Asthma and lower airway disease
Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack

https://doi.org/10.1016/j.jaci.2009.08.044Get rights and content

Background

Epidermal growth factor receptor ligands, such as epidermal growth factor (EGF) and amphiregulin, may play key roles in tissue remodeling in asthma. However, the kinetics of EGF and amphiregulin secretion in the airway after an acute asthma attack and the effect of prolonged airway exposure to these ligands on airway remodeling are unknown.

Objective

To measure the EGF and amphiregulin concentrations in sputa obtained from patients with asthma under various conditions, and to examine the effects of EGF and amphiregulin on the proliferation or differentiation of airway structural cells.

Methods

Epidermal growth factor and amphiregulin levels were measured by ELISA in sputum specimens collected from 14 hospitalized children with asthma during an acute asthma attack, 13 stable outpatients with asthma, 8 healthy control children, and 7 children with respiratory tract infections. The effects of EGF and amphiregulin on the proliferation and/or differentiation of normal human bronchial epithelial cells (NHBE), bronchial smooth muscle cells (BSMC), and normal human lung fibroblasts (NHLF) were examined.

Results

The sputum levels of EGF were significantly higher for about a week after an acute asthma attack compared with the levels in stable subjects with asthma and control subjects. In contrast, upregulation of amphiregulin in the sputa of patients with asthma was observed only during the acute attack. EGF caused proliferation of NHBE, BSMC, and NHLF, whereas amphiregulin induced proliferation of only NHBE. Prolonged exposure of NHBE to EGF and amphiregulin induced mucous cell metaplasia in an IL-13–independent manner.

Conclusion

Acute asthma attacks are associated with hypersecretion of EGF and amphiregulin in the airway. Recurrent acute attacks may aggravate airway remodeling.

Section snippets

Study population

The study was approved by the Ethics Committee of Kanagawa Children's Medical Center and Nihon University Hospital, and all subjects provided written informed consent for participation, in accordance with the Helsinki Declaration of the World Medical Association. Fourteen children with asthma hospitalized for treatment of an acute attack, 13 stable outpatients before and after therapy with inhaled corticosteroids, 8 healthy controls, and 7 outpatients with respiratory tract infections without

Comparison of the levels of EGF and amphiregulin in the sputa of children with asthma collected during an asthma exacerbation and after recovery

Initially, we measured the concentrations of EGF, amphiregulin, TGF-α, and HB-EGF in the sputum samples of 6 patients with asthma collected during an exacerbation and after recovery. The concentration of HB-EGF in all the sputum samples was under the detection limit of the ELISA kit. The concentrations of TGF-α in the sputum samples were much lower than those of EGF and amphiregulin. The results are shown in this article's Table E1 in the Online Repository at www.jacionline.org. Therefore, we

Discussion

In this study, we measured, for the first time, the concentrations of EGF and amphiregulin in sputum samples from patients with asthma obtained during an acute attack and also during the recovery phase. We found that the sputum EGF levels in these patients with asthma increased during the acute attack and remained elevated during the recovery phase after the acute attack. In contrast, the sputum concentrations of amphiregulin and tryptase were only transiently elevated during the acute attack (

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    Supported in part by Grants-in-Aid for Scientific Research (C) programs of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (project nos. 18604009 and 20591195, awarded to Y.O.), the Nihon University Joint Research Grant for 2008 (awarded to Y.O), a grant from the National Institute of Biomedical Innovation (project no. ID05-24, awarded to H.S. and Y.O.), and the Matching Fund Subsidy for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (to C.R).

    Disclosure of potential conflict of interest: H. Saito has received research support from the National Institute of Biomedical Innovation. The rest of the authors have declared that they have no conflict of interest.

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