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


CONCLUSIONS
Acute asthma attacks are associated with hypersecretion of EGF and amphiregulin in the airway. Recurrent acute attacks may aggravate airway remodeling.
Enomoto
Yukinori
Y
Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan.
Orihara
Kanami
K
Takamasu
Tetsuya
T
Matsuda
Akio
A
Gon
Yasuhiro
Y
Saito
Hirohisa
H
Ra
Chisei
C
Okayama
Yoshimichi
Y
D000208:Acute Disease; D000293:Adolescent; D066258:Amphiregulin; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D055271:Mucin 5AC / Q000819:agonists / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013183:Sputum / Q000737:chemistry
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases