Bronchial and Bronchoalveolar Specimens

Elliot and colleagues studied isolated aggregations of lymphoid cells in the cartilaginous airways from postmortem tissues of nonsmokers and smokers, and nonfatal and fatal cases of asthma. These aggregations of lymphocytes were present in 70 to 100% of all cases, more often in distal airways, and confined to the outer airway wall in 80% of cases. However, aggregates with an area greater than 0.1 mm² were present more often in both groups of patients with asthma, whereas vascular structures were more common in cases of fatal asthma. Airways with aggregates had both increased airway dimensions and greater numbers of eosinophils and lymphomononuclear cells. The role played by these aggregates, and whether they are a cause or a result of persistent airway inflammation, remains to be determined.

Zhou and colleagues evaluated changes in bronchial smooth muscle size and contractile gene expression following in vitro conditions of growth arrest versus proliferation. Antiproliferative factors, such as TGF-ß, are found in abundance in asthma and other diseases. The authors were able to show that, in transformed cells, growth arrest led to an increase in smooth muscle cell size and contractile/synthetic gene expression. Therefore, it would appear that the controversy is not yet settled.

The amount of airway smooth muscle has long been known to be increased in asthma. However, it remains controversial whether the increase is caused by hyperplasia or hypertrophy. Woodruff and coworkers used endobronchial biopsy quantification of airway smooth muscle followed by laser microdisection, and concluded that the number of smooth muscle cells was increased in patients with asthma, but that there was no evidence for an increase in size or contractile mRNA related to the cells, as compared with the normal control subjects.

Fibroblasts have been reported in lavage fluid from patients with asthma. In this study by Larsen and coworkers fibroblasts could be cultured from lavage fluid obtained from subjects with mild asthma, but not from control subjects. These fibroblasts exhibited a different phenotype from those obtained from endobronchial biopsies, having a different shape and greater mobility and producing greater amounts of fibrotic proteins. The actual tissue source of these lavage fibroblasts remains unclear.

Peng and colleagues assessed the role for the signal transducer and activator of transcription 6 (STAT6) in mediating IL-13–stimulated eotaxin release in human airway smooth muscle cells using antisense oligodeoxynucleotides (ODNs). Effective downregulation of STAT6 protein occurred with antisense but not with sense or scrambled ODNs. Eotaxin release induced by IL-13 or IL-4 (10 ng/ml) was reduced by 81 ± 4% and 74 ± 7%, respectively, in cells transfected with antisense ODNs (p < 0.001) but not with a sense ODN or a scrambled ODN. In contrast, eotaxin release induced by IL-1ß was unaffected by STAT6 antisense ODN. Inhibitors of both p42/p44 extracellular regulated kinase and p38 mitogen-activated protein kinase pathways abolished IL-13– and IL-4–dependent eotaxin release in STAT6 antisense ODN-transfected cells. By contrast, 25% of the response remained when each inhibitor was examined alone. These data indicate a role for both STAT6 and mitogen-activated protein kinase–dependent pathways in mediating eotaxin release from airway smooth muscle by IL-13 or IL-4.

To determine which pathological abnormalities are selectively associated with severe asthma, Benayoun and coworkers  did bronchial biopsies on 10 patients with intermittent asthma, 15 patients with mild-to-moderate persistent asthma, 15 patients with severe persistent asthma, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 control subjects. Severity of asthma was not related to mucosal eosinophilia, mucosal neutrophilia, epithelial damage, or thickness of the subepithelial basement membrane. Compared with patients with mild asthma or COPD, patients with severe persistent asthma had higher numbers of fibroblasts, greater deposition of collagen type III, larger mucosal gland areas, larger airway smooth muscle areas, increased cell size of airway smooth muscle, and increased expression of myosin light-chain kinase. Stepwise multivariate regression analysis revealed that the number of fibroblasts and cell size of airway smooth muscle were negatively correlated with FEV₁ in patients with asthma. The authors conclude that accumulation of fibroblasts and hypertrophy of smooth muscle (but not features of mucosal inflammation) in the proximal airway discriminate between patients with severe persistent asthma and patients with milder asthma or COPD.

In 52 patients with mild-to-moderate asthma, Sont and coworkers   compared fully automated image analysis of bronchial biopsy tissue with interactive digital cell counting and semiquantitative scoring of cytokine expression. Fully automated CD3⁺ cell counts showed perfect repeatability (r = 1.0) and were linearly correlated with the interactive procedure (r = 0.98). Automated densitometry showed perfect repeatability (r = 1.0) and a reasonable relationship with semiquantitative scoring of protein and messenger RNA expression (r = 0.43 to 0.89). Automated and semiquantitative assessments of changes in cytokine expression during 2 years of follow up were correlated (r = 0.40 to 0.84). The authors conclude that fully automated cell counts and densitometric analyses of bronchial biopsy tissue from patients with asthma are unbiased and decrease the variability in measures of inflammation.

Fabbri and coworkers  asked, "Do patients with fixed airway obstruction have distinct pathologic and functional characteristics depending on whether they have asthma or COPD?". Twenty-seven patients with COPD and 19 patients with asthma had similar FEV₁ (56% predicted in both groups) and airway hyperresponsiveness to methacholine (concentration producing a 20% decrease in FEV₁: 2.8 versus 1.2 mg/ml). Compared with the patients who had COPD, the patients with asthma had more eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane. The patients with asthma had lower residual volume, higher diffusing capacity, higher exhaled nitric oxide, less emphysema on computed tomography, and greater responsiveness to bronchodilators and glucocorticoids. The authors conclude that patients with asthma and COPD have distinct pathologic and functional characteristics even when the degree of airway obstruction is equivalent.

In a report from an international workshop, Jeffery and colleagues  describe the methods used for the assessment of endobronchial biopsies in clinical research, and the application of these methods in studies of pathogenesis and treatment.

Citations 1-10 of 10 total displayed.

Presence of Activated Mobile Fibroblasts in Bronchoalveolar Lavage from Patients with Mild Asthma

Kristoffer Larsen, Ellen Tufvesson, Johan Malmström, Matthias Mörgelin, Marie Wildt, Annika Andersson, Anna Lindström, Anders Malmström, Claes-Göran Löfdahl, György Marko-Varga, Leif Bjermer, and Gunilla Westergren-Thorsson
Am. J. Respir. Crit. Care Med. 170: 1049 -1056. First published online as doi:10.1164/rccm.200404-507OC [Abstract] [Full text]  

Role of Microvascular Permeability on Physiologic Differences in Asthma and Eosinophilic Bronchitis

Hiroshi Kanazawa, Saeko Nomura, and Junichi Yoshikawa
Am. J. Respir. Crit. Care Med. 169: 1125 -1130. First published online as doi:10.1164/rccm.200401-123OC [Abstract] [Full text]  

Hyperplasia of Smooth Muscle in Mild to Moderate Asthma without Changes in Cell Size or Gene Expression

Prescott G. Woodruff, Gregory M. Dolganov, Ronald E. Ferrando, Samantha Donnelly, Steven R. Hays, Owen D. Solberg, Roderick Carter, Hofer H. Wong, Peggy S. Cadbury, and John V. Fahy
Am. J. Respir. Crit. Care Med. 169: 1001 -1006. First published online as doi:10.1164/rccm.200311-1529OC [Abstract] [Full text]  

Human Bronchial Smooth Muscle Cell Lines Show a Hypertrophic Phenotype Typical of Severe Asthma

Limei Zhou, Jing Li, Adam M. Goldsmith, Dawn C. Newcomb, Diane M. Giannola, Robert G. Vosk, Eva M. Eves, Marsha R. Rosner, Julian Solway, and Marc B. Hershenson
Am. J. Respir. Crit. Care Med. 169: 703 -711. First published online as doi:10.1164/rccm.200307-964OC [Abstract] [Full text]  

Aggregations of Lymphoid Cells in the Airways of Nonsmokers, Smokers, and Subjects with Asthma

John G. Elliot, Cathryn M. Jensen, Slavko Mutavdzic, Jasmine P. Lamb, Neil G. Carroll, and Alan L. James
Am. J. Respir. Crit. Care Med. 169: 712 -718. First published online as doi:10.1164/rccm.200308-1167OC [Abstract] [Full text]  

Signaling Pathways Regulating Interleukin-13–stimulated Chemokine Release from Airway Smooth Muscle

Qi Peng, Takeshi Matsuda, and Stuart J. Hirst
Am. J. Respir. Crit. Care Med. 169: 596 -603. First published online as doi:10.1164/rccm.200307-888OC [Abstract] [Full text]  

Methods for the Assessment of Endobronchial Biopsies in Clinical Research: Application to Studies of Pathogenesis and the Effects of Treatment

Peter Jeffery, Stephen Holgate, and Sally Wenzel
Am. J. Respir. Crit. Care Med. 168: 1S-17S. [Full text]  

Fully Automated Assessment of Inflammatory Cell Counts and Cytokine Expression in Bronchial Tissue

Jacob K. Sont, Willem I. de Boer, W. Annemarie A. M. van Schadewijk, Katrien Grünberg, J. Han J. M. van Krieken, Pieter S. Hiemstra, and Peter J. Sterk
Am. J. Respir. Crit. Care Med. 167: 1496-1503. [Abstract] [Full text]  

Airway Structural Alterations Selectively Associated with Severe Asthma

Laurent Benayoun, Anne Druilhe, Marie-Christine Dombret, Michel Aubier, and Marina Pretolani
Am. J. Respir. Crit. Care Med. 167: 1360 -1368. First published online as doi:10.1164/rccm.200209-1030OC [Abstract] [Full text]  

Differences in Airway Inflammation in Patients with Fixed Airflow Obstruction Due to Asthma or Chronic Obstructive Pulmonary Disease

Leonardo M. Fabbri, Micaela Romagnoli, Lorenzo Corbetta, Gianluca Casoni, Kamelija Busljetic, Graziella Turato, Guido Ligabue, Adalberto Ciaccia, Marina Saetta, and Alberto Papi
Am. J. Respir. Crit. Care Med. 167: 418 -424. First published online as doi:10.1164/rccm.200203-183OC [Abstract] [Full text]