Tumor necrosis factor-α-induced leukocyte adhesion and microvessel permeability

Abstract

The objective of this study was to investigate whether leukocyte adhesion and/or emigration are critical steps in increased microvessel permeability during acute inflammation. To conduct this study, we combined autologous blood perfusion with a single microvessel perfusion technique, which allows microvessel permeability to be measured precisely after the endothelium has interacted with blood-borne stimuli. Experiments were carried out in intact venular microvessels in rat mesenteries. Firm attachment of leukocytes to endothelial cells was induced by intravenous injection of TNF-alpha (3.5 microg/kg) and resuming autoperfusion in a precannulated microvessel. Leukocyte emigration was facilitated by superfusion of formyl-Met-Leu-Phe-OH. Microvessel permeability was measured as hydraulic conductivity (L(p)) or the solute permeability coefficient to tetramethylrhodamine isothiocyanate-labeled alpha-lactalbumin before and after leukocyte adhesion and emigration in individually perfused microvessels. We found that perfusion of a microvessel with TNF-alpha did not affect basal microvessel permeability, but intravenous injection of TNF-alpha caused significant leukocyte adhesion. However, the significant leukocyte adhesion and emigration did not cause corresponding increases in either L(p) or solute permeability. Thus our results suggest that leukocyte adhesion and emigration do not necessarily increase microvessel permeability and the mechanisms that regulate the adhesion process act independently from mechanisms that regulate permeability. In addition, silver staining of endothelial boundaries demonstrated that leukocytes preferentially adhere at the junctions of endothelial cells. The appearance of the silver lines indicates that the TNF-alpha-induced firm adhesion of leukocyte to microvessel walls did not involve apparent changes in the junctional structure of endothelial cells, which is consistent with the results of permeability measurements.

Caveolin-1 scaffolding domain promotes leukocyte adhesion by reduced basal endothelial nitric oxide-mediated ICAM-1 phosphorylation in rat mesenteric venules

“…These findings also support that the process of leukocyte recruitments, such as adhesion and migration, may not necessarily cause vascular leakage. Our results that the increases in microvessel permeability only occurred upon the application of fMLP to vessels with AP-CAV-induced adherent leukocytes further support that the adhesion process alone can be dissociated with increases in microvessel permeability, and the additional stimulus-induced leukocyte oxidative burst is the direct cause of leukocyte adhesion-mediated increases in microvessel permeability (13,14,17,40,43,47,48). This could also explain the effective anti-inflammatory actions of systemically applied AP-CAV without reported injury of unaffected organs by several investigators (2)(3)(4)12).…”

Adenosine A2A receptor modulation of juvenile female rat skeletal muscle microvessel permeability

“…P s values of venules to RSA and to ␣-lactabumin in rat mesentery have been reported as 5.6 ϫ 10 Ϫ7 cm/s by Rumbaut and Huxley (45) and 50 ϫ 10 Ϫ7 cm/s by He and colleagues (60), respectively. The value of venular P s RSA (10.7 Ϯ 0.5 10 Ϫ7 cm/s) reported in the current study is almost twice that of venular mesentery P s RSA (45).…”

Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules

“…However, in the presence of adherent and migrating leukocytes, there was no significant increase in the basal Lp measured on day 4 vessels or plasma leakage measured with Evans blue up to 14 days after infection of the mice (13). Dissociation of adherent and migrating leukocytes from permeability increases has been reported by multiple studies (16,20,25,26,38,39). The mechanisms that initiate leukocyte adhesion have been demonstrated to be independent from those that trigger leukocyte oxidative burst, wherein the released reactive oxygen species are mainly responsible for increased permeability (16,39).…”