Cytokine mRNA expression in asthma is not restricted to the large airways

doi:10.1016/S0091-6749(98)70252-0

Journal of Allergy and Clinical Immunology

Volume 101, Issue 3, March 1998, Pages 386-390

https://doi.org/10.1016/S0091-6749(98)70252-0 Get rights and content

Abstract

Background: Although previous studies have established the presence of an eosinophil-rich cellular infiltrate in the small airways of asthmatic lungs, the expression of cytokines within the peripheral airways has been largely unexplored. The purpose of our study was to test the hypothesis that T_H2-type cytokines are increased in the peripheral airways and parenchyma of asthmatic lungs. Methods: The presence of messenger ribonucleic acid (mRNA) encoding both T-helper (T_H1)-type (IL-2, interferon-γ) and T_H2-type (IL-4, IL-5) cytokines in surgically resected lungs from six asthmatic and 10 nonasthmatic subjects was determined by in situ hybridization. Colocalization of IL-5 mRNA within the large and small airways was performed by simultaneous in situ hybridization and immunocytochemistry. Results: Expression of IL-5 mRNA-positive cells was significantly increased in the large and small airways and in the lung parenchyma of asthmatic subjects compared with nonasthmatic subjects. In the asthmatic individuals, the expression of IL-5 mRNA was increased in the small airways compared with the large airways. There was also an increase in the number of cells expressing IL-4 mRNA in the large and small asthmatic airways compared with the nonasthmatic airways. In contrast, the numbers of IL-2 and interferon-γ mRNA-positive cells did not differ between asthmatic and nonasthmatic individuals. Conclusions: We conclude that there is an increased expression of T_H2-type cytokines within the peripheral airways of asthmatic lungs and suggest that the small airways contribute to the pathophysiology of asthma. (J Allergy Clin Immunol 1998;101:386-90.)

Section snippets

Subjects

Lung tissue was obtained from 16 subjects selected from a cohort of 108 individuals entering the St. Paul's Hospital Lung Study between 1991 and 1995. The clinical characteristics of these asthmatic and nonasthmatic patients have been described previously. ³ Briefly, patients undergoing lung resection for bronchial carcinoma who fulfilled the clinical criteria used to establish a diagnosis of asthma (n = 6) were matched with 10 individuals who did not demonstrate these features. Diagnostic

Results

The asthmatic and nonasthmatic patients were well matched for age, sex, and cigarette smoking history³ (p > 0.05). The subjects with asthma had a mean percent predicted FEV₁ and standard deviation of 82.5% ± 22.1%, which was similar to that of the nonasthmatic control subjects: 89.2% ± 15.3% (p > 0.05). Histologic studies of the lungs revealed that the Pi of the airways varied between 0.8 and 16.4 mm, with a similar frequency of distribution of size between the two groups.³

Positive in situ

Discussion

This study demonstrates an increase in the numbers of IL-4 and IL-5 mRNA-positive cells within the airways of patients with asthma compared with nonasthmatic control subjects matched for age, sex, smoking history, and airway size. More importantly, cells expressing IL-5 mRNA were significantly increased in airways less than 2 mm Pi in the asthmatic subjects compared with the nonasthmatic control subjects, and in the asthmatic subjects these were found to be significantly elevated compared with

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The use of MP up to 6½ years was safe and effective, with significant changes to ACQ-7 and FEF_25%–75% associated with MP treatment, but not the FEV₁. A higher magnitude of changes was observed among super-responders than the rest of the cohort. Changes in FEF_25%–75% were more meaningful than changes in FEV₁ in evaluating pulmonary function responsiveness of severe eosinophilic asthma to MP.
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Could transthoracic ultrasound be useful to suggest a small airways disease in severe uncontrolled asthma?
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Citation Excerpt :
In particular, patients with asthma are characterized by a condition of underlying chronic inflammation of the airways, which, in the long term, can lead to bronchial remodeling.27,28 Several studies directly assessed small airway abnormalities in patients who died of acute asthma attacks29–34 and in patients with severe asthma,11,35–37 through the use of invasive surgical or postmortem sampling methods or of transbronchial biopsies. The chest HRCT scan represents the reference standard method of imaging for investigating morphologic changes in the lung parenchyma and bronchi.
Transthoracic ultrasound (TUS) is an accepted complementary tool in the diagnostic process of several pleuro-pulmonary diseases. However, to the best of our knowledge, TUS findings in patients with severe asthma have never been systematically described.
To explore if TUS examination is a useful imaging method in suggesting the presence of a “small airways disease” in patients with severe uncontrolled asthma.
Seventy-two consecutive subjects with a diagnosis of severe uncontrolled asthma were enrolled. The presence of a “small airways disease” was assessed through the execution of pulmonary function tests. All the patients underwent a complete TUS examination and a chest high resolution computed tomography (HRCT), which was regarded as the reference standard for comparison with TUS findings.
Pulmonary function tests results have confirmed a reduction in expiratory flows relative to the small airways and a condition of hyperinflation in 78% and 82% of our patients, respectively. The main signs observed in the TUS examination were a thickened and/or irregular pleural line and the lack or reduction of the “gliding sign.” TUS showed high sensitivity and specificity in suggesting the presence of hyperinflation and distal airways inflammation according to the HRCT scan. K Cohen's coefficients showed substantial agreement between the 2 diagnostic tests.
TUS in patients with severe uncontrolled asthma can provide useful information on the state of the peripheral lung, suggesting the execution of a second-line HRCT scan for better assessment of eventual alterations that may represent the underlying causes of nonresponse to treatment.
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In recent years special interest has been expressed for the contribution of small airways in the pathophysiology, clinical manifestations and treatment of asthma and COPD. Small airways contribute little to the total respiratory resistance so that extensive damage of small airways may occur before the appearance of any symptoms, and this is the reason why they are characterized as the “silent zone” of airways. Furthermore, the peripheral localization of the small airways and their small diameter constitutes difficult their direct assessment. Thus, they are usually studied indirectly, taking advantage of the effects of their obstruction, such as premature closure, air trapping, heterogeneity of ventilation, and lung volume dependence of airflow limitation. Today, several heterogeneous methods for the assessment of small airways are available. These can be either functional (spirometry, plethysmography, resistance measurements, nitrogen washout, alveolar nitric oxide, frequency dependence of compliance, flow-volume curves breathing mixture of helium–oxygen) or imaging (mainly through high resolution computed tomography). The above-mentioned methods are summarized in Table 1. However, no method is currently considered as the “gold standard” and it seems that combinations of tests are needed. Furthermore, it is not clear whether the small airways are affected in all patients with asthma or COPD and their clinical significance remains under investigation. Well-designed future studies with large numbers of patients are expected to reveal which of the methods for assessing the small airways is the most accurate, reliable and reproducible, for which patients, and which can be used for the evaluation of the effects of treatment.
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Inflammatory processes in the asthmatic lung involve the large and small airway and alveolar sites. Leukotriene B₄ (LTB₄) is an important disease marker, but its role in inflammation of the small airways in asthma has not been established yet.
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Sixty-eight children (9–17 years old, 33 children with asthma and 35 controls) underwent fractional exhaled nitric oxide (FeNO) measurements, lung function testing, and collection of fractionated exhaled breath condensate using a capnograph-based approach. The LTB₄ concentrations in the small airway or alveolar and large airway fractions were correlated to disease status, lung function impairment, and clinical parameters.
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^☆: From ^aMeakins-Christie Laboratories, McGill University, Montreal; and ^bPulmonary Research Laboratory, St. Paul's Hospital, University of British Columbia, Vancouver.

^☆☆: Supported by the Respiratory Health Network Center of Excellence. Dr. Minshall is a recipient of a Medical Research Council/Canadian Lung Association Fellowship.

^★: Reprint requests: Dr. Qutayba Hamid, Meakins-Christie Laboratories, 3626 St. Urbain St., McGill University, Montreal, Quebec, Canada H2X 2P2.

^★★: 1/1/87175

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Cytokine mRNA expression in asthma is not restricted to the large airways☆,☆☆,★,★★

Abstract

Section snippets

Subjects

Results

Discussion

Blood

Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma

Am Rev Respir Dis

Airway mucosal inflammation even in patients with newly diagnosed asthma

Am Rev Respir Dis

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

Eur Respir J

Small airways dimensions in asthma and in chronic obstructive pulmonary disease

Am Respir Rev Dis

A model of airway narrowing in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

Expression of mRNA for interleukin-5 in mucosal biopsies from asthma

J Clin Invest

Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma

N Engl J Med

Phenotype of cells expressing mRNA for Th2-type (interleukin-4 and interleukin-5) and Th1-type (interleukin 2 and interferon-γ) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects

Am J Respir Cell Mol Biol