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Vol. 149, Suppl. 1, 2009
Issue release date: June 2009
Int Arch Allergy Immunol 2009;149(suppl 1):87–93

Neutrophilic Inflammation and CXC Chemokines in Patients with Refractory Asthma

Kikuchi S. · Kikuchi I. · Takaku Y. · Kobayashi T. · Hagiwara K. · Kanazawa M. · Nagata M.
Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan

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Background: There is evidence that eosinophils and neutrophils are simultaneously increased in the airways of some patients with chronic refractory asthma. The mechanisms by which neutrophils accumulate in the airways of asthmatics remain to be elucidated, however, chemoattractants for neutrophils such as CXC chemokines may affect either the accumulation or functional status of neutrophils in such patients. The objective of the present study was to identify the CXC chemokine responsible for the neutrophilic and possibly eosinophilic inflammation observed in the airways of patients with refractory asthma. Methods: Following the inhalation of hypertonic saline, induced sputum was obtained from 14 healthy controls, 16 patients with mild well-controlled nonrefractory asthma, and 14 patients with refractory asthma. Concentrations of CXC chemokines and differential inflammatory cell counts were determined. Results: The percentages of induced sputum eosinophils were significantly higher both in patients with nonrefractory asthma and in patients with refractory asthma. On the other hand, the percentages of neutrophils were increased only in sputum from patients with refractory asthma. The concentration of IL-8, but not ENA-78 or GRO-α, was also significantly increased in induced sputum from patients with refractory asthma. The concentration of IL-8 correlated significantly with the percentages of neutrophils. Conclusions: The results of the present study suggest that IL-8, but not ENA-78 or GRO-α, may contribute to the observation of neutrophilic inflammation in patients with refractory asthma.

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  1. Wenzel SE, Szefler SJ, Leung DYM, Sloan SI, Rex MD, Martin RJ: Bronchoscopic evaluation of severe asthma. Am J Resp Crit Care Med 1997;156:737–743.
  2. Gibson PG, Simpson JL, Saltos N: Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329–1336.
  3. Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ: Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999;353:2213–2214.
  4. Douwes J, Gibson P, Pekkanen J, Pearce N: Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643–648.
  5. The ENFUMOSA Study Group: The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003;22:470–477.
  6. Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, Hunt LW, Gleich GJ: Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993;148:713–719.
  7. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ: Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160:1532–1539.
  8. 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.
  9. Kikuchi S, Nagata M, Kikuchi I, Hagiwara K, Kanazawa M: Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int Arch Allergy Immunol 2005;137(suppl 1):7–11.
  10. Pober JS, Gimbrone MA Jr, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA: Overlapping patterns of activation of human endothelial cells by interleukin-1, tumor necrosis factor, and immune interferon. J Immunol 1986;137:1893–1896.
  11. Smart SJ, Casale TB: TNF-α-induced transendothelial neutrophil migration is IL-8 dependent. Am J Physiol 1994;266:238–245.
  12. Kikuchi S, Kikuchi I, Hagiwara K, Kanazawa M, Nagata M: Association of tumor necrosis factor-α and neutrophilic inflammation in severe asthma. Allergol Int 2005;54:621–625.
  13. 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.
  14. Donninger H, Glashoff R, Haitchi HM, Syce JA, Ghildyal R, van Rensburg E, Bardin PG: Rhinovirus induction of the CXC chemokine epithelial-neutrophil activating peptide-78 in bronchial epithelium. J Infect Dis 2003;187:1809–1817.
  15. Barnes PJ: New molecular targets for the treatment of neutrophilic diseases. J Allergy Clin Immunol 2007;119:1055–1062.
  16. Shute JK, Vrugt B, Lindley IJ, Holgate ST, Bron A, Albers R: Free and complexed interleukin-8 in blood and bronchial mucosa in asthma. Am J Respir Crit Care Med 1997;155:1877–1883.
  17. Tillie-Leblond I, Pugin J, Marquette CH, Lamblin C, Saulnier F, Brichet A, Wallaert B, Tonnel AB, Gosset P: Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmatics. Am J Respir Crit Care Med 1999;159:487–494.
  18. Gibson PG, Simpson JL, Saltos N: Heterogeneity of airway inflammation in patient asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329–1336.
  19. Pignatti P, Moscato G, Casarini S, Delmastro M, Poppa M, Brunetti G, Pisati P, Balbi B: Downmodulation of CXCL8/IL-8 receptors on neutrophils after recruitment in the airways. J Allergy Clin Immunol 2005;115:88–94.
  20. Kikuchi I, Kikuchi S, Kobayashi T, Hagiwara K, Kanazawa M, Nagata M: Eosinophil trans-basement migration induced by IL-8 and neutrophils. Am J Respir Cell Mol Biol 2006;34:760–765.
  21. American Thoracic Society: Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000;162:2341–2351.

    External Resources

  22. Keatings VM, Evans DJ, O’Connor BJ, Barnes PJ: Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings, and bronchoalveolar lavage fluid. Thorax 1997;52:372–374.
  23. Pepe C, Foley S, Shannon J, Lemiere C, Olivenstein R, Ernst P, Ludwig MS, Martin JG, Hamid Q: Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol 2005;116:544–549.
  24. Fukakusa M, Bergeron C, Tulic MK, Fiset PO, Al Dewachi O, Laviolette M, Hamid Q, Chakir J: Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-γ-inducible protein 10 expression in asthmatic airway mucosa. J Allergy Clin Immunol 2005;115:280–286.
  25. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR, Busse WW: The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 2000;105:1169–1177.
  26. Lummus ZL, Alam R, Bernstein JA, Bernstein DI: Diisocyanate antigen-enhanced production of monocyte chemoattractant protein-1, IL-8, and tumor necrosis factor-α by peripheral mononuclear cells of workers with occupational asthma. J Allergy Clin Immunol 1998;102:265–274.
  27. Wos M, Sanak M, Soja J, Olechnowicz H, Busse WW, Szczeklik A: The presence of rhinovirus in lower airways of patients with bronchial asthma. Am J Respir Crit Care Med 2008;177:1082–1089.
  28. Nakajima H, Gleich GJ, Kita H: Constitutive production of IL-4 and IL-10 and stimulated production of IL-8 by normal peripheral blood eosinophils. J Immunol 1996;156:4859–4866.
  29. Smart SJ, Casale TB: Pulmonary epithelial cells facilitate TNF-α-induced neutrophil chemotaxis. A role for cytokine networking. J Immunol 1994;152:4087–4094.
  30. Becker S, Quay J, Soukup J: Cytokine (tumor necrosis factor, IL-6, and IL-8) production by respiratory syncytial virus-infected human alveolar macrophages. J Immunol 1991;147:4307–4312.
  31. Burke SM, Issekutz TB, Mohan K, Lee PW, Shmulevitz M, Marshall JS: Human mast cell activation with virus-associated stimuli leads to the selective chemotaxis of natural killer cells by a CXCL8-dependent mechanism. Blood 2008;111:5467–5476.
  32. Cassatella MA: The production of cytokines by polymorphonuclear neutrophils. Immunol Today 1995;16:21–26.
  33. Henson PM, Wenzel SE: Neutrophils and their mediators in asthma; in Busse WW, Holgate ST (eds): Asthma and Rhinitis. Oxford, Blackwell Science, 2000, pp 503–530.

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