Microvascular dysfunction induced by nonsteroidal anti-inflammatory drugs: role of leukocytes

The objectives of this study were to determine whether 1) the leukocyte-endothelial cell adhesion observed in venules exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) is accompanied by enhanced albumin extravasation, and 2) leukocytes mediate this endothelial cell barrier dysfunction. Intravital video microscopy was used to monitor leukocyte-endothelial cell adhesion and the leakage of fluorescein isothiocyanate-labeled albumin in rat mesenteric venules exposed to either indomethacin or aspirin. Both NSAIDs induced the recruitment of adherent and emigrated leukocytes with temporally related increases in albumin leakage. Agents that effectively decreased or prevented the NSAID-induced leukocyte adherence/emigration (leukotriene B4 receptor antagonist or adhesion molecule-specific monoclonal antibodies) also blocked the corresponding albumin leakage response. These findings indicate that adherent and/or emigrating leukocytes mediate the early endothelial cell barrier dysfunction elicited by NSAIDs.