Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

Respiratory Research

Paul M O'Byrne³  Dirk Bredenbröker¹  Richard M Watson³  Tara Strinich³  Francine Deschesnes²  Joanne Milot²  Kieran J Killian³  MyLinh Duong³  Johanne Côté²  Christine Schmid-Wirlitsch¹  Louis-Philippe Boulet²  Gail M Gauvreau³ 

[1] NYCOMED GmbH, Konstanz, Germany;Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada;Department of Medicine, McMaster University, Hamilton, Ontario, Canada

关键词: eosinophils;    neutrophils;    sputum;    inflammation;    PDE4 inhibitor;    allergen challenge;    Allergic asthma;   

Others  :  796782
DOI  :  10.1186/1465-9921-12-140

 received in 2011-09-01, accepted in 2011-10-26,  发布年份 2011

【 摘 要 】

Background

Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.

Methods

25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV₁ was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.

Results

Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV₁ (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.

Conclusions

This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.

Trial Registration

ClinicalTrials.gov: NCT01365533

【 授权许可】

   
2011 Gauvreau et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Fahy JV, Wong H, Liu J, Boushey HA: Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am J Respir Crit Care Med 1995, 152:53-8.
• [2]Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemiere C, Foley S, Cicora L, Ludwig M, Hamid Q, Martin JG: Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008, 133:420-426.
• [3]Qiu Y, Zhu J, Bandi V, Guntupalli KK, Jeffery PK: Bronchial mucosal inflammation and upregulation of CXC chemoattractants and receptors in severe exacerbations of asthma. Thorax 2007, 62:475-482.
• [4]Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ: Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997, 155:542-548.
• [5]Nguyen LT, Lim S, Oates T, Chung KF: Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir Med 2005, 99:200-207.
• [6]Schudt C, Gantner F, Tenors H, Hatzelmann A: Therapeutic potential of selective PDE inhibitors in asthma. Pulm Pharmacol Ther 1999, 12:123-129.
• [7]Beavo JA: Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995, 75:725-748.
• [8]Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, M2-124 and M2-125 study groups: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009, 374:685-694.
• [9]Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF, M2-127 and M2-128 study groups: Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009, 374:695-703.
• [10]Pryzwansky KB, Madden VJ: Type 4A cAMP-specific phosphodiesterase is stored in granules of human neutrophils and eosinophils. Cell Tissue Res 2003, 312:301-311.
• [11]Peter D, Jin SL, Conti M, Hatzelmann A, Zitt C: Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4. J Immunol 2007, 178:4820-4831.
• [12]Sawai T, Ikai K, Uehara M: Cyclic adenosine monophosphate phosphodiesterase activity in peripheral blood mononuclear leucocytes from patients with atopic dermatitis: correlation with respiratory atopy. Br J Dermatol 1998, 138:846-848.
• [13]Hanifin JM, Chan SC: Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Invest Dermatol 1995, 105(1 Suppl):84S-8S.
• [14]Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, Schudt C, Tenor H: The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010, 23:235-256.
• [15]Boulet LP, Gauvreau G, Boulay ME, O'Byrne P, Cockcroft DW: The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti-inflammatory therapies. Allergy 2007, 62:1101-1110.
• [16]O'Byrne PM, Dolovich J, Hargreave FE: Late asthmatic responses. Am Rev Respir Dis 1987, 136:740-751.
• [17]Gauvreau GM, Lee JM, Watson RM, Irani AM, Schwartz LB, O'Byrne PM: Increased numbers of both airway basophils and mast cells in sputum after allergen inhalation challenge of atopic asthmatics. Am J Respir Crit Care Med 2000, 161:1473-1478.
• [18]Gauvreau GM, Watson RM, O'Byrne PM: Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999, 160:640-647.
• [19]Aalbers R, Kauffman HF, Vrugt B, Koeter GH, de Monchy JG: Allergen-induced recruitment of inflammatory cells in lavage 3 and 24 h after challenge in allergic asthmatic lungs. Chest 1993, 103:1178-1184.
• [20]Woolley KL, Adelroth E, Woolley MJ, Ellis R, Jordana M, O'Byrne PM: Effects of allergen challenge on eosinophils, eosinophil cationic protein, and granulocyte-macrophage colony-stimulating factor in mild asthma. Am J Respir Crit Care Med 1995, 151:1915-1924.
• [21]Bentley AM, Meng Q, Robinson DS, Hamid Q, Kay AB, Durham SR: Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am J Respir Cell Mol Biol 1993, 8:35-42.
• [22]Nouri-Aria KT, Irani AM, Jacobson MR, O'brien F, Varga EM, Till SJ, Durham SR, Schwartz LB: Basophil recruitment and IL-4 production during human allergen-induced late asthma. J Allergy Clin Immunol 2001, 108:205-211.
• [23]Gauvreau GM, Boulet LP, Cote J, Deschesnes F, Duong M, Killian K, Obminski G, Strinich TX, Watson RM, Cerasoli F, Schmid-Wirlitsch C, Bredenbröker D, O'Byrne PM: Effects of roflumilast on airway inflammation and function following allergen challenge in patients with allergic asthma [abstract]. Am J Respir Crit Care Med 2007, 175:A484.
• [24]Bateman ED, Izquierdo JL, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, Leichtl S, Bredenbröker D: Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol 2006, 96:679-686.
• [25]Cockcroft DW: Measure of airway responsiveness to inhaled histamine or methacholine; method of continuous aerosol generation and tidal breathing inhalation. In Airway responsiveness: measurement and interpretation. Edited by Hargreave FE, Woolcock AJ. Mississauga: Astra Pharmaceuticals Canada Ltd; 1985:22-28.
• [26]Cockcroft DW, Murdock KY, Kirby J, Hargreave F: Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am Rev Respir Dis 1987, 135:264-267.
• [27]Pizzichini E, Pizzichini MM, Efthimiadis A, Evans S, Morris MM, Squillace D, Gleich GJ, Dolovich J, Hargreave FE: Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med 1996, 154:308-317.
• [28]Bethke TD, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Hauschke D, David M, Lahu G, Zech K, Hermann R, Siegmund W: Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Int J Clin Pharmacol Ther 2006, 44:572-579.
• [29]Harbinson PL, MacLeod D, Hawksworth R, O'Toole S, Sullivan PJ, Heath P, Kilfeather S, Page CP, Costello J, Holgate ST, Lee TH: The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 1997, 10:1008-1014.
• [30]Louw C, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, Bardin PG: Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge. Respiration 2007, 74:411-417.
• [31]van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbröker D, Bardin PG: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol 2005, 116:292-298.
• [32]Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007, 62:1081-1087.
• [33]Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ: Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol 2007, 152:481-492.
• [34]Hatzelmann A, Schudt C: Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001, 297:267-279.
• [35]Gauvreau GM, Doctor J, Watron R, Jordana M, O'Byrne PM: Effects of inhaled budesonide on allergen-induced airway responses and airway inflammation. Am J Respir Crit Care Med 1996, 154:1267-1271.
• [36]Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR: Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 2010, 65:384-390.
• [37]Grootendorst DC, Gauw SA, Baan R, Kelly J, Murdoch RD, Sterk PJ, Rabe KF: Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Pulm Pharmacol Ther 2003, 16:115-120.