CHEST COPD (ELISA) CXCL9 CXCL10 CXCL11 CCL5

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1 CHEST COPD COPD CXCR3 CCR5 Claudia Costa, MD; Rogerio Rufino, MD; Suzanne L. Traves, PhD;Jose Roberto Lapa e Silva, MD; Peter J. Barnes, DSc, FCCP; and Louise E. Donnelly, PhD COPD CD4 CD8 T CXCR3 CCR5 COPD CXCR3 CXCL9 CXCL1 CXCL11 CCR5 CCL5 (n = 18) (n = 2) COPD (n = 35) (ELISA) CXCL9 CXCL1 CXCL11 CCL5 COPD CXCL9 CXCL1 CXCL11 CCL5 CXCL pg / ml (IQR ) 1.4pg/mL(IQR 1.4) (P.1) 8.5pg/mL(IQR 16.) CXCL1 16.9pg/mL(IQR ) 3.7 pg / ml (IQR 18.8) (P.5) 11.3 pg / ml (IQR ) CXCL pg / ml (IQR ) 33.5 pg / ml (IQR ) (P.5) 49.8 pg / ml (IQR ) CCL pg / ml (IQR ) 33.5 pg / ml (IQR ) (P.1) CCL5 63. pg / ml (IQR ) P.1 FEV 1 FEV 1 /FVC CXCR3 CCL5 COPD COPD 36

2 CCR5; (chemokines); (COPD); CXCR3; (sputum) DTT = dithiothreitol; ELISA = enzyme-linked immunosorbent assay; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IFN = interferon; IQR = interquartile range COPD [1 2] T [3] CD4 CD8 [4] COPD [5] T COPD CD4 /CD8 T CD8 [3,4] COPDT CXCR3 CCR5 [6] COPD CXCR3 CXCL1 ( 1 kd IFN ) [7,8] CXCR3 CD8 From Airway Disease (Drs. Costa, Rufino, Traves, Barnes, and Donnelly), National Heart and Lung Institute, Imperial College London, London, UK; and Laboratorio Multidisciplinar de Pesquisa (Dr. Lapa e Silva), Hospital Universitrio Clementino Fraga Filho/Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. This study was supported by the National Heart and Lung Institute, London, UK; Committee for Postgraduate Courses in Higher Education, Brazil; and National Council for Scientific and Technological Development, Brazil. Correspondence to: Louise E. Donnelly, PhD, Airway Disease, National Heart and Lung Institute, Dovehouse St, London,SW3 6LY, UK; l.donnelly@imperial.ac.uk COPD CD8 [7] CXCR3 B COPDB [1] CXCR3 12 [6] COPD T COPD CCR5 RANTES ( T ) / CCL5 1α (CCL3) 1β (CCL4) [9] CXCR3 3 IFN γ (CXCL9) CXCL1 IFN T α (CXCL11) [1] CXCL11 [11] CXCR3 CCR3 [12] CXCL11 CCR5 [13] CXCL9 [14] CXCR3 T CXCL9 CXCL1 CXCL11 CCL5 IFN γ COPD Th1 / Tc1 [15] COPD CXCR3 IFN γ 3 CXCR3 [16] COPD [17] CXCL1 CHEST

3 1 (1) COPD / / 8/1 13/7 22/13 / (2 3) / y FEV 1 /% (2 4) FEV 1 /FVC (2 4) (1) (2) COPD P.1 (3) COPD P.1 (4) COPD P.1 [18] [9] CXCR3 CCR5 COPD COPD CXCL9 CXCL1 CXCL11 CCL5 Rio de Janeiro Clementino Fraga Filho Rio de Janeiro Pedro Ernesto Rio de Janeiro Brompton Harefield COPD (GOLD) [19] 4wk COPD Pin [2] 4 µg (Ultra-NEB 99 Devilbiss Somerse PA) 3% 4% 5% ( / ) 7min (PEF) 1% 2 COPD (1) COPD /x ( ) ( ) 549. ( ) /x ( ) ( ) 122. ( ) / % 62.2 ( ) 43.5 ( ) 3. ( ) (3) /x ( ) 173. ( ) 29. ( ) / % 35.2 ( ) 5.1 (3. 7.1) 68 (3 75.) /x1 5. (. 4.) 1.5 (. 6.5) 4. (2. 23.) (3) /x1 5.5 (. 1.). (. 1.5) 2. (. 5.) (2) CD4 + /x1 5. (. 1.). (. 1.). (. 1.) CD8 + /x1 5. (. 1.). (. 1.) 1. (. 4.) (2 3) /x (. 3.). (. 2.). (. 3.) (1) (IQR) (2) COPD P.5 (3) COPD P.1 38

4 3 DTT (1) CCL5 CXCL9 CXCL1 CXCL11 FEV 1 /%.38 (3).45 (4).27 (2).3 (3) FEV 1 /FVC.39 (4).48 (4).27 (2).37 (3).32 (3).31 (3).29 (2).28 (2) /%.31 (3).24 (2).29 (2).33 (3) (2).3 /%.42 (4).32 (3).44 (4).26 (2) (1) Spearman (2) P.5 (3) P.1 (4) P.1 2h (3 g) 4 (DTT).1% ( / ) 1 min 4 Dulbecco.5% ( / ) DTT 5min (3 g) /ml ( 3 shandon cheshire UK) Diff- Quick (Laborclin Pinhais Brazil) T CD4 (Sigma Chemical St. Louis MO) CD8 (Sigma Chemical) CCL5 CXCL9 CXCL1 CXCL1 (ELISA) (R&D Systems Minneapolis MN) DTT DTT 7.8pg/mL GraphPad Prism (GraphPad Softwate San Diego CA) STATA 8. (StataCorp LP College Station TX) (IQR) CXCL9 CXCL1 CXCL9 / pg ml -1 CXCL1 / pg ml -1 CXCL11 / pg ml A B C (n = 18) (n = 2) COPD (n = 35) COPD CXCR3 COPD ELISA CXCL9 (A) CXCL1 (B) CXCL11 (C) * P.5 *** P.1 CHEST

5 Tobit CXCL11 CCL5 P.5 15 A COPD FEV 1 FEV 1 /FVC ( 1) COPD COPD 6 GOLD CCL5 / pg ml (n = 18) (n = 2) COPD (n = 35) B 9 COPD CD8 T ( ) CD8 T COPD CCL5 / pg ml -1 7 ( 3) COPD ( 3) 5 GOLD (n =6) GOLD (n = 13) GOLD + (n =16) CXCR3 CXCR3CXCL9 1.4 pg / ml (IQR 1.4) 8.5 pg / ml (IQR 6.) COPD 14.3 pg / ml (IQR ) CXCL1 3.7 pg / ml (IQR 18.8) 11.3 pg / ml (IQR ) COPD 16.9pg/mL(IQR )CXCL pg / ml (IQR ) 49.8 pg / ml (IQR ) COPD 58.1 pg / ml (IQR ) COPD 2 COPD CCL5 COPD ELISA CCL5 A CCL5 ( DTT) B COPD CCL5 (GOLD ) ** P.1 *** P.1 COPD 33.5 pg / ml (IQR ) 63.pg/mL(IQR ) COPD 6.4 pg / ml (IQR ) ( 2A) CCL5 ( 1) COPD COPD COPD CCL5 CCL5 CCL5 GOLD (GOLD 31

6 ) CCL5 ( 2B) COPD ( ) CXCL9 CXCL1 CXCL11 CCL5 CCL5 CXCL9 CXCL1 CXCL11 (FEV 1 FEV 1 /FVC) ( 3 3) CCL5 CXCL9 CXCL1 CXCL11 ( 3) CXCL1 () CCL5 CXCL9 CXCL11 ( CXCL9 / pg ml A CXCL1 / pg ml B CXCL11 / pg ml C CCL5 / pg ml D FEV 1 /% 3 FEV 1 FEV 1 CXCL9 (A) FEV 1 CXCL1 (B) FEV 1 CXCL11 (C) FEV 1 CCL5 (D) COPD CHEST

7 4 COPD (1) CCL5 CXCL9 CXCL1 CXCL11 FEV 1 /%.62 (4).39 (2).2.26 FEV 1 /FVC.43 (2) (2) / % (2) (2).8 /%.47 (4) (4) (4).6.8 CD (2).7.11 CD (4).6.9 (1) Spearman (2) P.5 COPD COPD CXCR3 COPD () [3] COPD CXCL9 [27] CXCR3 [28] (3) P.1 (4) P.1 COPD r =.38 r =38 r =.23) COPD CXCL9 CXCL1 CXCL11 ( 4) CCL5 CXCL1 ( 4) COPD [21-23] [24] DTT [25,26] COPD CXCR3 CXCR3 CCL5 (FEV 1 FEV 1 /FVC) CXCR3 GOLD COPD COPD CCL5 CXCR3 T [29] COPD COPD ( ) COPD CXCL11 CXCL11 CXCR3 CXCR3 T CXCR3 CXCL11 T COPD COPD CXCR3 [31] COPD [1] CXCR3 COPD CD8 T CD8 312

8 COPD CXCL1 COPD COPDCXCL9 CXCL1 CXCL11 CCL5 CXCR3 CCL5 COPD 1 Hogg JC, et al. N Engl J Med 24;35: Hogg JC. Lancet 24;364: Saetta M, et al. Am J Respir Crit Care Med 1999;16: Jeffery PK. Novartis Found Symp 21;234: Cosio MG, et al. Chest 22;121(Suppl):16S 165S 6 Grumelli S, et al. PLoS Med 24;1:e8 7 Saetta M, et al. Am J Respir Crit Care Med 22;165: Hardaker EL, et al. FASEB J 24;18: Donnelly LE, et al. Trends Pharmacol Sci 26;27: Stanford MM, et al. J Leukoc Biol 23;74: Cole KE, et al. J Exp Med 1998;187: Xanthou G, et al. Eur J Immunol 23;33: Petkovic V, et al. J Leukoc Biol 24;76: Fulkerson PC, et al. Proc Natl Acad Sci U S A 24;11: Annunziato F, et al. J Leukoc Biol 1999;65: Sauty A, et al. J Immunol 1999;162: Culpitt SV, et al. Am J Respir Crit Care Med 1999;16: Spurrell JC, et al. Am J Physiol Lung Cell Mol Physiol 25; 289:L85 L95 19 Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease NHLB/WHO workshop report. Bethesda, MD: National Institutes of Health, 21;1 1; publication No Pin I, et al. Thorax 1992;47: Keatings VM, et al. Am J Respir Crit Care Med 1997;155: Nightingale JA, et al. Am J Respir Crit Care Med 2;162: Culpitt SV, et al. Respir Med 25;99: Hargreave FE, et al. Am J Respir Crit Care Med 1999;16: S53 S57 25 Woolhouse IS, et al. Thorax 22;57: Beier J, et al. J Lab Clin Med 24;144: Bhowmik A, et al. Thorax 1998;53: Gasperini S, et al. J Immunol 1999;162: Thomas RA, et al. Chest 24;126: Sauty A, et al. J Immunol 21;167: Belperio JA, et al. J Immunol 22;169: CHEST 28;133: CHEST

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