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1 The Brooke Laboratories, and 4 Histochemistry Research Unit, Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, and 2 Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, UK. 3 University Hospital of Northern Sweden, Umeå, Sweden
CORRESPONDENCE: D. E. Davies, The Brooke Laboratories, Mailpoint 888, Southampton General Hospital, Southampton, SO16 6YD, UK. Fax: 44 2380701771. E-mail: donnad@soton.ac.uk
Keywords: ß2-Adrenoceptor agonist, bronchial epithelium, corticosteroid, epidermal growth factor receptor, intracellular signal transduction, tyrosine kinase
Received: August 24, 2004
Accepted February 18, 2005
A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation.
Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-
Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release.
These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.
in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release.
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