Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of
cardiovascular diseases including
atherosclerosis and
heart failure. Acute
p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in
myocardial ischemia/
reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor,
SB-239063, inhibits
ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague-Dawley rats were treated with either
SB-239063 (10 mgkg(-1)),
dexamethasone (3 mgkg(-1)) or vehicle 1h prior to
ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous
rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min
ischemia, and at several time points during a 90 min reperfusion period.
Ischemia caused a 3-fold increase in adherent leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals.
SB-239063, at a dose known to inhibit
p38 MAPK activity in vivo (10 mgkg(-1)), had no effect on
ischemia/reperfusion-induced leukocyte adhesion, the number of rolling leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast,
dexamethasone completely blocked leukocyte adhesion in response to
ischemia/reperfusion, and reduced expression of
E-selectin,
intercellular adhesion molecule-1 (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1). We conclude that
p38 MAPK may not play a role in initial leukocyte recruitment in response to
ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.