Neutrophil-dependent augmentation of PAF-induced vasoconstriction and albumin flux in coronary arterioles

Abstract

Platelet-activating factor (PAF) has been implicated in the pathogenesis of ischemic heart disease, reperfusion injury, and inflammatory reactions. Although neutrophils have been shown to primarily mediate PAF-induced microvascular dysfunction, the vasoactive effect of PAF and its neutrophil-dependent mechanism have not been directly and systematically studied in coronary resistance vessels. Therefore, the aim of this study was to examine the effects of PAF on coronary arteriolar function and neutrophil dynamics using an isolated and perfused microvessel preparation. Topical application of PAF to the vessels induced a dose-dependent decrease in the diameter but an increase in the apparent permeability coefficient of albumin. Disruption of the endothelium abolished the vasomotor response to PAF, and perfusion of neutrophils significantly augmented PAF-induced changes in vasomotor tone and permeability. Furthermore, the interaction between neutrophils and the endothelium was studied in the intact perfused coronary arterioles. Under control conditions, there were no adherent neutrophils observed in the vessels at varied intraluminal flow velocities. However, administration of PAF caused neutrophil adhesion to the endothelium of coronary arterioles at low flow velocities. Western blot analysis indicated that PAF upregulated the expression of intercellular adhesion molecule-1 in cultured coronary microvascular endothelial cells. Taken together, the results suggest that 1) PAF induces vasoconstriction and hyperpermeability in coronary arterioles via an endothelium-dependent and neutrophil-mediated mechanism, and 2) PAF is able to stimulate neutrophil adhesion in coronary arterioles under a condition of low flow rate.

Myosin Light Chain Phosphorylation in Neutrophil-Stimulated Coronary Microvascular Leakage

“…Compared with C5a, the effects of platelet-activating factor (PAF) on neutrophil dynamics and permeability were examined in the same isolated microvessel model. 32 The results showed that PAF was able to induce microvascular hyperpermeability by activating both the endothelium and neutrophils. The dual effect of PAF renders it of limited utility in obtaining information exclusive to neutrophildependent events.…”

“…32,33 For activation, neutrophils were mixed with human recombinant C5a (10 Ϫ8 mol/L) and added to the suffusion bath at 10 5 to 10 7 cells/mL. The stimulus intensity of C5a was derived from previous dose-response studies by us and others in which an optimal effect on neutrophil activation and interaction with microvascular endothelium was observed at 10 Ϫ8 mol/L.…”

Neutrophil airway influx by platelet-activating factor in asthma: role of adhesion molecules and LTB4expression

“…PAF can also promote macrophage-1 antigen (MAC-1) (CD11b/CD18)-dependent neutrophil adhesion to endothelial cells through P-selectin [19,20] and PAF by itself can increase leukocyte adhesion without altering vessel diameter [21]. Likewise, PAF can facilitate CD11b upregulation and L-selectin shedding induced by neutrophils [22], and can also cause neutrophil adhesion to the endothelium by upregulating intercellular adhesion molecule (ICAM)-1 [23]. Furthermore, PAF has the potential to promote neutrophil recruitment by stimulating the release of LTB 4 by airway cells in asthmatic patients [24,25], a mechanism also observed following MAC-1 overexpression by PAF [26].…”

Macromolecule permeability of in situ and excised rodent skeletal muscle arterioles and venules

“…Neutrophil interactions with the vessel wall are central to the cascade of events that occurs in inflammation (34), and it is established that signaling events in both neutrophils and endothelial cells that are initiated on neutrophil adhesion to the endothelial surface are necessary for responses that ultimately result in alteration of microvascular barrier function, thus enabling leukocyte transmigration across the vascular wall and into the tissue (33, 36). Interestingly, leukocyte interactions with endothelium have also been implicated in increases in microvessel permeability (9,10,12,13,24,40), suggesting that at least under some conditions, neutrophil interactions and permeability changes might have processes in common.Increased permeability to water and solutes is a well-documented feature of the inflamed venular microcirculation, and while there is a substantial body of information addressing biophysical aspects of microvascular permeability, considerably less is known about the mechanisms underlying permeability regulation (29). Thus, for example, while it is known that permeability to water can be regulated separately from selectivity to macromolecules (17), the mechanisms underlying this dichotomy are not understood.…”

“…Neutrophil interactions with the vessel wall are central to the cascade of events that occurs in inflammation (34), and it is established that signaling events in both neutrophils and endothelial cells that are initiated on neutrophil adhesion to the endothelial surface are necessary for responses that ultimately result in alteration of microvascular barrier function, thus enabling leukocyte transmigration across the vascular wall and into the tissue (33,36). Interestingly, leukocyte interactions with endothelium have also been implicated in increases in microvessel permeability (9,10,12,13,24,40), suggesting that at least under some conditions, neutrophil interactions and permeability changes might have processes in common.…”