Abstract
Background: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (FeNO) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of FeNO and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test.
Methods: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. FeNO was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (δN2) and the closing volume (CV) were assessed from the single breath washout curve.
Results: The median FeNO level was 30.4 ppb (range 10.1–82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6–2.7), and the mean (SD) δN2 value was 1.1 (0.4)% N2/l. FeNO was positively associated with δN2 (rs = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs = –0.58; p = 0.017) and CV as a percentage of vital capacity (rs = 0.58; p = 0.019).
Conclusions: FeNO and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.
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Selected References
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- Alving K., Weitzberg E., Lundberg J. M. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J. 1993 Oct;6(9):1368–1370. [PubMed] [Google Scholar]
- Bousquet J., Jeffery P. K., Busse W. W., Johnson M., Vignola A. M. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000 May;161(5):1720–1745. doi: 10.1164/ajrccm.161.5.9903102. [DOI] [PubMed] [Google Scholar]
- Buist A. S., Ross B. B. Predicted values for closing volumes using a modified single breath nitrogen test. Am Rev Respir Dis. 1973 May;107(5):744–752. doi: 10.1164/arrd.1973.107.5.744. [DOI] [PubMed] [Google Scholar]
- Carroll N., Elliot J., Morton A., James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis. 1993 Feb;147(2):405–410. doi: 10.1164/ajrccm/147.2.405. [DOI] [PubMed] [Google Scholar]
- Cosio M., Ghezzo H., Hogg J. C., Corbin R., Loveland M., Dosman J., Macklem P. T. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med. 1978 Jun 8;298(23):1277–1281. doi: 10.1056/NEJM197806082982303. [DOI] [PubMed] [Google Scholar]
- Dworski R., Murray J. J., Roberts L. J., 2nd, Oates J. A., Morrow J. D., Fisher L., Sheller J. R. Allergen-induced synthesis of F(2)-isoprostanes in atopic asthmatics. Evidence for oxidant stress. Am J Respir Crit Care Med. 1999 Dec;160(6):1947–1951. doi: 10.1164/ajrccm.160.6.9903064. [DOI] [PubMed] [Google Scholar]
- Fukuchi Y., Cosio M., Murphy B., Engel L. A. Intraregional basis for sequential filling and emptying of the lung. Respir Physiol. 1980 Sep;41(3):253–266. doi: 10.1016/0034-5687(80)90075-4. [DOI] [PubMed] [Google Scholar]
- Haley K. J., Sunday M. E., Wiggs B. R., Kozakewich H. P., Reilly J. J., Mentzer S. J., Sugarbaker D. J., Doerschuk C. M., Drazen J. M. Inflammatory cell distribution within and along asthmatic airways. Am J Respir Crit Care Med. 1998 Aug;158(2):565–572. doi: 10.1164/ajrccm.158.2.9705036. [DOI] [PubMed] [Google Scholar]
- Hamid Q., Song Y., Kotsimbos T. C., Minshall E., Bai T. R., Hegele R. G., Hogg J. C. Inflammation of small airways in asthma. J Allergy Clin Immunol. 1997 Jul;100(1):44–51. doi: 10.1016/s0091-6749(97)70193-3. [DOI] [PubMed] [Google Scholar]
- Kharitonov S. A., Barnes P. J. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001 Jun;163(7):1693–1722. doi: 10.1164/ajrccm.163.7.2009041. [DOI] [PubMed] [Google Scholar]
- Kharitonov S. A., Donnelly L. E., Montuschi P., Corradi M., Collins J. V., Barnes P. J. Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma. Thorax. 2002 Oct;57(10):889–896. doi: 10.1136/thorax.57.10.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kharitonov S., Alving K., Barnes P. J. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J. 1997 Jul;10(7):1683–1693. doi: 10.1183/09031936.97.10071683. [DOI] [PubMed] [Google Scholar]
- Massaro A. F., Mehta S., Lilly C. M., Kobzik L., Reilly J. J., Drazen J. M. Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am J Respir Crit Care Med. 1996 May;153(5):1510–1514. doi: 10.1164/ajrccm.153.5.8630594. [DOI] [PubMed] [Google Scholar]
- Mauad Thais, Silva Luis F. F., Santos Mario A., Grinberg Lea, Bernardi Fabiola D. C., Martins Milton A., Saldiva Paulo H. N., Dolhnikoff Marisa. Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma. Am J Respir Crit Care Med. 2004 May 19;170(8):857–862. doi: 10.1164/rccm.200403-305OC. [DOI] [PubMed] [Google Scholar]
- Montuschi P., Corradi M., Ciabattoni G., Nightingale J., Kharitonov S. A., Barnes P. J. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med. 1999 Jul;160(1):216–220. doi: 10.1164/ajrccm.160.1.9809140. [DOI] [PubMed] [Google Scholar]
- OTIS A. B., MCKERROW C. B., BARTLETT R. A., MEAD J., MCILROY M. B., SELVER-STONE N. J., RADFORD E. P., Jr Mechanical factors in distribution of pulmonary ventilation. J Appl Physiol. 1956 Jan;8(4):427–443. doi: 10.1152/jappl.1956.8.4.427. [DOI] [PubMed] [Google Scholar]
- Perrier Arnaud, Roy Pierre-Marie, Sanchez Olivier, Le Gal Grégoire, Meyer Guy, Gourdier Anne-Laurence, Furber Alain, Revel Marie-Pierre, Howarth Nigel, Davido Alain. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med. 2005 Apr 28;352(17):1760–1768. doi: 10.1056/NEJMoa042905. [DOI] [PubMed] [Google Scholar]
- Quanjer P. H., Tammeling G. J., Cotes J. E., Pedersen O. F., Peslin R., Yernault J. C. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5–40. [PubMed] [Google Scholar]
- Ricciardolo F. L., Timmers M. C., Geppetti P., van Schadewijk A., Brahim J. J., Sont J. K., de Gouw H. W., Hiemstra P. S., van Krieken J. H., Sterk P. J. Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma. J Allergy Clin Immunol. 2001 Aug;108(2):198–204. doi: 10.1067/mai.2001.116572. [DOI] [PubMed] [Google Scholar]
- Robbins R. A., Hadeli K., Nelson D., Sato E., Hoyt J. C. Nitric oxide, peroxynitrite, and lower respiratory tract inflammation. Immunopharmacology. 2000 Jul 25;48(3):217–221. doi: 10.1016/s0162-3109(00)00220-4. [DOI] [PubMed] [Google Scholar]
- Shaw R. J., Djukanovic R., Tashkin D. P., Millar A. B., du Bois R. M., Orr P. A. The role of small airways in lung disease. Respir Med. 2002 Feb;96(2):67–80. doi: 10.1053/rmed.2001.1216. [DOI] [PubMed] [Google Scholar]
- Silkoff P. E., Robbins R. A., Gaston B., Lundberg J. O., Townley R. G. Endogenous nitric oxide in allergic airway disease. J Allergy Clin Immunol. 2000 Mar;105(3):438–448. doi: 10.1067/mai.2000.104938. [DOI] [PubMed] [Google Scholar]
- Sterk P. J., Fabbri L. M., Quanjer P. H., Cockcroft D. W., O'Byrne P. M., Anderson S. D., Juniper E. F., Malo J. L. Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:53–83. [PubMed] [Google Scholar]
- Sterk P. J., Quanjer P. H., van Zomeren B. C., Wise M. E., van der Lende R. The single breath nitrogen test in epidemiological surveys; an appraisal. Bull Eur Physiopathol Respir. 1981;17(3):381–397. [PubMed] [Google Scholar]
- Tsoukias N. M., George S. C. A two-compartment model of pulmonary nitric oxide exchange dynamics. J Appl Physiol (1985) 1998 Aug;85(2):653–666. doi: 10.1152/jappl.1998.85.2.653. [DOI] [PubMed] [Google Scholar]
- Van Hoydonck P. G. A., Wuyts W. A., Vanaudenaerde B. M., Schouten E. G., Dupont L. J., Temme E. H. M. Quantitative analysis of 8-isoprostane and hydrogen peroxide in exhaled breath condensate. Eur Respir J. 2004 Feb;23(2):189–192. doi: 10.1183/09031936.03.00049403. [DOI] [PubMed] [Google Scholar]
- Verbanck Sylvia, Schuermans Daniël, Paiva Manuel, Vincken Walter. Nonreversible conductive airway ventilation heterogeneity in mild asthma. J Appl Physiol (1985) 2002 Dec 6;94(4):1380–1386. doi: 10.1152/japplphysiol.00588.2002. [DOI] [PubMed] [Google Scholar]
- de Gouw H. W., Hendriks J., Woltman A. M., Twiss I. M., Sterk P. J. Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma. Am J Respir Crit Care Med. 1998 Jul;158(1):315–319. doi: 10.1164/ajrccm.158.1.9703005. [DOI] [PubMed] [Google Scholar]
- in 't Veen J. C., Beekman A. J., Bel E. H., Sterk P. J. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med. 2000 Jun;161(6):1902–1906. doi: 10.1164/ajrccm.161.6.9906075. [DOI] [PubMed] [Google Scholar]