukocyte Adherence ◽  
No Donor ◽  
Rolling Leukocytes ◽  
Adherent Leukocytes ◽  
Generating System

The objective of this study was to determine whether the antiadhesive effects of NO for leukocytes are related to its ability to scavenge superoxide in vivo. Intravital microscopy was used to monitor leukocyte adherence and flux as well as velocity and number of rolling leukocytes in 25- to 40-microns venules. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX-XO), was infused into the mesenteric circulation in untreated animals and in animals pretreated with either superoxide dismutase (SOD) or the NO donor, SIN 1. In another series of studies, the mesenteric preparation was superfused with either platelet-activating factor (PAF) or leukotriene B4 (LTB4) followed by the administration of either SIN 1 or SOD. HX-XO infusion caused a significant increase in the number of rolling and adherent leukocytes (responses that were entirely inhibited by SOD or SIN 1). SOD and SIN 1 both attenuated the PAF-induced but not the LTB4-induced leukocyte adherence. The observation that both SOD and SIN 1 inhibit leukocyte adhesion only under conditions associated with superoxide formation (HX-XO and PAF, but not LTB4) strongly suggests that the antiadhesion properties of NO are related to its ability to inactivate the superoxide anion.

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.

Leukocyte-induced vascular protein leakage in cat mesentery

1991 ◽  
Vol 261 (6) ◽  
pp. H1872-H1879 ◽  
Author(s):  
P. Kubes ◽  
M. B. Grisham ◽  
J. A. Barrowman ◽  
T. Gaginella ◽  
D. N. Granger
Keyword(s):  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Superoxide Production ◽  
Vascular Integrity ◽  
Fourfold Increase ◽  
Protein Leakage ◽  
Pmn Functions

The overall objective of this study was to determine whether leukocyte adherence and/or emigration is a prerequisite for the increased vascular protein leakage associated with acute inflammation. An in vivo preparation was used to monitor intestinal vascular protein leakage as well as polymorphonuclear leukocyte (PMN) adhesion and emigration in feline mesenteric microvessels exposed to platelet-activating factor (PAF) and leukotriene B4 (LTB4). Local intra-arterial infusion of PAF (4 ng/min) produced a fourfold increase in vascular protein leakage. A 50-fold higher concentration of LTB4 had no effect on vascular protein efflux. LTB4, however, did potentiate the PAF-induced vascular protein leakage. Both inflammatory mediators caused leukocytes to adhere to endothelial cells in postcapillary venules; however, leukocyte emigration was observed only in the presence of PAF. PAF-induced leukocyte adhesion and emigration and the increased vascular protein leakage were inhibited by a monoclonal antibody (MoAb IB4) directed against the common beta-subunit of the adhesive glycoprotein complex CD11/CD18. MoAb IB4 also prevented LTB4-induced leukocyte adhesion. Both PAF and LTB4 caused degranulation of cat PMNs in vitro, yet superoxide production was stimulated by PAF only. The data derived from these in vivo and in vitro studies indicate that leukocyte adhesion per se does not necessarily lead to increased vascular protein leakage and leukocyte emigration. Adhesion-dependent PMN functions such as emigration and superoxide production may play an important role in producing the alterations in vascular integrity observed in inflamed microvessels.

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.

Modulation of leukocyte migration in mesenteric interstitium

1994 ◽  
Vol 267 (4) ◽  
pp. H1573-H1577 ◽  
Author(s):  
K. Bienvenu ◽  
N. Harris ◽  
D. N. Granger
Keyword(s):  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Leukocyte Migration ◽  
Cathepsin G ◽  
In Vivo Model ◽  
Migration Rates ◽  
Inflammatory Stimuli

Intravital videomicroscopy was used to monitor the migration of leukocytes in rat mesenteric interstitium following exposure of the mesentery to either N-formylmethionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), platelet-activating factor (PAF), or ischemia-reperfusion (I-R). All inflammatory stimuli resulted in interstitial migration rates that were higher than those measured in unstimulated extravasated leukocytes. The median migration rate of cells stimulated with FMLP was significantly higher than those observed during superfusion with either LTB4 or PAF or following exposure to I-R. The enhanced leukocyte migration rates elicited by I-R were not attenuated by treatment with PAF- and LTB4-receptor antagonists, suggesting that these lipid mediators are not the inflammatory mediators responsible for I-R-induced leukocyte migration. Additional experiments revealed that the rate of leukocyte migration associated with FMLP stimulation was not significantly altered by either inhibitors of neutrophilic elastase and cathepsin G, a monoclonal antibody directed against the leukocyte adhesion glycoprotein CD11/CD18, or by altering interstitial hydration. This in vivo model provides a useful new approach for defining the factors that modulate leukocyte migration within the extravascular compartment.

Modulation of PAF-induced leukocyte adherence and increased microvascular permeability

1990 ◽  
Vol 259 (5) ◽  
pp. G859-G864 ◽  
Author(s):  
P. Kubes ◽  
M. Suzuki ◽  
D. N. Granger
Keyword(s):  
Hydrogen Peroxide ◽  
Monoclonal Antibody ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Microvascular Permeability ◽  
Leukocyte Adherence ◽  
Microvascular Endothelium ◽  
Leukocyte Adhesion Molecule ◽  
Mesenteric Microvessels ◽  
Adherent Leukocytes

The objective of this study was to assess whether superoxide and leukocyte adhesion glycoproteins (CD18) mediate the leukocyte adherence to mesenteric microvessels and increased intestinal microvascular permeability induced by platelet-activating factor (PAF). PAF was infused into the arterial supply of an isolated autoperfused segment of cat intestine. Thirty minutes into the infusion, the number of adherent leukocytes within mesenteric venules was measured. This was followed by intravenous administration of either human recombinant superoxide dismutase (hSOD), hydrogen peroxide-inactivated hSOD, or a monoclonal antibody against the leukocyte adhesion molecule CD18 (MoAb IB4), and 30 min later, adherence measurements were repeated. hSOD and MoAb IB4 produced a 30 and 66% decrease, respectively, in leukocyte adherence, whereas inactivated hSOD had no effect. Adherence of PAF-activated cat neutrophils to plastic was reduced only by MoAb IB4, suggesting that PAF-induced leukocyte adherence is mediated by both CD18 and superoxide and that endothelium is necessary for the superoxide-mediated adhesion. In a correlate study, hSOD and MoAb IB4 were shown to attenuate the PAF-induced increase in microvascular permeability by 40 and 70%, respectively. These data indicate that the increased microvascular permeability induced by PAF can be attenuated when leukocyte adherence to microvascular endothelium is reduced using molecules that either bind to CD18 adhesive glycoproteins or scavenge superoxide.

scholarly journals Regulation of human neutrophil aggregation: comparable latent times, activator sensitivities, and exponential decay in aggregability for FMLP, platelet-activating factor, and leukotriene B4

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3460-3468 ◽  
Author(s):  
YP Rochon ◽  
MM Frojmovic
Keyword(s):  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Variable Cross ◽  
Activator Concentration ◽  
Direct Measurements ◽  
Formyl Peptide ◽  
Activated Neutrophils ◽  
Neutrophil Aggregation ◽  
Protein Kinase C Activation

Abstract We have recently described a flow cytometry technique, whose sensitivity allows direct measurements of latent times before the onset of aggregation, and of rates, maximal extents, and reversibility of aggregation (J Leuk Biol 50:434, 1991). We report here that activators which stimulate sustained cellular signaling associated with increases in intracellular calcium (ionomycin) or protein kinase C activation (phorbol myristate acetate, PMA) cause complete (> or = 98%) and irreversible neutrophil aggregation, with latent times for the onset of aggregation inversely proportional to the activator concentration. In contrast, the receptor-specific activators leukotriene B4 (LTB4), formyl peptide FMLP, and platelet-activating factor (PAF) gave only partial and reversible aggregatory responses, limited by the following similar properties: latent times of 4.5 seconds +/- 1.5 seconds, independent of activator concentration; similar concentrations for onset of aggregation (approximately 1 nmol/L) that increased over a similar broad range of activator concentration, with one-half maximal rates of aggregation at 10 nmol/L to 30 nmol/L, corresponding to reported dissociation constant values; comparable limited recruitment and spontaneous reversibility of aggregation; absence of interactivator synergism; and similar exponential decays in activated cell stickiness (refractoriness), with t1/2 = 15 to 30 seconds. Variable cross- desensitization was seen between LTB4 and FMLP depending on donor and activator concentrations. In vivo, these properties are expected to provide localization of the aggregatory response, minimizing the otherwise detrimental effects of circulating activated neutrophils.

scholarly journals Lack of Platelet-Activating Factor Receptor Attenuates Experimental Food Allergy but Not Its Metabolic Alterations regarding Adipokine Levels

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Nathália Vieira Batista ◽  
Roberta Cristelli Fonseca ◽  
Denise Perez ◽  
Rafaela Vaz Sousa Pereira ◽  
Juliana de Lima Alves ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Allergy ◽  
Inflammatory Process ◽  
Platelet Activating Factor ◽  
Oral Challenge ◽  
Tissue Loss ◽  
Lack Of Information ◽  
Paf Receptor ◽  
Rolling Leukocytes

Platelet-activating factor (PAF) is known to be an important mediator of anaphylaxis. However, there is a lack of information in the literature about the role of PAF in food allergy. The aim of this work was to elucidate the participation of PAF during food allergy development and the consequent adipose tissue inflammation along with its alterations. Our data demonstrated that, both before oral challenge and after 7 days receiving ovalbumin (OVA) diet, OVA-sensitized mice lacking the PAF receptor (PAFR) showed a decreased level of anti-OVA IgE associated with attenuated allergic markers in comparison to wild type (WT) mice. Moreover, there was less body weight and adipose tissue loss in PAFR-deficient mice. However, some features of inflamed adipose tissue presented by sensitized PAFR-deficient and WT mice after oral challenge were similar, such as a higher rate of rolling leukocytes in this tissue and lower circulating levels of adipokines (resistin and adiponectin) in comparison to nonsensitized mice. Therefore, PAF signaling through PAFR is important for the allergic response to OVA but not for the adipokine alterations caused by this inflammatory process. Our work clarifies some effects of PAF during food allergy along with its role on the metabolic consequences of this inflammatory process.

scholarly journals Short-term and long-term role of platelet activating factor as a mediator of in vivo platelet aggregation.

Circulation ◽  
1993 ◽  
Vol 88 (3) ◽  
pp. 1205-1214 ◽  
Author(s):  
P Golino ◽  
G Ambrosio ◽  
M Ragni ◽  
I Pascucci ◽  
M Triggiani ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activating Factor ◽  
Short Term

Role of nitric oxide in gut ischemia-reperfusion-induced hepatic microvascular dysfunction

1997 ◽  
Vol 273 (5) ◽  
pp. G1007-G1013 ◽  
Author(s):  
Yoshinori Horie ◽  
Robert Wolf ◽  
D. Neil Granger
Keyword(s):  
Nitric Oxide ◽  
Important Determinant ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Protective Action ◽  
Microvascular Dysfunction ◽  
Artery Occlusion ◽  
No Donor ◽  
Synthase Inhibitor

The overall objective of this study was to assess the contribution of an altered bioavailability of nitric oxide (NO) to the leukocyte adhesion and hypoxic stress elicited in the liver by gut ischemia-reperfusion (I/R). The accumulation of leukocytes, number of nonperfused sinusoids (NPS), and NADH autofluorescence were monitored (by intravital microscopy) in mouse liver after 15 min of superior mesenteric artery occlusion and 60 min of reperfusion. Leukostasis, NPS, and NADH autofluorescence (indicating hypoxia) were all increased in the liver at 60 min after gut I/R. The NO synthase inhibitor N G-monomethyl-l-arginine (l-NMMA) exaggerated the liver leukostasis elicited by gut I/R, responses that were prevented by coadministration of l-arginine. The NO donor diethylenetriamine-NO (DETA-NO) andl-arginine were both effective in attenuating the gut I/R-induced leukostasis and increased NADH autofluorescence, whereas neither DETA nord-arginine exerted a protective action. These findings indicate that NO is an important determinant of the liver leukostasis, impaired sinusoidal perfusion, and tissue hypoxia elicited by gut I/R.

Molecular determinants of lipid mediator-induced leukocyte adherence and emigration in rat mesenteric venules

1994 ◽  
Vol 266 (3) ◽  
pp. H847-H853 ◽  
Author(s):  
B. J. Zimmerman ◽  
J. W. Holt ◽  
J. C. Paulson ◽  
D. C. Anderson ◽  
M. Miyasaka ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Platelet Activating Factor ◽  
Leukotriene B4 ◽  
Intercellular Adhesion Molecule ◽  
Lipid Mediator ◽  
Leukocyte Rolling ◽  
Leukocyte Adherence ◽  
Intercellular Adhesion Molecule 1 ◽  
Rolling Velocity ◽  
Molecular Determinants

The objective of this study was to identify the molecular determinants of leukocyte rolling, adherence, and emigration elicited in postcapillary venules by the lipid mediators leukotriene B4 (LTB4) or platelet-activating factor (PAF). Leukocyte-endothelial cell adhesion and shear rate were monitored in rat mesenteric venules during superfusion with either LTB4 or PAF in the presence or absence of monoclonal antibodies (MAbs) directed against either leukocyte (CD18, CD11b) or endothelial cell [intercellular adhesion molecule 1 (ICAM-1), E-selectin, P-selectin] adhesion glycoproteins. In untreated animals and in animals receiving a nonbinding control MAb, LTB4 and PAF increased the number of both adherent (8- and 4-fold, respectively) and emigrated (14- and 8-fold, respectively) leukocytes, while reducing leukocyte rolling velocity (36 and 33%, respectively). The LTB4- and PAF-induced leukocyte adherence and emigration were significantly attenuated by pretreatment with MAbs directed against CD18, CD11b, ICAM-1, and E-selectin, but not P-selectin. The reduction in leukocyte rolling velocity induced by LTB4 was not affected by any of the MAbs; however, both P- and E-selectin MAbs significantly attenuated the reduction in leukocyte rolling velocity elicited by PAF. The results of this study indicate that the leukocyte adherence and emigration induced by both LTB4 and PAF are mediated by CD11b/CD18 on leukocytes and by ICAM-1 and E-selectin on endothelial cells. The molecular determinant of leukocyte rolling appears to be mediator specific, with the selectins mediating the rolling elicited by PAF.

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