Since leukocyte adhesion to endothelial cells is crucial for extravasation of leukocytes to sites of
inflammation, inhibition of cell-cell adhesion has been suggested as a means to achieve selective modulation of the immune system. We have, using a static in vitro adhesion assay involving adhesion of granulocytes to
tumor necrosis factor alpha (
TNFalpha)-stimulated human umbilical vein endothelial cells (HUVEC), found three substances--
uridine,
isomaltitol and 4-thiouridine-that, independently and significantly, reduced leukocyte adhesion by approximately 30-65%.
4-Thiouridine was also tested in an in vivo model of
Sephadex (SDX)-induced
lung inflammation with Sprague-Dawley rats. Intratracheal instillation of
Sephadex (5 mg/kg) alone resulted in a dramatic increase in lung
edema and total leukocyte count after 24 h. A differential count of bronchoalveolar lavage (BAL) cells indicated an increased influx of macrophages, eosinophils and neutrophils. Co-administration of
4-thiouridine significantly reduced lung
edema by 38%. There was also a significant reduction of the total leukocyte count by 58%. The differential leukocyte count indicated that eosinophil influx alone was reduced by 70%. After
Sephadex challenge, we found elevated levels of
TNFalpha--an important inflammatory mediator--in the bronchoalveolar lavage fluid (BALF).
TNFalpha levels were significantly reduced by more than 80% by co-administration of 4-thoiuridine. These results suggest that
uridine,
isomaltitol and, especially,
4-thiouridine affect adhesion between leukocytes and activated endothelium, and warrant further in vitro and in vivo studies.