Platelet-activating factor-induced microvascular dysfunction: role of adherent leukocytes

Platelet-activating factor (PAF) has been implicated in the pathogenesis of intestinal mucosal injury associated with endotoxemia, inflammation, allergic reactions, and ischemia-reperfusion. Although it is generally held that PAF initiates mucosal injury by enhancing transcapillary fluid and protein exchange, the effects of PAF on the intestinal microvasculature have not been defined to date. In this study we examined the influence of local intrarterial infusions of PAF (4, 20, and 40 ng/min) on intestinal transcapillary, lymphatic, and transmucosal water and protein fluxes. All of these parameters were increased by each of the concentrations of PAF. PAF caused a large rise in venous hematocrit without a corresponding increase in venous plasma protein concentration and a 14- to 37-fold increase in vascular protein flux. Local intra-arterial infusion of PAF promoted leukocyte adherence to mesenteric venular endothelium, a process that is inhibited by the monoclonal antibody, MoAb IB4. PAF-induced increments in intestinal lymph flow, venous hematocrit, and vascular protein flux were greatly attenuated in animals treated with MoAb IB4. The results of this study indicate that PAF promotes the filtration of fluid and protein across intestinal capillaries. These microvascular effects of PAF are mediated, in part, by adherent leukocytes.

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Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

Physiological Reviews ◽

10.1152/physrev.2000.80.4.1669 ◽

2000 ◽

Vol 80 (4) ◽

pp. 1669-1699 ◽

Cited By ~ 245

Author(s):

Giuseppe Montrucchio ◽

Giuseppe Alloatti ◽

Giovanni Camussi

Keyword(s):

Cardiovascular System ◽

Cell Biology ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Experimental Studies ◽

Platelet Activating Factor ◽

Biologically Active ◽

Endothelial Cell Migration

Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

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Role of Free Radicals and Lipid Peroxidation in Gastric Mucosal Injury Induced by Ischemia-Reperfusion in Rats

Scandinavian Journal of Gastroenterology ◽

10.3109/00365528909091124 ◽

1989 ◽

Vol 24 (sup162) ◽

pp. 55-58 ◽

Cited By ~ 27

Author(s):

S. Ueda ◽

T. Yoshikawa ◽

S. Takahashi ◽

H. Ichikawa ◽

M. Yasuda ◽

...

Keyword(s):

Lipid Peroxidation ◽

Free Radicals ◽

Ischemia Reperfusion ◽

Mucosal Injury ◽

Gastric Mucosal Injury

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The Role of Granulocyte-Derived Oxidants in Intestinal Mucosal Injury

Effects of Immune Cells and Inflammation on Smooth Muscle and Enteric Nerves ◽

10.1201/9780367813024-24 ◽

2020 ◽

pp. 295-303

Author(s):

Tamaki Yamada ◽

Matthew B. Grisham

Keyword(s):

Mucosal Injury ◽

Intestinal Mucosal Injury

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

Blood ◽

10.1182/blood.v85.9.2553.bloodjournal8592553 ◽

1995 ◽

Vol 85 (9) ◽

pp. 2553-2558 ◽

Cited By ~ 42

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.5.g1007 ◽

1997 ◽

Vol 273 (5) ◽

pp. G1007-G1013 ◽

Cited By ~ 4

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.

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Effects of hypoproteinemia on blood volume and arterial pressure of volume-loaded dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.5.h1317 ◽

1990 ◽

Vol 259 (5) ◽

pp. H1317-H1324

Author(s):

R. D. Manning

Keyword(s):

Body Weight ◽

Arterial Pressure ◽

Blood Volume ◽

Plasma Protein ◽

Protein Concentration ◽

Control Period ◽

Plasma Protein Concentration ◽

Autologous Plasma ◽

Protein Mass

Studies were performed in 14 conscious, anephric dogs to clarify the role of blood volume in the genesis of hypertension. The dogs were splenectomized and had plasma protein concentration (PPC) reduced to 2.7 g/dl by daily plasmapheresis for 9 days. This hypoproteinemia resulted in a 20% decrease in both blood volume and mean arterial pressure. On the 10th day the dogs were nephrectomized. On the 11th day after a 3-h control period with plasmapheresis, lactated Ringer equivalent to 10 or 20% of body weight was intravenously infused. By 25 h postinfusion blood volume had not increased, and the dogs were still hypotensive. At 25 h plasma protein mass was returned to normal by intravenous infusion of autologous plasma, the average blood volume of the three low PPC groups increased approximately 50%, and the arterial pressure increased greater than 60%. The decrease in PPC shifted the regression of blood volume on sodium space down the blood volume axis. In conclusion, the dependence of arterial pressure on blood volume was demonstrated by the decrease in both blood volume and arterial pressure after PPC reduction, the constancy of blood volume and pressure during Ringer infusion, and the increase in both volume and pressure after plasma infusion.

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