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GM-CSF is underestimated as a mediator of acute exacerbations of COPD
Inflammatory indicators and therapeutic targets in COPD during exacerbations
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Gary P Anderson, Senior Lecturer The University of Melbourne, Louis Irving, John A. Hamilton, Ross Vlahos, and Steven Bozinovski
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gpa{at}unimelb.edu.au Gary P Anderson, et al.
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To the Editor In their recent report on inflammatory correlates in induced sputum during severe exacerbations of COPD Tsoumakidou and colleagues reported on levels of GM-CSF (1). Their data showed that GM-CSF increased during exacerbations (stable 35.8 (range 0-142), exacerbation 110 (0-1010) pg/mL) although this increase was ‘not statistically significant’. We are concerned that the ELISA method used in this study substantially underestimates the likely contribution of GM-CSF to AECOPD. During local infection or in response to endotoxin GM-CSF is very rapidly consumed in biological fluids by receptor internalization which leads to artificially low levels when measured by ELISA (2). In animal models GM-CSF is difficult to detect by ELISA under conditions where neutralizing GM-CSF leads to pronounced suppression of inflammation (3, 4). Given that GM-CSF is implicated in (i) inflammation triggered by gram negative bacteria products and non-infectious particulates implicated in COPD exacerbations (ii) regulation of Toll-like receptor expression important for innate immune defenses in the lung (iii) activation of the inflammatory transcription factor NFKB and AP-1 known to be involved in COPD and (iv) neutrophil and macrophage activation and survival (3, 4, 5, 6) we feel it is apposite to adopt more sensitive and appropriate methods before excluding GM-CSF as a determinant of acute exacerbations of COPD. 1. Tsoumakidou, M., N. Tzanakis, G. Chrysofakis, and N.M. Siafakas. 2005. Nitrosative Stress, Heme Oxygenase-1 Expression and Airway Inflammation During Severe Exacerbations of COPD. Chest 127:1911-1918. 2. Metcalf, D., N.A. Nicola, S. Mifsud, and L. Di Rago. 1999. Receptor clearance obscures the magnitude of granulocyte-macrophage colony -stimulating factor responses in mice to endotoxin or local infections. Blood 93:1579-1585. 3. Bozinovski, S., J.E. Jones, R. Vlahos, J.A. Hamilton, and G.P. Anderson. 2002. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem 277:42808-42814. 4. Bozinovski, S., J. Jones, S.J. Beavitt, A.D. Cook, J.A. Hamilton, and G.P. Anderson. 2004. Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR- 4. Am J Physiol Lung Cell Mol Physiol 286:L877-885. 5. Ebner, K., A. Bandion, B.R. Binder, R. de Martin, and J.A. Schmid. 2003. GMCSF activates NF-kappaB via direct interaction of the GMCSF receptor with IkappaB kinase beta. Blood 102:192-199. 6. Fujii, T., S. Hayashi, J.C. Hogg, R. Vincent, and S.F. Van Eeden. 2001. Particulate matter induces cytokine expression in human bronchial epithelial cells. Am J Respir Cell Mol Biol 25:265-271. |
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Hiroyasu Yasuda, MD, PhD Tohoku University School of Medicine, Mutsuo Yamaya, Katsutoshi Nakayama, Takahiko Sasaki, Daisuke Inoue, Motoki Yoshida, Hidetada Sasaki
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yasuda{at}geriat.med.tohoku.ac.jp Hiroyasu Yasuda, et al.
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To the editor: We read with great interest the article by Tsoumakidou and colleagues on airway inflammation demonstrating increases in nitrosotyrosine positive and heme oxygenase (HO)-1 positive inflammatory cells in induced sputum samples at the severe exacerbations compared with those at stable conditions in patients with chronic obstructive pulmonary disease (COPD).1 We completely agree with their non-invasive method to study the main mechanism of COPD exacerbation in vivo by immunocytochemical analysis. Furthermore, we think highly of their direct demonstration regarding an up -regulation of HO-1 protein with an increase in oxidative stress in sputum cells in patients with exacerbated COPD that has not been fully proven in spite of several speculations about it.2, 3 We think that Tsoumakidou, et al. demonstrated two important facts.1 First, nitrosative stress and HO-1 induction in the lung were significantly associated with COPD exacerbation in patients with COPD even if they were treated with long-acting ƒÀ2-agonists, short-acting antichollinergic agents and inhaled corticosteroids before the exacerbations.1 This is consistent with our previous report that exhaled carbon monoxide (CO) levels and blood carboxyhemoglobin (Hb-CO) concentration may be good indictors of disease activity of COPD regardless of the corticosteroids inhalation therapy.2, 3 Second, they also demonstrated that increases in interleukin-8 levels and myeloperoxidase levels in sputum were strongly associated with the onset of COPD exacerbations.1 This means that an increase in nitrosative stress related to the activated neutrophils may still play a key role at the exacerbation of COPD in patients treated with inhaled corticosteroids therapy. Although, N-acetylcysteine, a potent antioxidant agent, did not reduce the frequency of exacerbation of COPD in patients treated with inhaled corticosteroids therapy,4 Tsoumakidou and colleagues suggest that the new therapeutic targets regarding COPD exacerbation may be to suppress nitrosative stress and to control excessively activated neutrophil in the lung.1 In summary, endogenously produced CO levels from up-regulated HO-1 in airway may be a good indicator as an inflammatory marker and nitrosative stress and excessively activated neutrophil in the lung may be therapeutic targets of COPD exacerbation. References 1. Tsoumakidou M, Tzanakis N, Chrysofakis G, et al. Nitrosative stress, heme oxygenase-1 expression and airway inflammation during severe exacerbations of COPD. Chest 2005; 127:1911-1918 2. Yasuda H, Yamaya M, Nakayama K, et al. Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171:1246-51 3. Yasuda H, Yamaya M, Nakayama K, et al. Increased blood carbon monoxide from endogenous production in chronic obstructive pulmonary disease. Am J Respir Crit Care Med (in press) 4. Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of N- acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005;365:1552-1560 |
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