Background: Neutrophilic inflammation is a major feature of chronic obstructive pulmonary disease (COPD), and several novel therapies aim at the suppression of neutrophils in COPD. Due to the abundance and redundancy of mediators involved in neutrophilic inflammation, there is an ongoing controversy about the feasibility of such anti-neutrophilic approaches. Systemic chemotherapy has broad side effects, including neutrophil toxicity. Objectives: In this observational study, we have measured cellular and neutrophil-related inflammatory markers in induced sputum of COPD patients with unresectable non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Methods: 15 COPD/NSCLC patients were followed during their first course of chemotherapy with cisplatin (60 mg/m2 days 1 and 7) and etoposide (100 mg/m2 days 3, 4, and 5). Sputum induction was performed before, and 3 weeks after chemotherapy. Peripheral blood count, sputum total cells and differentials, and the concentrations of the inflammatory markers interleukin (IL)-8, and matrix metalloproteinase (MMP)-9 in sputum supernatant were analyzed. Results: Similar to COPD controls (n = 12), COPD/NSCLC patients had increased levels of absolute and relative sputum neutrophils, IL-8, and MMP-9 at baseline, when compared with healthy controls (n = 14, p < 0.001, all comparisons). After chemotherapy, there was a significant reduction in peripheral blood leukocytes (pre: 10,736 ± 550, post: 6,536 ± 1,064 cells/µl, p = 0.002) and log neutrophils (pre: 8.9 ± 0.09, post: 8.1 ± 0.2 cells/µl, p = 0.004), whereas log sputum neutrophils (pre: 0.3 ± 0.37, post: 0.18 ± 0.3 cells × 106/ml, p = 0.1) , IL-8 (pre 15.9 ± 3.8, post: 17.7 ± 3.6 ng/ml, p = 0.7), and log MMP-9 (pre: 5.3 ± 0.57, post: 5.6 ± 0.7 ng/ml, p = 0.33) remained unchanged. Conclusion: A single course of platinum-based chemotherapy markedly decreases peripheral blood neutrophils, but has no effect on inflammatory patterns of induced sputum in COPD patients with unresectable NSCLC.

Keywords:
COPD, Induced sputum, Neutrophils, Chemotherapy, Cytokines
1.
Thurlbeck WM: Pathology of chronic obstructive pulmonary disease. Clin Chest Med 1990;11:389–404.
2.
Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al: Severity of airflow limitiation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998;158:1277–1285.
3.
Stockley RA: Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 1999;160:S49–S52.
4.
Rennard SI: Inflammation and repair processes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S12–S16.
5.
McNulty CA, Symon FA, Wardlaw AJ: Characterization of the integrin and activation steps mediating human eosinophil and neutrophil adhesion to chronically inflamed airway endothelium. Am J Respir Cell Mol Biol 1999;20:1251–1259.
6.
Adams DH, Lloyd AR: Chemokines: Leucocyte recruitment and activation cytokines. Lancet 1997;349:490–495.
7.
Mikami M, Llewellyn-Jones CG, Bayley D, Hill SL, Stockley RA: The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med 1998;157:723–728.
8.
Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ: Increased neutrophils and cytokines, TNF-α and IL-8, in induced sputum of non-asthmatic patients with dry cough. Thorax 1999;54:234–237.
9.
Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen TK, et al: Randomised double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. Br Med J 2000;320:1297–1303.
10.
Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ: Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1635–1639.
11.
Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ: Effects of inhaled and oral glucocorticosteroids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997;155:542–548.
12.
Barnes PJ: Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S72–S79.
13.
Groenke L, Beeh KM, Wang JH, Kornmann O, Beier J, Cameron R, Brauburger J, Muecke M, Holz O, Joerres RA, Shaw M, Bindschedler M, Buhl R, Magnussen H: LTB 019A, a leukotriene B4 receptor antagonist, has no effect on the levels of neutrophils, MPO, IL-8 and TNF-alpha in induced sputum of patients with COPD. Am J Respir Crit Care Med 2002;165:A598.
14.
Fishman P, Levi J, Notti I, Djaldetti M: Synthesizing activity and ultrastructural findings of human blood cells after incubation with cis-platinum ‘in vitro’. Biomedicine 1981;34:78–82.
15.
Fumarulo R, De Rinaldis P, Riccardi S, Giordano D: Effects of cis-platin on the contractile system of polymorphonuclear leukocytes. G Batteriol Virol Immunol 1982;75:224–232.
16.
Fumarulo R, Riccardi S, Restaino A, Giordano D: Effect of cisplatin on the oxidative metabolism of polymorphonuclear leukocytes in cancer patients. Tumori 1984;70:227–229.
17.
Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME: Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum 1992;35:376–384.
18.
Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163:1256–1276.
19.
Beeh KM, Kornmann O, Lill J, Buhl R: Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: Correlation with lung function. Thorax 2001;56:557–560.
20.
MacNee W, Wiggs B, Belzberg AS, Hogg JC: The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med 1989;321:924–928.
21.
Than TA, Ogino T, Omori M, Okada S: Monochloramine inhibits etoposide-induced apoptosis with an increase in DNA aberration. Free Radic Biol Med 2001;30:932–940.
22.
Lee E, Lindo T, Jackson N, Meng-Choong L, Reynolds P, Hill A, et al: Reversal of human neutrophil survival by leukotriene B4 receptor blockade and 5-lipoxygenase activating protein inhibitors. Am J Respir Crit Care Med 1999;160:2079–2085.
23.
Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C: Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 1999;83:866–869.
24.
Yuan A, Yang PC, Yu CJ, Chen WJ, Lin FY, Kuo SH, et al: Interleukin-8 messenger ribonucleic acid expression correlates with tumor progression, tumor angiogenesis, patient survival, and timing of relapse in non-small-cell lung cancer. Am J Respir Crit Care Med 2000;162:1957–1963.
25.
Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC, Yang PC: Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. J Clin Oncol 2002;20:900–910.
© 2003 S. Karger AG, Basel
2003
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