Rolipram inhibits leukocyte-endothelial cell interactions in vivo through P- and E-selectin downregulation

1 Rolipram, a selective phosphodiesterase (PDE) type 4 inhibitor. was used to characterize leukocyte recruitment mechanisms in models of acute and subacute inflammation. Intravital microscopy within the rat mesenteric microcirculation was employed. 2 Mesentery superfusion with PAF (0. 1 mum) induced a significant increase in leukocyte rolling flux, adhesion and emigration at 60 min. Rolipram pretreatment. markedly inhibited these parameters by 100, 95 and 95% respectively. 3 Similar effects were observed when the mesentery was superfused with LPS (1 mug ml(-1)) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 4 LPS exposure of the mesentery for 4 hr caused a greater increase in leukocyte rolling flux. adhesion and emigration which were inhibited by rolipram administration by 51, 71 and 81% respectively. 5 Immunohistochemistry revealed a significant increase in P-selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 6 LPS exposure of the mesentery for 4 h caused a significant increase in P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Rolipram pretreatment down-regulated both P- and E-selectin expression but had no effect on ICAM-1 and VCAM-1 expression. 7 Significant increases in plasma cyclic AMP levels were detected at 4.5 h after rolipram administration. 8 In conclusion, we have demonstrated that rolipram is a potent in vivo inhibitor of leukocyte-endothelial cell interactions. The effects observed are mediated through endothelial P- and E-selectin downregulation. Therefore, selective PDE-4 inhibitors may be useful in the control of different inflammatory disorders.