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Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability.
Br J Pharmacol 2007; 152(4):481-92BJ

Abstract

BACKGROUND AND PURPOSE

The present study addressed the effects of the investigational PDE4 inhibitor roflumilast on leukocyte-endothelial cell interactions and endothelial permeability in vivo and in vitro.

EXPERIMENTAL APPROACH

In vivo, intravital video-microscopy was used to determine effects of roflumilast p.o. on leukocyte-endothelial cell interactions and microvascular permeability in rat mesenteric venules. In vitro, the effects of roflumilast N-oxide, the active metabolite of roflumilast in humans, and other PDE4 inhibitors on neutrophil adhesion to tumour necrosis factor alpha (TNFalpha)-activated human umbilical vein endothelial cells (HUVEC), E-selectin expression and thrombin-induced endothelial permeability was evaluated. Flow cytometry was used to determine the effect of roflumilast on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced CD11b upregulation on human neutrophils.

KEY RESULTS

In vivo, roflumilast, given 1 h before lipopolysaccharide (LPS), dose-dependently reduced leukocyte-endothelial cell interactions in rat mesenteric postcapillary venules. It also diminished histamine-induced microvascular permeability. Immunohistochemical analyses revealed that roflumilast prevented LPS-induced endothelial P- and E-selectin expression. In vitro, roflumilast N-oxide concentration-dependently suppressed neutrophil adhesion to TNFalpha-activated HUVEC and CD11b expression on fMLP-stimulated neutrophils. It also reduced TNFalpha-induced E-selectin expression on HUVEC, when PDE3 activity was blocked. HUVEC permeability elicited by thrombin was concentration-dependently suppressed by roflumilast N-oxide. While roflumilast N-oxide was as potent as roflumilast at inhibiting stimulated endothelial cell and neutrophil functions, both compounds were significantly more potent than the structurally unrelated PDE4 inhibitors, rolipram or cilomilast.

CONCLUSIONS AND IMPLICATIONS

These findings further support earlier observations on the inhibition of inflammatory cell influx and protein extravasation by roflumilast in vivo.

Authors+Show Affiliations

Department of Pharmacology, University of Valencia, Valencia, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17704822

Citation

Sanz, M-J, et al. "Roflumilast Inhibits Leukocyte-endothelial Cell Interactions, Expression of Adhesion Molecules and Microvascular Permeability." British Journal of Pharmacology, vol. 152, no. 4, 2007, pp. 481-92.
Sanz MJ, Cortijo J, Taha MA, et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007;152(4):481-92.
Sanz, M. J., Cortijo, J., Taha, M. A., Cerdá-Nicolás, M., Schatton, E., Burgbacher, B., ... Morcillo, E. J. (2007). Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. British Journal of Pharmacology, 152(4), pp. 481-92.
Sanz MJ, et al. Roflumilast Inhibits Leukocyte-endothelial Cell Interactions, Expression of Adhesion Molecules and Microvascular Permeability. Br J Pharmacol. 2007;152(4):481-92. PubMed PMID: 17704822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. AU - Sanz,M-J, AU - Cortijo,J, AU - Taha,M A, AU - Cerdá-Nicolás,M, AU - Schatton,E, AU - Burgbacher,B, AU - Klar,J, AU - Tenor,H, AU - Schudt,C, AU - Issekutz,A C, AU - Hatzelmann,A, AU - Morcillo,E J, Y1 - 2007/08/20/ PY - 2007/8/21/pubmed PY - 2008/3/21/medline PY - 2007/8/21/entrez SP - 481 EP - 92 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 152 IS - 4 N2 - BACKGROUND AND PURPOSE: The present study addressed the effects of the investigational PDE4 inhibitor roflumilast on leukocyte-endothelial cell interactions and endothelial permeability in vivo and in vitro. EXPERIMENTAL APPROACH: In vivo, intravital video-microscopy was used to determine effects of roflumilast p.o. on leukocyte-endothelial cell interactions and microvascular permeability in rat mesenteric venules. In vitro, the effects of roflumilast N-oxide, the active metabolite of roflumilast in humans, and other PDE4 inhibitors on neutrophil adhesion to tumour necrosis factor alpha (TNFalpha)-activated human umbilical vein endothelial cells (HUVEC), E-selectin expression and thrombin-induced endothelial permeability was evaluated. Flow cytometry was used to determine the effect of roflumilast on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced CD11b upregulation on human neutrophils. KEY RESULTS: In vivo, roflumilast, given 1 h before lipopolysaccharide (LPS), dose-dependently reduced leukocyte-endothelial cell interactions in rat mesenteric postcapillary venules. It also diminished histamine-induced microvascular permeability. Immunohistochemical analyses revealed that roflumilast prevented LPS-induced endothelial P- and E-selectin expression. In vitro, roflumilast N-oxide concentration-dependently suppressed neutrophil adhesion to TNFalpha-activated HUVEC and CD11b expression on fMLP-stimulated neutrophils. It also reduced TNFalpha-induced E-selectin expression on HUVEC, when PDE3 activity was blocked. HUVEC permeability elicited by thrombin was concentration-dependently suppressed by roflumilast N-oxide. While roflumilast N-oxide was as potent as roflumilast at inhibiting stimulated endothelial cell and neutrophil functions, both compounds were significantly more potent than the structurally unrelated PDE4 inhibitors, rolipram or cilomilast. CONCLUSIONS AND IMPLICATIONS: These findings further support earlier observations on the inhibition of inflammatory cell influx and protein extravasation by roflumilast in vivo. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17704822/Roflumilast_inhibits_leukocyte_endothelial_cell_interactions_expression_of_adhesion_molecules_and_microvascular_permeability_ L2 - https://doi.org/10.1038/sj.bjp.0707428 DB - PRIME DP - Unbound Medicine ER -