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

Received 8 April 2009; received in revised form 23 July 2009; accepted 20 August 2009.

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.

Key words: Amphiregulin, bronchial asthma, bronchial epithelial cells, epidermal growth factor, tissue remodeling

a Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan

b Department of Environmental Immuno-Dermatology, Yokohama City University School of Medicine, Kanagawa, Japan

c Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

d Department of Allergy, Kanagawa Children's Medical Center, Kanagawa, Japan

Reprint requests: Yoshimichi Okayama, MD, PhD, Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, 30-1 Oyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.

Tetsuya Takamasu, MD, Department of Allergy, Kanagawa Children's Medical Center, Kanagawa, Japan.

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.

PII: S0091-6749(09)01328-1

doi:10.1016/j.jaci.2009.08.044

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