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Rolipram inhibits leukocyte‐endothelial cell interactions in vivo through P‐ and E‐selectin downregulation
Author(s) -
Sanz MaríaJesús,
Alvarez Angeles,
Piqueras Laura,
Cerdá Miguel,
Issekutz Andrew C,
Lobb Roy R,
Cortijo Julio,
Morcillo Esteban J
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704644
Subject(s) - rolipram , intravital microscopy , downregulation and upregulation , chemistry , intercellular adhesion molecule 1 , phosphodiesterase inhibitor , medicine , in vivo , cell adhesion , endocrinology , cell adhesion molecule , endothelial stem cell , inflammation , pharmacology , phosphodiesterase , biology , immunology , cell , microcirculation , in vitro , biochemistry , enzyme , microbiology and biotechnology , gene
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. Mesentery superfusion with PAF (0.1 μ M ) 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. Similar effects were observed when the mesentery was superfused with LPS (1 μg ml −1 ) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 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. Immunohistochemistry revealed a significant increase in P‐selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 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. Significant increases in plasma cyclic AMP levels were detected at 4.5 h after rolipram administration. 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.British Journal of Pharmacology (2002) 135 , 1872–1881; doi: 10.1038/sj.bjp.0704644