Fluticasone Propionate Downregulates Nasal Fibroblast Functions Involved in Airway Inflammation and RemodelingSilvestri M.a · Sabatini F.a · Scarso L.b · Cordone A.c · Dasic G.d · Rossi G.A.a
aPulmonary Department, bBlood Center, Giannina Gaslini Institute, Genoa, cPediatric Department, University of Genoa, dGlaxoSmithKline S.p.A., Verona, Italy
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Background: Besides being highly effective in the treatment of allergic and nonallergic rhinitis with eosinophilia, intranasal corticosteroids appear to be useful in reducing nasal polypoid lesions and the likelihood of polyp recurrence after surgery. We evaluated the ability of fluticasone propionate to downregulate fibroblast functions related to nasal inflammation and remodeling. Methods: Primary nasal polyp tissue-derived fibroblasts were stimulated with tumor necrosis factor (TNF)-α or interleukin (IL)-4 or basic fibroblast growth factor (bFGF) in the presence of fluticasone propionate (0.1–100 nM). Fibroblast proliferation, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression and eotaxin release were then evaluated. Results: As compared with unstimulated cultures, a significant increase in fibroblast proliferation was observed when the cells were stimulated with bFGF (p < 0.05), but not with TNF-α or IL-4 (p > 0.05). TNF-α induced an upregulation of ICAM-1 expression (p < 0.05), which was not seen in fibroblasts cultured in the presence of IL-4 or bFGF. No changes in VCAM-1 expression were induced by TNF-α, IL-4 or bFGF, whereas both TNF-α and IL-4 increased eotaxin release (p < 0.05). Both bFGF-induced fibroblast proliferation and TNF-α-induced ICAM-1 expression were significantly reduced by fluticasone, starting at the dose of 1 and 10 nM, respectively (p < 0.05). Fluticasone at concentrations of 1–100 nM effectively inhibited eotaxin release by TNF-α- or IL-4-stimulated fibroblasts (p < 0.05). Conclusions: The pharmacologic activity of fluticasone in patients with chronic upper airway inflammatory disease may include inhibition of resident fibroblast functions involved in airway inflammation and remodeling.
© 2002 S. Karger AG, Basel
Connel JT: Nasal hypersensitivity; in Gupta S, Good RA (eds): Comprehensive Immunology. New York, Plenum, 1979, vol 6, pp 397–416.
Dolovich J, Ohtoshi T, Jordana M, Gauldie J, Denburg J: Nasal polyps: Local inductive microenvironment in the pathogenesis of the inflammation; in Mygind N, Pipkorn U (eds): Rhinitis and Asthma. Munksgaard, 1990, pp 233–241.
Mygind N, Dahl R, Bachert C: Nasal polyposis, eosinophil dominated inflammation, and allergy. Thorax 2000;55(suppl 2):S79–S83.
- Nakagawa T, Yamane H, Nakai Y, Shigeta T, Takashima T, Takeda Z: Comparative assessment of cell proliferation and accumulation of extracellular matrix in nasal polyps. Acta Otolaryngol Suppl 1998;538:205–208.
- Norlander T, Westrin KM, Fukami M, Stierna P, Carlsoo B: Experimentally induced polyps in the sinus mucosa: A structural analysis of the initial stages. Laryngoscope 1996;106:196–203.
- Powers MR, Qu Z, LaGesse PC, Liebler JM, Wall MA, Rosenbaum JT: Expression of basic fibroblast growth factor in nasal polyps. Ann Otol Rhinol Laryngol 1998;107:891–897.
- Redington AE, Howarth PH: Airway remodelling in asthma. Thorax 1997;52:310–312.
- Meyer JE, Berner I, Teran LM, Bartels J, Sticherling M, Schroder JM, Maune S: RANTES production by cytokine-stimulated nasal fibroblasts: Its inhibition by glucocorticoids. Int Arch Allergy Immunol 1998;117:60–67.
- Vancheri C, Ohtoshi T, Cox G, Xaubet A, Abrams JS, Gauldie J, Dolovich J, Denburg J, Jordana M: Neutrophilic differentiation induced by human upper airway fibroblast-derived granulocyte/macrophage colony stimulating factor (GM-CSF). Am J Respir Cell Mol Biol 1991;4:11–17.
- Nonaka M, Pawankar R, Saji F, Yagi T: Eotaxin synthesis by nasal polyp fibroblasts. Acta Otolaryngol 1999;119:816–820.
- Saji F, Nonaka M, Pawankar R: Expression of RANTES by IL-1 beta and TNF-alpha stimulated nasal polyp fibroblasts. Auris Nasus Larynx 2000;27:247–252.
Roche WR: Fibroblasts and extracellular matrix in bronchial asthma; in Busse W, Holgate ST (eds): Asthma and Rhinitis. Cambridge, Blackwell Science, 1995, pp 554–562.
- Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S: Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 1998;102:783–788.
- Doucet C, Brouty-Boyé D, Pottin-Clemenceau C, Jasmin C, Canonica GW, Azzarone B: IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int Immunol 1998;10:1421–1433.
Takafuji S, Shoji S, Ito K, Yamamoto K, Nakagawa T: Eosinophil degranulation in the presence of lung fibroblasts. Int Arch Allergy Immunol 1998;117:52–54.
- Spoelstra FM, Postma DS, Hovenga H, Noordhoek JA, Kauffman HF: Interferon-gamma and interleukin-4 differentially regulate ICAM-1 and VCAM-1 expression on human lung fibroblasts. Eur Respir J 1999;14:759–766.
- Springer TA: Adhesion receptors of the immune system. Nature 1990;346:425–434.
- Jahnsen FL, Haraldsen G, Aanesen JP, Haye R, Brandtzaeg P: Eosinophil infiltration is related to increased expression of vascular cell adhesion molecule-1 in nasal polyps. Am J Respir Cell Mol Biol 1995;12:624–632.
- Hamilos DL, Thawley ST, Kramper MA, Kamil A, Hamid QA: Effects of intranasal fluticasone on cellular infiltration, endothelial adhesion molecule expression and proinflammatory cytokine mRNA in nasal polyp disease. J Allergy Clin Immunol 1999;103:79–87.
- Badia L, Lund V: Topical corticosteroids in nasal polyposis. Drugs 2001;61:573–578.
- Spoelstra FM, Postma DS, Hovenga H, Noordhoek JA, Kauffman HF: Budesonide and formoterol inhibit ICAM1 and VCAM-1 expression on human lung fibroblasts. Eur Respir J 2000;15:68–74.
- Silvestri M, Oddera S, Crimi P, Rossi GA: Frequency and specific sensitization to inhalant allergens within nuclear families of children with asthma and/or rhinitis. Ann Allergy Asthma Immunol 1997;79:512–516.
- Oddera S, Silvestri M, Scarso L, Testi R, Rossi GA: Salmeterol inhibits the allergen-induced mononuclear cell proliferation and downregulates GM-CSF release and HLA-DR expression by monocytes. Pulm Pharmacol Ther 1997;10:43–49.
- Rossi GA, Sacco O, Balbi B, Oddera S, Mattioni T, Corte G, Ravazzoni C, Allegra L: Human ciliated bronchial epithelial cells: Expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction. Am J Respir Cell Mol Biol 1990;3:431–439.
- Coste A, Brugel L, Maitre B, Boussat S, Papon JF, Wingerstmann L, Peynegre R, Escudier E: Inflammatory cells as well as epithelial cells in nasal polyps express vascular endothelial growth factor. Eur Respir J 2000;15:367–372.
- Knight D: Epithelium-fibroblast interactions in response to airway inflammation. Immunol Cell Biol 2001;79:160–164.
Petruson B, Hansson HA, Petrusson K: Insulinlike growth factor I immunoreactivity in nasal polyps. Arch Otolaryngol Head Neck Surg 1988;144:1272–1275.
- Wang QP, Escudier E, Roudot-Thoraval F, Abd-Al Samad I, Peynegre R, Coste A: Myofibroblast accumulation induced by transforming growth factor-β is involved in the pathogenesis of nasal polyps. Laryngoscope 1997;107:926–931.
- Hoshi S, Goto M, Koyama N, Nomoto K, Tanaka H: Regulation of vascular smooth muscle cell proliferation by nuclear factor-kappaB and its inhibitor, I-kappaB. J Biol Chem 2000;275:883–889.
- Noso N, Sticherling M, Bartels J, Mallet AI, Christophers E, Schroder JM: Identification of an N-terminally truncated form of the chemokine RANTES and granulocyte-macrophage colony stimulating factor as major eosinophil attractant released by cytokine-stimulated dermal fibroblasts. J Immunol 1996;156:1946–1953.
- Finotto S, Ohno I, Marshall JS, Gauldie J, Denburg JA, Dolovich J, Clark DA, Jordana M: TNF-alpha production by eosinophils in upper airways inflammation (nasal polyposis). J Immunol 1994;153:2278–2289.
- Chen C, Chou C, Sun Y, Huang W: Tumor necrosis factor alpha-induced activation of downstream NF-kappaB site of the promoter mediates epithelial ICAM-1 expression and monocyte adhesion. Involvement of PKCalpha, tyrosine kinase, and IKK2, but not MAPKs, pathway. Cell Signal 2001;13:543–553.
- Tessier PA, Cattaruzzi P, McColl SR: Inhibition of lymphocyte adhesion to cytokine-activated synovial fibroblasts by glucocorticoids involves the attenuation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 gene expression. Arthritis Rheum 1996;39:226–234.
- Bloemen PG, Van den Tweel MC, Henricks PA, Engels F, Van de Velde MJ, Blomjous FJ, Nijkamp FP: Stimulation of both human bronchial epithelium and neutrophils is needed for maximal interactive adhesion. Am J Physiol 1996;270:L80–L87.
- Jankowski R: Eosinophils in the pathogenesis of nasal polyposis. Acta Otolaryngol 1996;116:160–163.
- Lantero S, Alessandri G, Spallarossa D, Scarso L, Rossi GA: Stimulation of eosinophil IgE low-affinity receptor leads to increased adhesion molecule expression and cell migration. Eur Respir J 2000;16:940–946.
- Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, Smith H, Shi X, Gonzalo JA, Newman W, Guterriez-Ramos JC, Mackay CR: Cloning of human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest 1996;97:604–612.
- Matsukura S, Stellato C, Plitt JR, Bickel C, Miura K, Georas SN, Casolaro V, Schleimer RP: Activation of eotaxin gene transcription by NF-kappaB and STAT6 in human airway epithelial cells. J Immunol 1999;163:6876–6883.
- Rothenberg ME, Ownbey R, Mehlhop PD, Loiselle PM, van de Rijn M, Bonventre JV, Oettgen HC, Leder P, Luster AD: Eotaxin triggers eosinophil-selective chemotaxis and calcium flux via a distinct receptor and induces pulmonary eosinophilia in the presence of interleukin 5 in mice. Mol Med 1996;2:334–348.
- Griffiths-Johnson DA, Collins PD, Rossi AG, Jose PJ, Williams TJ: The chemokine, eotaxin, activates guinea-pig eosinophils in vitro and causes their accumulation into the lung in vivo. Biochem Biophys Res Commun 1993;197:1167–1172.
- Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, Truong O, Hsuan JJ, Williams TJ: Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med 1994;179:881–887.
- Holmberg K, Juliusson S, Balder B, Smith DL, Richards DH, Karlsson G: Fluticasone propionate aqueous nasal spray in the treatment of nasal polyposis. Ann Allergy Asthma Immunol 1997;78:270–276.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.