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 microM) 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 microg 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 h 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.
Sanz
María-Jesús
MJ
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain. maria.j.sanz@uv.es
Alvarez
Angeles
A
Piqueras
Laura
L
Cerdá
Miguel
M
Issekutz
Andrew C
AC
Lobb
Roy R
RR
Cortijo
Julio
J
Morcillo
Esteban J
EJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D019040:E-Selectin / Q000096:biosynthesis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008297:Male; D019007:P-Selectin / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*
D019040:E-Selectin; D019007:P-Selectin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram