Luísa Geraldes 1

Ana Todo-Bom 2

Carlos Loureiro 2

Resumo

Faz-se uma revisão sobre métodos de avaliação da inflamação nas vias aéreas que contribuam para o diagnóstico, terapêutica e prognóstico de patologias como a rinossinusite e a asma. Serão também considerados métodos susceptíveis de fornecer informação relevante sobre inflamação na DPOC.

A inflamação crónica das vias aéreas condiciona fenómenos obstrutivos objectivados na função respiratória basal, na hiperreactividade brônquica e nasal e em quadros clínicos de dificuldade respiratória. A tomografia computorizada informa sobre as dimensões do lúmen, a espessura das paredes brônquicas e os índices de densidade pulmonar, alterações que decorrem da inflamação e remodelação das vias aéreas.

Os métodos directos recorrem a análise imunoistoquímica de tecidos e de fluidos em condições basais ou após estimulação. Os eosinófilos aumentam em biópsias, lavados nasais e broncoalveolares na asma e na rinite e modificam-se com a terapêutica. Ocorrem alterações nas proteínas e expressão de RNAm de mediadores envolvidos na activação celular.

A expectoração induzida identifica inflamação eosinofílica que se relaciona inversamente com a função ventilatória.

Em cada ciclo respiratório o ar é enriquecido em compostos voláteis produzidos no decurso da respiração celular. A FENO é o biomarcador mais estudado e os seus níveis estão elevados na asma.

No condensado do ar expirado identificam-se espécies reactivas de oxigénio, derivados de membrana, citocinas e quimiocinas pró-inflamatórias.

Se a avaliação não invasiva da inflamação for fidedigna e reprodutível, será imprescindível na monitorização das doenças das vias aéreas.

Palavras-chave: Asma, exames auxiliares de diagnóstico, inflamação, rinite.

Airways inflammation evaluation. Upper and lower airways 

It is done a review of evaluation methods of the inflammation in upper airways and bronchi used for diagnosis, therapeutic approach and prognosis of pathologies like rhinosinusitis and asthma. It is also analysed methods that supply relevant information of inflammation in COPD.

The chronic inflammation of the airways is associated to respiratory distress, obstruction in basal lung function tests and to bronchial and nasal hyperreactivity.

Computerized tomography informs about lumen dimensions, bronchial walls thickness and pulmonary density. These changes are associated to inflammation and to remodelling of the airways.

Localized inflammation in respiratory tract can be detected by modifications of systemic inflammatory markers.

The direct evaluation of inflammatory airways changes are based on immune, histological and chemical analysis of lung tissue obtained by biopsies and by fluids recoil in basal conditions or after stimulation. The eosinophils are increased in biopsies and in nasal and bronchoalveolar lavage in asthma and rhinitis and can change with therapy. Proteins and mRNA expression of cellular activation mediators are also observed.

The induced sputum identifies eosinophilic inflammation that is inversely associated with lung function parameters. In each respiratory cycle the air is enriched in organic volatile compounds produced by cellular breathing. FENO is the bio marker more deeply studied in asthma and its increase is well documented in this disorder. In the exhaled air condensed, reactive oxygen species, membrane mediators, cytokines, and chemokines are identified.

If the non invasive evaluation of inflammation became reliable and reproducible it will be indispensable in monitoring the airways diseases.

Key-words: Asthma, evaluation methods, inflammation, rhinitis.

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Bibliografia

1. Global Initiative for Asthma. Global strategy for asthma management and prevention. Washington, DC: National Institutes of Health; National Heart, Lung and Blood Institute, 2003. Updated 2004. NIH publication No. 02 -3659. Available at: http://www.ginasthma.com (accessed Jun 2005).

2. Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis management and prevention of chronic obstructive pulmonary disease Bethesda, MD: World Health Organization and US National Heart, Lung and Blood Institute, 2003.

3. Brightling CE, Symon FA, Birring SS, Bradding P, Wardlaw AJ, Pavord ID. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003; 58:528 -532.        [ Links ]

4. McCormack L, Enright. Making the Diagnosis of Asthma Respiratory Care 2008; 53: 583-590.

5. Ward C Inter -relationships between airway inflammation, reticular basement membrane thickening and bronchial hyper -reactivity to methacholine in asthma; asystematic bronchoalveolar lavage and airway biopsy analysis. Clin Exp Allergy 2005; 35:1565-1571.

7. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing -1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000; 161: 309-329.

8. Grootendorst DC, Rabe KF. Mechanisms of bronchial hyperreactivity in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004; 1: 77-87.

9. Porsbjerg C, Rasmussen L, Thomsen SF, Brannan JD, Anderson SD, Backer V. Response to mannitol in asymptomatic subjects with airway hyper –responsiveness to methacholine. Clin Exp Allergy 2007; 37: 22-28.

10. Sheahan P, Walsh RM, Walsh MA, Costello RW, Induction of nasal hyper -responsiveness by allergen challenge in allergic rhinitis: the role of afferent and efferent nerves. Clin Exp Allergy 2005; 35: 45 -51.

11. Ketai L, Harkins M, Fiato KL, Iwamoto GK. Exhaled nitric oxide and bronchial wall thickening in asthmatics during and after acute exacerbation: evidence of bronchial wall remodeling. J Asthma 2005; 42: 667 -671.

12. Marchac V, Emond S, Mamou -Mani T, Le Bihan-Benjamin C, Le Bourgeois M, De Blic J. Thoracic CT in pediatric patients with difficult -to -treat asthma. AJR Am J Roentgenol 2002; 179: 1245 -1252.

13. Ketai L, Coutsias C, Williamson S, Coutsias V. Thin -section CT evidence of bronchial thickening in children with stable asthma: bronchoconstriction or airway remodeling? Acad Radiol 2001; 8: 257 -264.

14. Jain N, Covar RA, Gleason MC, Newell JD Jr, Gelfand EW, Spahn JD. Quantitative computed tomography detects peripheral airway disease in asthmatic children. Pediatr Pulmonol 2005; 40: 211 -218.

15. Ueda T, Niimi A, Matsumoto H, Takemura M, Hirai T, Yamaguchi M. Role of small airways in asthma: investigation using high -resolution computed tomography. J Allergy Clin Immunol 2006; 118: 1019-1025.

17. Samee S, Altes T, Powers P, de Lange EE, Knight-Scott J, Rakes G. Imaging the lungs in asthmatic patients by using hyperpolarized helium -3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol 2003; 111: 1205 -1211.

18. Dourado M. Fisiopatologia laboratorial. In: Mota Pinto, A. Fisiopatologia – Fundamentos e aplicações. Lidel Edições técnicas 2007: 23 -28.

19. Fujita M, Ueki S, Ito W, Chiba T, Takeda M, Saito N, Kayaba H. C-Reactive protein levels in the serum of asthmatic patients. Ann Allergy Asthma Immunol 2007; 99: 48 -53.

20. Todo -Bom A, Mota Pinto A, Vale Pereira S, Alves V, Dourado M, Santos Rosa M, et al. Substance P in long-lasting asthma:Immunoinflammatory pathways. Allergy Clin Immunol Int – J World Allergy Org 2006; 18: 242 -248.

21. Black PH. Stress and the inflammatory response: A review of neurogenic inflammation. Brain Behav Immun 2002; 16: 622 -653.

22. Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Panizzolo C, et al. Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med 2006; 174: 975 -981.

23. Suzuki T, Chow CW, Downey GP. Role of innate immune cells and their products in lung immunopathology. Int J Biochem Cell Biol 2008; 40: 1348 -1361.

24. Laitinen LA, Laitinen A, Altraja A, Virtanen I, Kampe M, Simonsson BG, Karlsson SE, Hakansson L, Venge P, Sillastu H. Bronchial biopsy findings in inter-mittent or “early” asthma J Allergy Clin Immunol 1996; 98: S33 -540.

25. Siddiqui S, Mistry V, Doe C, Roach K, Morgan A, Wardlaw A, Pavord I, Bradding P, Brightling C. Airway hyperresponsiveness is dissociated from airway wall structural remodelling J Allergy Clin Immunol 2008;122: 335 -341.

27. Jeffery PK, Haahtela T. Allergic rhinitis and asthma: inflammation in a one -airway condition BMC Pulm Med 2006; 30 (Supl 1):S5.

28. Barczyk A, Pierzcha W, Kon O, Cosio B, Adcock I, Barnes P. Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J Allergy Clin Immunol 2006;117:1484 -1492.

29. Francis JN, Sabroe I, Lloyd CM, Durham SR, Till SJ. Elevated CCR6+ CD4+ T lymphocytes in tissue compared with blood and induction of CCL20 during the asthmatic late response Clin Exp Immunol 2008; 152: 440 -447.

30. Ciprandi G, Cirillo I, Klersy C, Tosca M, Marseglia G. Nasal eosinophils and reversibility to the decongestion test in patients with perennial allergic rhinitis. Allergy Asthma Proc 2007; 28: 292 -295.

31. Salib R,. Lau L, Howarth P. The novel use of the human nasal epithelial cell line RPMI 2650 as an invitro model to study the influence of allergens and cytokines on transforming growth factor -b gene expression and protein release. Clin Exp Allergy 2005; 35: 811-819.

32. Powel D, Huskisson R, Carney A, Jenkins D, McEuen A, Walls A, Jones N. Mucosal T -cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells Allergy 2004; 59: 204-212.

33. Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, Krug N. Segmental allergen challenge in patients with atopic asthma leads to increased IL -9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 2003; 111: 1319 -1327.

34. Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non -severe asthma. Thorax 2008; 63: 784-790.

35. Johansson MW, Kelly EA, Busse WW, Jarjour NN, Mosher DF. Up -regulation and activation of eosinophil integrins in blood and airway after segmental lung antigen challenge. J Immunol 2008; 180: 7622 -7635.

37. Braunstahl G, Overbeek S, Kleinjan A, Prins J, Hoogsteden H, Fokkens W. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001; 107: 469 -476.

38. Miadonna A, Milazzo N, Lorini M, Sala A, Tedeschi A. Nasal neutrophilia and release of myeloperoxidase induced by nasal challenge with platelet activating factor: different degrees of responsiveness in atopic and nona topic subjects. J Allergy Clin Immunol 1996; 97: 947 -954.

39. Woodruff, P. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol 200;108: 753 -758.

40. Catherine L. Airway inflammation assessed by invasive and noninvasive means in severe asthma: Eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol 2006; 118:1033 -1039.

41. Deveci F, Ilhan N, Turgut T, Akpolat N, Kirkil G, Muz MH. Glutathione and nitrite in induced sputum from patients with stable and acute asthma compared with controls. Ann Allergy Asthma Immunol 2004; 93:91 -97.

42. Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholineresponsiveness in patients with mild asthma. Thorax 1998; 53: 91-95.

43. Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitricoxide correlates with airway hyperresponsiveness in steroid -naivepatients with mild asthma. Am J Respir Crit Care Med 1998;157: 894-898.

44. Taylor D, Nitric oxide as a clinical guide for asthma management. J Allergy Clin Immunol 2006;117: 259 -262.

45. Sergei A, Kharitonov, Barnes PJ. FCCP exhaled biomarkers. Chest 2006; 130: 1541 -1546.

47. Travers J, Marsh S, Aldington S, Williams M, Shirtcliffe P, Pritchard A, Weatherall M, Beasley R. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007;176: 238 -242.

48. Boot JD, de Kam ML, Mascelli MA, Miller B, van Wijk RG, de Groot H, Cohen AF, Diamant Z. Nasal nitric oxide: longitudinal reproducibility and the effects of a nasal allergen challenge in patients with allergic rhinitis. Allergy 2007; 62: 378 -384.

49. Donnelly LE, Barnes PJ. Expression of heme oxygenase in human airway epithelial cells. Am J Respir Cell Mol Biol 2001; 24: 295.

50. Zayasu K, Sekizawa K, Okinaga S, et al. Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1997; 156:1140.

51. Uasuf CG, Jatakanon A, James A, et al. Exaled carbon monoxide in childhood asthma. J Pediatr 1999; 135: 569.

52. Pearson P, Lewis S, Britton J, Fogarty A. Exhaled carbon monoxide levels in atopic asthma: a longitudinal study. Respir Med 2005; 99: 1292 -1296.

53. Ramirez -Prieto MT, Garcia -Rio F, Villamor J. Role of oxidative stress in respiratory diseases and its monitoring Med Clin 2006; 127: 386 -396.

54. Dragonieri S. An electronic nose in the discrimination of patients with asthma and controls. J Allergy Clin Immunol 2007; 120: 856 -862.

55. Barreto M, Pia Villa M, Olita C, Martella S, Ciabattoni G, Montuschi P. 8 -Isoprostane in exhaled breath condensate (EBC) and exercise -induced bronchoconstriction in asthmatic children and adolescents. Chest 2008; 27. [Epub ahead of print]

57. Kiełbasa B, Moeller A, Sanak M, Hamacher J, Hutterli M, Cmiel A, Szczeklik A, Wildhaber JH. Eicosanoids in exhaled breath condensates in the assessment of childhood asthma. Pediatr Allergy Immunol 2008; 19: 660-669.

58. Zietkowski Z, Tomasiak MM, Skiepko R, Bodzenta-Lukaszyk A. RANTES in exhaled breath condensate of stable and unstable asthma patients. Respir Med 2008; 102: 1198 -1202.

59. Coop C, Hagan LL, Dice JP. Exhaled breath condensate pH in the evaluation of asthma. Allergy Asthma Proc 2008; 29: 51 -54.

60. Accordino R, Visentin A, Bordin A, Ferrazzoni S, Marian E, Rizzato F, Canova C, Venturini R, Maestrelli P. Long -term repeatability of exhaled breath condensate pH in asthma. Respir Med 2008; 102: 377 -381.

61. Romieu I, Barraza -Villarreal A, Escamilla -Nunez C, Almstrand AC, Diaz -Sanchez D, Sly PD, Olin AC. Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma. J Allergy Clin Immunol 2008; 121: 903 -909.

62. Zietkowski Z, Skiepko R, Tomasiak MM, Bodzenta-Lukaszyk A Endothelin -1 in exhaled breath condensate of stable and unstable asthma patients. Respir Med 2008; 102: 470 -474.

63. Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P, Loudikes S: pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med 2002; 165: 1364 -1370.

64. Piacentini GL, Peroni D, Crestani E, Zardini F, Bodini A, Costella S, Boner A. Exhaled air temperature in asthma: methods and relationship with markers of disease. Clin Exp Allergy 2007; 37: 415 -419.

65. Horvath I, Hunt J, Barnes PJ, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005; 26: 523-548.

67. Kostikas K, Koutsokera A, Papiris S, Gourgoulianis KI, Loukides S. Exhaled breath condensate in patients with asthma: implications for application in clinical practice. Clin Exp Allergy 2008; 38: 557-565.

1 Interna do 5.º ano da especialidade de Imunoalergologia dos HUC

2 Assistente Hospitalar Graduado em Imunoalergologia dos HUC

Correspondência/Correspondence to:

Serviço de Imunoalergologia

Departamento de Ciências Pneumológicas e Alergológicas dos Hospitais da Universidade de Coimbra

3000-075 Coimbra

Recebido para publicação/received for publication: 08.12.12

Aceite para publicação/accepted for publication: 09.01.12