A randomized, placebo-controlled trial of roflumilast effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease

American Journal of Respiratory and Critical Care Medicine

Volumn 192, Issue 8, 2015, Pages 934-942

  Wells, J Michael ^a,b,c,d   Jackson, Patricia L ^a,b,c   Viera, Liliana ^a,b,c   Bhatt, Surya P ^a,b   Gautney, Joshua ^e   Handley, Guy ^e   King, R Wilson ^a,c   Xu, Xin ^a,c   Gaggar, Amit ^a,c,d   Bailey, William C ^a,b   Dransfield, Mark T ^a,b,d   Blalock, J Edwin ^a,b,c  

^a University of Alabama at Birmingham   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^c UAB Program in Protease and Matrix Biology   (United States)

^d BIRMINGHAM VA MEDICAL CENTER   (United States)

^e UNIVERSITY OF ALABAMA SCHOOL OF MEDICINE   (United States)

Author keywords

COPD; Neutrophil; Proline glycineproline; Prolyl endopeptidase; Roflumilast

Indexed keywords

AMINOPEPTIDASE; GLYCINE; INTERLEUKIN 8; LEUKOCYTE ELASTASE; LEUKOTRIENE A4; PLACEBO; PROLINE; PROLYL ENDOPEPTIDASE; ROFLUMILAST; AMINOPYRIDINE DERIVATIVE; BENZAMIDE DERIVATIVE; CYCLOPROPANE DERIVATIVE; EPOXIDE HYDROLASE; LEUKOTRIENE A4 HYDROLASE; PHOSPHODIESTERASE IV INHIBITOR; SERINE PROTEINASE;

ADULT; ARTICLE; BLOOD ANALYSIS; CARDIOPULMONARY EXERCISE TEST; CHRONIC BRONCHITIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL ARTICLE; COLUMN CHROMATOGRAPHY; CONTROLLED STUDY; COUGHING; DIARRHEA; DISEASE SEVERITY; DRUG SAFETY; ELECTROSPRAY; ENZYME ACTIVITY; EXERCISE TOLERANCE; FEMALE; HUMAN; INFLAMMATION; INSOMNIA; LUNG FUNCTION; MALE; NAUSEA; NEUTROPHIL; NEUTROPHIL COUNT; OUTCOME ASSESSMENT; PLEURISY; PNEUMONIA; PRIORITY JOURNAL; PROTEIN DEGRADATION; QUALITY OF LIFE; QUALITY OF LIFE ASSESSMENT; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; SPUTUM ANALYSIS; ST. GEORGE RESPIRATORY QUESTIONNAIRE; UPPER RESPIRATORY TRACT INFECTION; WEIGHT REDUCTION; AGED; BRONCHITIS, CHRONIC; DOUBLE BLIND PROCEDURE; ENZYMOLOGY; FORCED EXPIRATORY VOLUME; IMMUNOLOGY; METABOLISM; MIDDLE AGED; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SIGNAL TRANSDUCTION; SPIROMETRY; SPUTUM; TREATMENT OUTCOME; VITAL CAPACITY;

AGED; AMINOPYRIDINES; BENZAMIDES; BRONCHITIS, CHRONIC; CYCLOPROPANES; DOUBLE-BLIND METHOD; EPOXIDE HYDROLASES; EXERCISE TOLERANCE; FEMALE; FORCED EXPIRATORY VOLUME; GLYCINE; HUMANS; INFLAMMATION; MALE; MIDDLE AGED; NEUTROPHILS; PHOSPHODIESTERASE 4 INHIBITORS; PROLINE; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; QUALITY OF LIFE; SERINE ENDOPEPTIDASES; SIGNAL TRANSDUCTION; SPIROMETRY; SPUTUM; TREATMENT OUTCOME; VITAL CAPACITY;

EID: 84945586371     PISSN: 1073449X     EISSN: 15354970     Source Type: Journal    
DOI: 10.1164/rccm.201503-0543OC     Document Type: Article

References (43)

1. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. National vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics. National Vital Statistics System 2013;61:1-117.
2. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al.; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:1065-1072.
3. Stnescu D, Sanna A, Veriter C, Kostianev S, Calcagni PG, Fabbri LM, Maestrelli P. Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 1996;51:267-271.
4. Stockley RA. Neutrophils and the pathogenesis of COPD. Chest 2002;121(Suppl. 5):151S-155S.
5. Mannino DM. Chronic obstructive pulmonary disease: definition and epidemiology. Respir Care 2003;48:1185-1191; discussion 1191-1183.
6. Ferguson GT. Recommendations for the management of COPD. Chest 2000;117(Suppl. 2):23S-28S.
7. Kim V, Benditt JO, Wise RA, Sharafkhaneh A. Oxygen therapy in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:513-518.
8. Scanlon PD, Connett JE,Waller LA, Altose MD, BaileyWC, Buist AS, Tashkin DP; Lung Health Study Research Group. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: The Lung Health Study. Am J Respir Crit Care Med 2000;161:381-390.
9. Miller M, Cho JY, Pham A, Friedman PJ, Ramsdell J, Broide DH. Persistent airway inflammation and emphysema progression on CT scan in ex-smokers observed for 4 years. Chest 2011;139:1380-1387.
10. Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469-473.
11. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176: 154-161.
12. 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.
13. 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.
14. Antoniu SA. New therapeutic options in the management of COPD: focus on roflumilast. Int J Chron Obstruct Pulmon Dis 2011;6:147-155.
15. 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.
16. Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, Folkerts G, Nijkamp FP, Blalock JE. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med 2006;12:317-323.
17. Wells JM, O'Reilly PJ, Szul T, Sullivan DI, Handley G, Garrett C, McNicholas CM, Roda MA, Miller BE, Tal-Singer R, et al. An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014;190:51-61.
18. Hardison MT, Galin FS, Calderon CE, Djekic UV, Parker SB, Wille KM, Jackson PL, Oster RA, Young KR, Blalock JE, et al. The presence of a matrix-derived neutrophil chemoattractant in bronchiolitis obliterans syndrome after lung transplantation. J Immunol 2009;182:4423-4431.
19. Gaggar A, Jackson PL, Noerager BD, O'Reilly PJ, McQuaid DB, Rowe SM, Clancy JP, Blalock JE. A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol 2008;180:5662-5669.
20. Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, Shastry S, Rowe SM, Shim YM, Hussell T, et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 2010;330:90-94.
21. Haeggström JZ. Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. J Biol Chem 2004;279:50639-50642.
22. O'Reilly PJ, Jackson PL, Wells JM, Dransfield MT, Scanlon PD, Blalock JE. Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations. BMJ Open 2013;3:e004140.
23. O'Reilly PJ, Hardison MT, Jackson PL, Xu X, Snelgrove RJ, Gaggar A, Galin FS, Blalock JE. Neutrophils contain prolyl endopeptidase and generate the chemotactic peptide, PGP, from collagen. J Neuroimmunol 2009;217:51-54.
24. Vestbo J, Hurd SS, AgustAG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347-365.
25. O'Reilly P, Jackson PL, Noerager B, Parker S, Dransfield M, Gaggar A, Blalock JE. N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD. Respir Res 2009;10:38.
26. Calverley PM, Martinez FJ, Fabbri LM, Goehring UM, Rabe KF. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstruct Pulmon Dis 2012;7:375-382.
27. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015;385:857-866.
28. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al.; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319-338.
29. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-117.
30. Sutherland ER, Pak J, Langmack EL, Silkoff PE, Martin RJ. Safety of sputum induction in moderate-to-severe chronic obstructive pulmonary disease. Respir Med 2002;96:482-486.
31. in 't Veen JC, de Gouw HW, Smits HH, Sont JK, Hiemstra PS, Sterk PJ, Bel EH. Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma. Eur Respir J 1996;9: 2441-2447.
32. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation: the St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321-1327.
33. Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest 2003;124: 2182-2191.
34. Ko FW, Leung TF, Wong GW, Ngai J, To KW, Ng S, Hui DS. Measurement of tumor necrosis factor-alpha, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2009;4:79-86.
35. Bollinger JG, Thompson W, Lai Y, Oslund RC, Hallstrand TS, Sadilek M, Turecek F, Gelb MH. Improved sensitivity mass spectrometric detection of eicosanoids by charge reversal derivatization. Anal Chem 2010;82:6790-6796.
36. Abdul Roda M, Sadik M, Gaggar A, Hardison MT, Jablonsky MJ, Braber S, Blalock JE, Redegeld FA, Folkerts G, Jackson PL. Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation. PLoS One 2014;9:e97594.
37. 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.
38. Overbeek SA, Braber S, Koelink PJ, Henricks PA, Mortaz E, LoTam Loi AT, Jackson PL, Garssen J, Wagenaar GT, Timens W, et al. Cigarette smoke-induced collagen destruction; key to chronic neutrophilic airway inflammation? PLoS One 2013;8:e55612.
39. Braber S, Koelink PJ, Henricks PA, Jackson PL, Nijkamp FP, Garssen J, Kraneveld AD, Blalock JE, Folkerts G. Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown. Am J Physiol Lung Cell Mol Physiol 2011;300:L255-L265.
40. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, et al.; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-698.
41. Han MK, Tayob N, Murray S, Dransfield MT, Washko G, Scanlon PD, Criner GJ, Casaburi R, Connett J, Lazarus SC, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 2014;189:1503-1508.
42. Kim V, Davey A, Comellas AP, Han MK, Washko G, Martinez CH, Lynch D, Lee JH, Silverman EK, Crapo JD, et al.; COPDGene Investigators. Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir Res 2014;15:52.
43. Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, Hersh CP, Stinson D, Silverman EK, Criner GJ; COPDGene Investigators. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest 2011;140:626-633.