Active oxidants mediate IFN-alpha-induced microvascular alterations in rat mesentery

The present study was designed to investigate the influences of IFN-alpha on the microcirculatory hemodynamics. The mesenteric microcirculation of male Wistar rats was observed through an intravital fluorescence microscopic system. The leukocyte behavior, RBC velocity, and albumin leakage were monitored simultaneously before and after a continuous infusion of IFN-alpha. In other rats, the oxidant-sensitive fluorescence probe dihydrorhodamine-123 (DHR) fluorescence was observed in the same set up. Administration of IFN-alpha increased the number of adherent and emigrated leukocytes and decreased the RBC velocity in mesenteric venules. Oxidative stress indicated by DHR fluorescence was exacerbated in microvessels of IFN-alpha-treated rats. Following the leukocyte recruitment and oxidative stress, an exaggerated albumin leakage was observed. Thrombus formation in venules and hemorrhage along venules were frequently observed in rats treated with IFN-alpha. N,N'-dimethylthiourea, a scavenger of hydrogen peroxide and a hydroxyl radical, largely prevented these microvascular responses. Pretreatment of rats with mAb directed against either CD18 or ICAM-1 also attenuated the IFN-alpha-induced microvascular alterations. It is concluded, therefore, that a high concentration of IFN-alpha stimulates CD18/ICAM-1-dependent adhesive interactions with endothelial cells and oxidant production of leukocytes, which leads to microcirculatory derangements characterized by decreased barrier function and reduced anticoagulant activity of venular endothelial cells.