You have full text access to this OnlineOpen article

Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability

  1. M-J Sanz1,2,
  2. J Cortijo1,2,3,
  3. M A Taha1,
  4. M Cerdá-Nicolás2,4,
  5. E Schatton5,
  6. B Burgbacher5,
  7. J Klar5,
  8. H Tenor5,
  9. C Schudt5,
  10. A C Issekutz6,
  11. A Hatzelmann5,
  12. E J Morcillo1,2,7,*

Article first published online: 29 JAN 2009

DOI: 10.1038/sj.bjp.0707428

Issue

British Journal of Pharmacology

British Journal of Pharmacology

Volume 152, Issue 4, pages 481–492, October 2007

Additional Information

How to Cite

Sanz, M.-J., Cortijo, J., Taha, M. A., Cerdá-Nicolás, M., Schatton, E., Burgbacher, B., Klar, J., Tenor, H., Schudt, C., Issekutz, A. C., Hatzelmann, A. and Morcillo, E. J. (2007), Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. British Journal of Pharmacology, 152: 481–492. doi: 10.1038/sj.bjp.0707428

Author Information

  1. 1

    Department of Pharmacology, University of Valencia, Valencia, Spain

  2. 2

    Ciber CB06/06/0027 ‘Respiratory Diseases’, Carlos III Health Institute, Spanish Ministry of Health, Madrid, Spain

  3. 3

    Research Foundation, University General Hospital Consortium, University of Valencia, Valencia, Spain

  4. 4

    Department of Pathology, University of Valencia, Valencia, Spain

  5. 5

    Department of Biochemistry, Nycomed GmbH, Konstanz, Germany

  6. 6

    Division of Immunology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

  7. 7

    Clinical Pharmacology Unit, University Clinical Hospital, University of Valencia, Valencia, Spain

*Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibanez, 15; E-46010 Valencia, Spain. E-mail: esteban.morcillo@uv.es

Publication History

  1. Issue published online: 29 JAN 2009
  2. Article first published online: 29 JAN 2009
  3. (Received April 5, 2007, Revised May 30, 2007, Accepted July 19, 2007)

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (290K)

References

  • Banner KH, Trevethick MA (2004). PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci 25: 430–436.
  • Berends C, Dijkhuizen B, de Monchy JG, Dubois AE, Gerritsen J, Kauffman HF (1997). Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram. Eur Respir J 10: 1000–1007.
  • Bethke TD, Bohmer GM, Hermann R, Hauns B, Fux R, Morike K et al. (2007). Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J Clin Pharmacol 47: 26–36.
  • Birukova AA, Zagranichnaya T, Fu P, Alekseeva E, Chen W, Jacobson J et al. (2007). Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac/Rap1-dependent Rac activation. Exp Cell Res 313: 2504–2520.
  • Blease K, Burke-Gaffney A, Hellewell PG (1998). Modulation of cell adhesion molecule expression and function on human lung microvascular endothelial cells by inhibition of phosphodiesterases 3 and 4. Br J Pharmacol 124: 229–237.
    Direct Link:
  • Boswell-Smith V, Page CP (2006). Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of respiratory disease. Expert Opin Investig Drugs 15: 1105–1113.
  • Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R (2001). In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 297: 280–290.
  • Burgess JK, Oliver BG, Poniris MH, Ge Q, Boustany S, Cox N et al. (2006). A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro. J Allergy Clin Immunol 118: 649–657.
  • Cullere X, Shaw SK, Andersson L, Hirahishi J, Luscinska FW, Mayadas TN (2005). Regulation of vascular endothelial barrier function by Epac, a cAMP-mediated exchange factor for Rap GTPase. Blood 105: 1950–1955.
  • Derian CK, Santulli RJ, Rao PE, Solomon HF, Barrett JA (1995). Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 154: 308–317.
  • Draijer R, Atsma DE, van der LA, van Hinsbergh VW (1995). cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. Circ Res 76: 199–208.
  • Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, Takahura N et al. (2005). Cyclic AMP potentiates vascular endothelial cadherin-mediated cell–cell contact to enhance endothelial barrier function through an Epac-Rap1 signalling pathway. Mol Cell Biol 25: 136–146.
  • Giembycz MA (2005). Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2: 326–333.
  • Growcott EJ, Spink KG, Ren X, Afzal S, Banner KH, Wharton J (2006). Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells. Respir Res 7: 9.
  • Harris NR, Russell JM, Granger DN (1994). Mediators of endotoxin-induced leukocyte adhesion in mesenteric postcapillary venules. Circ Shock 43: 155–160.
  • Hasko G, Cronstein BN (2004). Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25: 33–39.
  • Hatzelmann A, Schudt C (2001). Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 297: 267–279.
  • Hauns B, Hermann R, Hunnemeyer A, Herzog R, Hauschke D, Zech K et al. (2006). Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects. J Clin Pharmacol 46: 1146–1153.
  • House SD, Lipowsky HH (1987). Leukocyte–endothelium adhesion: microhemodynamics in mesentery of the cat. Microvasc Res 34: 363–379.
  • Houslay MD, Schafer P, Zhang KY (2005). Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10: 1503–1519.
  • Jaffe EA, Nachman RL, Becker CG, Minick CR (1973). Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52: 2745–2756.
  • Johnston B, Gaboury JP, Suematsu M, Kubes P (1999). Nitric oxide inhibits microvascular protein leakage induced by leukocyte adhesion-independent and adhesion-dependent inflammatory mediators. Microcirculation 6: 153–162.
  • Johnston B, Walter UM, Issekutz AC, Issekutz TB, Anderson DC, Kubes P (1997). Differential roles of selectins and the alpha4-integrin in acute, subacute, and chronic leukocyte recruitment in vivo. J Immunol 159: 4514–4523.
  • Jones NA, Boswell-Smith V, Lever R, Page CP (2005). The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 18: 93–101.
  • Kooistra MRH, Corada M, Dejana E, Bos JL (2005). Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS lett 579: 4966–4972.
  • Kubes P, Kerfoot SM (2001). Leukocyte recruitment in the microcirculation: the rolling paradigm revisited. News Physiol Sci 16: 76–80.
  • Kuijpers TW, Hakkert BC, Hoogerwerf M, Leeuwenberg JF, Roos D (1991). Role of endothelial leukocyte adhesion molecule-1 and platelet-activating factor in neutrophil adherence to IL-1-prestimulated endothelial cells. Endothelial leukocyte adhesion molecule-1-mediated CD18 activation. J Immunol 147: 1369–1376.
  • Kumar RK, Herbert C, Thomas PS, Wollin L, Beume R, Yang M et al. (2003). Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. J Pharmacol Exp Ther 307: 349–355.
  • Kumari M, Cover PO, Poyser RH, Buckingham JC (1997). Stimulation of the hypothalamic–pituitary–adrenal axis in the rat by three selective type-4 phosphodiesterase inhibitors: in vitro and in vivo studies. Br J Pharmacol 121: 459–468.
    Direct Link:
  • Kung TT, Crawley Y, Luo B, Young S, Kreutner W, Chapman RW (2000). Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram: involvement of endogenously released corticosterone and catecholamines. Br J Pharmacol 130: 457–463.
    Direct Link:
  • Langeler EG, van Hinsbergh VW (1988). Characterization of an in vitro model to study the permeability of human arterial endothelial cell monolayers. Thromb Haemost 60: 240–246.
  • Ley K, Allietta M, Bullard DC, Morgan S (1998). Importance of E-selectin for firm leukocyte adhesion in vivo. Circ Res 83: 287–294.
  • Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G (2005). Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 172: 848–853.
  • Mata M, Sarria B, Buenestado A, Cortijo J, Cerda M, Morcillo EJ (2005). Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax 60: 144–152.
  • McCluskie K, Klein U, Linnevers C, Ji Y, Yang A, Husfeld C et al. (2006). Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. J Pharmacol Exp Ther 319: 468–476.
  • Meliton AY, Munoz NM, Lambertino A, Boetticher E, Learoyd J, Zhu X et al. (2006). Phosphodiesterase 4 inhibition of beta2-integrin adhesion caused by leukotriene B4 and TNF-alpha in human neutrophils. Eur Respir J 28: 920–928.
  • Morandini R, Ghanem G, Portier-Lemarie A, Robaye B, Renaud A, Boeynaems JM (1996). Action of cAMP on expression and release of adhesion molecules in human endothelial cells. Am J Physiol 270: H807–H816.
  • Ortiz JL, Cortijo J, Valles JM, Bou J, Morcillo EJ (1993). Rolipram inhibits airway microvascular leakage induced by platelet-activating factor, histamine and bradykinin in guinea-pigs. J Pharm Pharmacol 45: 1090–1092.
  • Peter D, Jin SLC, Conti M, Hatzelmann A, Zitt C (2007). Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. J Immunol 178: 4820–4831.
  • Pettipher ER, Eskra JD, Labasi JM (1997). The inhibitory effect of rolipram on TNF-α production in mouse blood ex vivo is dependent upon the release of corticosterone and adrenaline. Cytokine 9: 582–586.
  • Pober JS, Slowik MR, De Luca LG, Ritchie AJ (1993). Elevated cyclic AMP inhibits endothelial cell synthesis and expression of TNF-induced endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1. J Immunol 150: 5114–5123.
  • Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroeker D, Bethke TD (2005). Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366: 563–571.
  • Raeburn D, Underwood SL, Lewis SA, Woodman VR, Battram CH, Tomkinson A et al. (1994). Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. Br J Pharmacol 113: 1423–1431.
  • Ross SE, Williams RO, Mason LJ, Mauri C, Marinova-Mutafchieva L, Malfait AM et al. (1997). Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram. J Immunol 159: 6253–6259.
  • Sanz MJ, Alvarez A, Piqueras L, Cerda M, Issekutz AC, Lobb RR et al. (2002). Rolipram inhibits leukocyte-endothelial cell interactions in vivo through P- and E-selectin downregulation. Br J Pharmacol 135: 1872–1881.
    Direct Link:
  • Sanz MJ, Cortijo J, Morcillo EJ (2005a). PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther 106: 269–297.
  • Sanz MJ, Nabah YN, Cerda-Nicolas M, O'Connor JE, Issekutz AC, Cortijo J et al. (2005b). Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression. Br J Pharmacol 144: 190–201.
    Direct Link:
  • Sato Y, Sato S, Yamamoto T, Ishikawa S, Onizuka M, Sakakibara Y (2002). Phosphodiesterase type 4 inhibitor reduces the retention of polymorphonuclear leukocytes in the lung. Am J Physiol Lung Cell Mol Physiol 282: L1376–L1381.
  • Schierwagen C, Bylund-Fellenius AC, Lundberg C (1990). Improved method for quantification of tissue PMN accumulation measured by myeloperoxidase activity. J Pharmacol Methods 23: 179–186.
  • Seybold J, Thomas D, Witzenrath M, Boral S, Hocke AC, Burger A et al. (2005). Tumor necrosis factor-alpha-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability. Blood 105: 3569–3576.
  • Simon SI, Hu Y, Vestweber D, Smith CW (2000). Neutrophil tethering on E-selectin activates beta 2 integrin binding to ICAM-1 through a mitogen-activated protein kinase signal transduction pathway. J Immunol 164: 4348–4358.
  • Sommer N, Loschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP et al. (1995). The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med 1: 244–248.
  • Springer TA (1994). Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76: 301–314.
  • Sullivan GW, Lee DD, Ross WG, DiVietro JA, Lappas CM, Lawrence MB et al. (2004). Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. J Leukoc Biol 75: 127–134.
  • Sullivan GW, Rieger JM, Scheld WM, Macdonald TL, Linden J (2001). Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A(2A) receptor agonists. Br J Pharmacol 132: 1017–1026.
    Direct Link:
  • Suttorp N, Ehreiser P, Hippenstiel S, Fuhrmann M, Krull M, Tenor H et al. (1996). Hyperpermeability of pulmonary endothelial monolayer: protective role of phosphodiesterase isoenzymes 3 and 4. Lung 174: 181–194.
  • Suttorp N, Weber U, Welsch T, Schudt C (1993). Role of phosphodiesterases in the regulation of endothelial permeability in vitro. J Clin Invest 91: 1421–1428.
  • Vignola AM (2004). PDE4 inhibitors in COPD—a more selective approach to treatment. Respir Med 98: 495–503.
  • Walter UM, Ayer LM, Manning AM, Frenette PS, Wagner DD, Hynes RO et al. (1997a). Generation and characterization of a novel adhesion function blocking monoclonal antibody recognizing both rat and mouse E-selectin. Hybridoma 16: 355–361.
  • Walter UM, Ayer LM, Wolitzky BA, Wagner DD, Hynes RO, Manning AM et al. (1997b). Characterization of a novel adhesion function blocking monoclonal antibody to rat/mouse P-selectin generated in the P-selectin-deficient mouse. Hybridoma 16: 249–257.
  • Wollin L, Barsig J, Marx D, Wohlsen A, Beume R (2003). Inhibition by roflumilast versus cilomilast of pulmonary leukocyte accumulation and TNFα release in a rat model of LPS-induced pulmonary neutrophilia. Eur Respir J 22: 107s.
  • Wollin L, Bundschuh DS, Wohlsen A, Marx D, Beume R (2006). Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. Pulm Pharmacol Ther 19: 343–352.
  • Wollner A, Wollner S, Smith JB (1993). Acting via A2 receptors, adenosine inhibits the upregulation of Mac-1 (Cd11b/CD18) expression on FMLP-stimulated neutrophils. Am J Respir Cell Mol Biol 9: 179–185.
View Full Article (HTML) Get PDF (290K)