Molecular determinants of reperfusion-induced leukocyte adhesion and vascular protein leakage.

Abstract

The adherence and emigration of leukocytes have been implicated as a rate-limiting step in the microvascular dysfunction associated with reperfusion of ischemic tissues. The objective of the present study was to define the relation between leukocyte-endothelial cell adhesion and albumin leakage in rat mesenteric venules exposed to ischemia and reperfusion (I/R). Leukocyte adherence and emigration as well as albumin extravasation were monitored in single post-capillary venules using intravital fluorescence microscopy. Ischemia (0, 10, 15, or 20 minutes) was induced by complete occlusion of the superior mesenteric artery, and all parameters were monitored for 30 minutes after reperfusion. The magnitude of the leukocyte adherence and emigration and albumin leakage elicited by I/R was positively correlated with the duration of ischemia. The albumin leakage response was also highly correlated with the number of adherent and emigrated leukocytes. Monoclonal antibodies against the adhesion glycoproteins CD18, CD11b, intercellular adhesion molecule-1 (ICAM-1) (at 10 and 30 minutes), and L-selectin (at 10 minutes), but not P- or E-selectin, reduced I/R-induced leukocyte adherence and emigration as well as albumin leakage. Platelet-leukocyte aggregates were formed in postischemic venules; the number of aggregates was reduced by antibodies against P-selectin, CD11b, CD18, and ICAM-1, but not E- or L-selectin. These results indicate that reperfusion-induced albumin leakage is tightly coupled to the adherence and emigration of leukocytes in postcapillary venules. This adhesion-dependent injury response is primarily mediated by CD11b/CD18 on activated neutrophils and ICAM-1 on venular endothelium and appears to require L-selectin-dependent leukocyte rolling.

Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Vascular Permeability Is Mediated by Intercellular Adhesion Molecule-1 (ICAM-1)

“…Previous reports have shown that leukocyte-endothelial interactions can trigger endothelial cell adherens and tight junction disorganization, 21,22 as well as increases in vascular permeability. 23 Others have demonstrated that VEGF has direct effects on vascular permeability. 24 In vitro studies have documented changes in electrical resistance and hydraulic conductivity in isolated endothelial monolayers treated with VEGF.…”

Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

“…11 As reperfusion injury ensues, endothelial disruption, expression of adhesion molecules, and leukocyte infiltration with subsequent activation of the entire inflammatory armamentarium occurs. 11,18 Some investigators have suggested that neutrophil infiltration and cumulative free radical release are the most important mediators of I/R injury. 19,20 Tacrolimus, as an immunomodulatory agent, is likely to have a profound effect on the inflammation avenue of I/R injury.…”

Ischemia-reperfusion injury in rats affects hydraulic conductivity in two phases that are temporally and mechanistically separate

“…Although XOD derived from endothelial cells contributes to the initial oxidant stress, ROS derived from adherent leukocytes may provide the more substantial and prolonged oxidant burst that occurs in IR injury (14). There is also evidence that leukocyte-endothelial binding mediated by adhesion molecules and subsequent leukocyte emigration into tissues is proportional to the degree of endothelial-cell barrier dysfunction, further supporting a primary role for adhesion molecules as a central regulator of local and distant IR-related injury (25). Taken together, these findings add to the growing evidence suggesting that ROS production and WBC adhesion events are interconnected (15,31).…”

“…Others have previously documented the importance of WBC adhesion in IR injury (22). Furthermore, monoclonal antibodies against ICAM-1 or against CD11/18 on neutrophils have been shown to reduce WBC adhesion and attenuate the increased vascular permeability during IR (25,36).…”