Assoc. Prof. Dr. Murat SEZERVakıf Gureba Training and Research Hospital
BronchoscopyIn the early 1970s, Reynolds and Newball were
among the first to report their experience with fiberoptic bronchoscopy and “bronchial” (bronchoalveolar) lavage (BAL) in order to obtain respiratory cells and secretions from human volunteers for in vitro analysis.Reynolds HY, Newball HH. J Lab Clin Med 1972; 84: 559–73
However, it was not until approximately 10 years later that studies were initiated in subjects with asthmaGodard PJ, Chaintreuil M, Damon M, et al. J Allergy Clin Immunol 1982; 70: 88–93
BronchoscopyBALEndobronchial brushingForceps biopsyTransbronchial biopsy
made it possible to evaluate the inflammation and remodelling within the lungs
BronchoscopyThese bronchoscopic studies let us have in
vivo information about
The role of inflammatory cells and mediators that play a role in asthma,
The severity of the disease
BronchoscopyStudies in asthmatic patients revealed that
there is a correlation between inflammatory cell infiltration, activation state of the released cytokines and physiological parameters.
Kraft M, Djukanovic R, Wilson S, et al. Am J Respir Crit Care Med 1996; 154: 1505-10
Kavuru MS, Dweik RA, Thomassen MJ. Clin Chest Med 1999; 20: 153-89
BronchoscopyThe interventional studies also gather new
information that can highlight the efficacy of current therapies and their mechanisms of action
Djukanovic R, Wilson JW, Britten KM, et al. Am Rev Respir Dis 1992; 145: 669-74
Jeffery PK, Godfrey RWA, Adelroth E, et al. Am Rev Respir Dis 1992; 145: 890-9
Anonymous. J Allergy Clin Immunol 1991; 88: 808-14
BronchoscopyThese studies increased our knowledge about
Pathophysiology of the allergic asthma and allergic rhinitis
Similarities and differences of the airway
Histology of the subtypes of persisting asthma
Busse WW, Wanner A, Adams K, et al. Am J Respir Crit Care Med 2005; 807: 16
Bronchoalveolar LavageGenerally it is well tolerated but it can cause
a decline in pulmonary function tests
BAL alone or together with other procedures do not significantly change the existing tissue inflammation, airway obstruction and airway hyperresponsiveness
Krug N, Teran LM, Redington AE, et al. Am J Respir Crit Care Med 1996; 53: 1391-7
Van Vyve T, Chanez P, Bousquet J, et al. Am Rev Respir Dis 1992; 46: 116-21
Bronchoalveolar LavageCough and postbronchoscopic fever can
follow BAL
Hypoksemia is less common due to standard use of oxygen inhalation during bronchoscopy
Van Vyve T, Chanez P, Bousquet J, et al. Am Rev Respir Dis 1992; 46: 116-21
Bronchoalveolar LavageStudies of BAL in asthma have revealed
increased numbers and activation of inflammatory cells and higher levels of mediators when compared to subjects without asthma
Asthma subjects show increased numbers of BAL eosinophils, even when the disease is mild and stable
Bousquet J, Chanez P, Lacoste JY, et al. N Engl J Med 1990; 3: 1033-9
Bronchoalveolar LavageMacrophage activation has been described in
symptomatic asthma and with nocturnal exacerbations
Wenzel SE, Trudeau JB, Westcott JY, et al. J Allergy Clin Immunol 1994; 94: 870-81
While BAL neutrophilia is not a predominant feature of mild to moderate asthma, it has been described in response to occupational challenge with isocyanate or grain dust and endotoxin-contaminated allergen extracts
Hunt LW, Gleich GJ, Ohnishi T, et al. Am J Respir Crit Care Med 1994; 149: 1471-5
Deetz DC, Jagielo PJ, Quinn TJ, et al. Am J Respir Crit Care Med 1997; 155: 254-9
Bronchoalveolar LavageSubgroups of the cells that are obtained with
BAL can be evaluated
In the BAL fluid of asthmatic patients eosinophil count and CD5+ T-lymphocytes with CD25 were significantly increased, while CD3, CD4, CD8, CD16/CD56 and CD19 percentages were not significantly different from that of control subjects
Harmancı E, Gülbaş Z, Özdemir N, et al. Tuberk Toraks 2001; 49: 187-92
Bronchoalveolar LavageMany mediators and cytokines have been
detected in BAL fluid of asthma patients, including:
IL-1 IL-6IL-2 IL-10IL-4 GM-CSFIL-5 TNF-α
Zangrilli JG, Peters SP. Cytokines in allergic airway disease. In Busse WW, Holgate ST, eds. Asthma and Rhinitis. Blackwell Scientific Publications, Cambridge. 1995, 426–436.
Bronchoalveolar LavageOther studies have noted increased levels of
mRNA for several cytokines in BAL cells, including:
TNF-α IL-4GM-CSF IL-5IL-1 IL-6IL-2 IL-13IL-3Zangrilli JG, Peters SP. Cytokines in allergic airway disease. In Busse WW, Holgate ST, eds. Asthma and Rhinitis. Blackwell Scientific Publications, Cambridge. 1995, 426–436.
Bronchoalveolar LavageOther mediators detected in BAL fluid
include:
LeukotrienesProstaglandinsHistamineTryptaseSoluble adhesion molecules
Bronchoalveolar LavageBronchoalveolar lavage has also been
performed to evaluate the effects of asthma therapies (corticosteroids, theophylline, beta-agonists, cromolyn sodium, nedocromil sodium, cetirizine, leukotriene inhibitors, etc.) on parameters of airway inflammation
Bronchial BiopsyThe use of bronchial biopsy for research
purposes in asthma was first reported in 1977
Molina C, Brun J, Coulet M, et al. Immunopathology of the bronchial mucosa in late onset asthma. Clin Allergy 1977; 7: 137–45
Bronchial biopsy provides valuable insight into the morphology of the asthmatic airways, enabling detailed study of the epithelium, basement membrane, and submucosa
Djukanovic R. Bronchial biopsies. In Holgate ST, Busse W, eds. Asthma and Rhinitis. Blackwell Scientific Publications, Boston. 1994, 118–129.
Bronchial BiopsyImmunohistochemical studies of bronchial
biopsies have enabled quantification of the inflammatory cells, such as mast cells, eosinophils, and T lymphocytes, and the extent of activation of these cells
Djukanovic R, Wilson JW, Britten KM, et al. Am Rev Respir Dis 1990; 142: 863–71
Azzawi M, Bradley B, Jeffery PK, et al. Am Rev Respir Dis 1990; 142: 1407–13
Bronchial BiopsyUsing transmission electron microscopy, it
has been possible to study the ultrastructure of inflammatory cells
Azzawi M, Bradley B, Jeffery PK, et al. Am Rev Respir Dis 1990; 142: 1407–13
The immunogold technique has localized cytokines to ultrastructural elements of cells and adhesion molecules within the epithelium
Lackie P, Baker JE, Gunthert U, et al. Am J Respir Cell Mol Biol 1997; 16: 14–22
Bronchial BiopsyKraft and colleagues reported the first study
in which transbronchial biopsies were obtained in asthma subjects. Prominent tissue eosinophilia was seen at 4:00 A.M. in asthma subjects with nocturnal decline in pulmonary functions compared to asthmatic subjects without nocturnal asthma.
Kraft M, Djukanovic R, Wilson S, et al. Am J Respir Crit Care Med 1996; 154: 1505–10
Bronchial BrushingThe techniques of BAL and bronchial brushing
not only provide complementary histologic information but also cells for in vitro study
The majority of cells obtained by brushing are bronchial epithelial cells
Bronchial epithelial cells release inflammatory mediators and participate in airway immune responses as antigen–presenting cells
Bronchial BrushingBronchial epithelial cells from asthmatic subjects
have also been shown to have enhanced expression of HLA-DR and ICAM-1 compared with normal subjects
Vignola AM, Campbell AM, Chanez P, et al. Am Rev Respir Dis 1993; 148: 689–94
They can also release mediators relevant to the pathogenesis of asthma, such as 15-hydroxy-eicosatetranoic acid (15 HETE), prostaglandin E2, and fibronectin
Campbell AM, Chanez P, Vignola AM, et al. Am Rev Respir Dis 1993; 147: 529–34
Bronchial BrushingEpithelial cells from asthmatic subjects have
also enhanced expression of GM-CSF, which decreases following treatment with inhaled steroids
Sousa AR, Poston RN, Lane SJ, et al. Am Rev Respir Dis 1993; 147: 1557–61
Segmental Allergen ChallengeThe majority of patients with asthma have allergic
sensitivities that can be used to provoke airway inflammation
Aerosolized allergen challenge results in the development of bronchial obstruction, airway hyperresponsiveness, eosinophilic infiltration and activation, increased superoxide production, and other indices of inflammation
de Monchy JGR, Kauffman HF, Venge P, et al. Am Rev Respir Dis 1985; 131: 373–6
Diaz P, Gonzalez MC, Galleguillos FR, et al. Am Rev Respir Dis 1989; 139: 1383–9
Calhoun WJ, Bush RK. J Allergy Clin Immunol 1990; 86: 306–13
Segmental Allergen ChallengeOnly a small and variable fraction of the dose
delivered by the nebulizer actually reaches the lower airway
Moreover, the site of deposition is unknown unless radiotracers are used, and in any case is uncontrolled
Finally, the quantity of allergen that can be delivered is limited by safety considerations due to airway obstruction
Segmental Allergen ChallengeUsing segmental allergen challenge allergen
dosing and localization are more precise, because allergen is delivered to a specific airway segment under direct visualization
Multiple segments can safely be challenged with different antigen doses (for dose–response studies)
The same dose can be used in multiple segments (for kinetic or interventional studies)
Calhoun WJ, Jarjour NN, Gleich GJ, et al. J Allergy Clin Immunol 1996; 98:S46–S50.
Kane GC, Pollice M, Kim CJ, et al. J Allergy Clin Immunol 1996; 97:646–54.
Shaver JR, Zangrilli JG, Cho SK, et al. Am J Respir Crit Care Med 1997; 155:442–8.
Segmental Allergen ChallengeThe degree of generalized bronchial
obstruction is less than that seen with aerosol challenge, and the degree of inflammation is greater
Calhoun WJ, Jarjour NN, Gleich GJ, et al. Am Rev Respir Dis 1993; 147: 1465–71
Instrumentation and BAL per se do not evoke generalized pulmonary inflammation
Calhoun WJ, Reed HE, Moest D, et al. Am Rev Respir Dis 1992; 145: 317–25
Jarjour NN, Calhoun WJ. Am Rev Respir Dis 1990; 142: 100–3
Segmental Allergen ChallengeSAC localizes allergen challenge to the small
airways, which are sites of inflammation and bronchial obstruction in asthma
Saetta M, DiStefano A, Rosina C, et al. Am Rev Respir Dis 1991; 143: 138–43
Kraft M, Djukanovic R, Wilson S, et al. Am J Respir Crit Care Med 1996; 154: 1505–10
Wagner EM, Liu MC, Weinmann GG, et al. Am Rev Respir Dis 1990; 141: 584–8
Segmental Allergen ChallengeWhile SAC is a powerful tool for studying
allergen-driven airway inflammation, care should be taken when extrapolating SAC findings to natural exacerbations of asthma
Segmental Allergen ChallengeWenzel and colleagues showed that the
concentration of leukotriene C4 was significantly greater after endobronchial allergen challenge in asthmatics compared to nonasthmatic atopics
Wenzel SE, Larsen GL, Johnston K, et al. Am Rev Respir Dis 1990; 142: 112–9
Preliminary data suggest that failure to secrete IL-10 after allergen challenge might also differentiate allergic asthma from allergic rhinitis subjects
Calhoun WJ, Hinton KL, Brick JJ, et al. Am J Respir Crit Care Med 1996; 153: A881
Segmental Allergen ChallengeShaver and colleagues reported that the
increase in BAL eosinophils and IL-5 in response to antigen SAC were similar in allergic asthmatic and allergic nonasthmatic subjects
Interestingly, subjects with documented late asthmatic response to whole lung challenge showed the strongest cellular and cytokine responses to SAC
Shaver JR, O’Connor JJ, Pollice M, et al. Am J Respir Crit Care Med 1993; 152: 1189–97
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