Glucocorticoids (GC) are extremely effective in attenuating leukocyte extravasation at sites of inflammation, but the mechanisms by which they mediate this effect remain unclear. Endotoxin (LPS) is a potent stimulus of leukocyte infiltration, and GC inhibit LPS-induced leukocyte recruitment. We hypothesized that LPS-induced recruitment is due to local induction of adhesion molecules, and that GC will inhibit this induction. Utilizing intravital microscopy, we demonstrated that superfusion of rat mesentery with LPS (l (ig/ml) results in a significant increase in leukocyte rolling and adherence (compared to sham-operated controls) by 30 min (57.8±6.2 vs. 17.4±5.3 cells/min and 5.2±0.7 vs. 1.2±0.4 cells/100 um respectively; n=6, p<0.05). Both rolling and adherence remained elevated for at least 2 hr. Administration of the P-selectin neutralizing mAb PB 1.3 (l mg/kg IV) 10 min prior to LPS superfusion significantly attenuated leukocyte rolling at 30 min (from 57.8±6.2 to 31.9±6.9 cells/min, p<0.05), but not at later time points, indicating a role for P-selectin in early LPS-induced rolling. Although PB1.3 only attenuated LPS-induced rolling at 30 min, leukocyte adherence was completely blocked for the entire 2 hr period, suggesting that P-selectin is essential for LPS-induced leukocyte adherence. Pretreatment of rats with the GC dexamethasone (0.5 mg/kg, subcutaneously) 18 hr prior to LPS superfusion dramatically inhibited the LPS-induced increases in leukocyte rolling and adherence at 30 min (19.9±5.0 cells/min and 1.6±0.8 cells/100 |4.m, n=6, p<0.01) and for the remainder of the 2 hr observation period. These data suggest that the anti-inflammatory effects of GC may be due in pan to GC-mediated reductions in P-selectin expression.
|Original language||English (US)|
|State||Published - Dec 1 1996|
ASJC Scopus subject areas
- Molecular Biology