Bronchial epithelial compression regulates epidermal growth factor receptor family ligand expression in an autocrine manner.
ABSTRACT The epidermal growth factor receptor (EGFR), an important signaling pathway in airway biology, is stimulated by compressive stress applied to human airway epithelial cells. Although the EGFR ligand, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is known to be released as a result of this stimulation, whether compressive stress enhances expression of other EGFR ligands, and the duration of mechanical compression required to initiate this response, is not known. Human airway epithelial cells were exposed to compressive stress, and expression of four EGFR ligands was examined by quantitative PCR. Cells were exposed to: (1) continuous compressive stress over 8 h, (2) compression with and without EGFR inhibitor (AG1478), or (3) time-limited compression (3.75, 7.5, 15, 30, and 60 min). Compressive stress produced a sustained upregulation of the EGFR ligands HB-EGF, epiregulin, and amphiregulin, but not transforming growth factor-alpha. Inhibition with AG1478 demonstrated that expression of HB-EGF, epiregulin, and amphiregulin is dependent on the signaling via the EGFR. Immunostaining for epiregulin protein demonstrated increased expression with compression and attenuation with EGFR inhibition. The response of all three EGFR ligands persisted long after the mechanical stimulus was removed. Taken together, these data suggest the possibility of a mechanically activated EGFR autocrine feedback loop involving selected EGFR ligands.
SourceAvailable from: Wiparat Manuyakorn[Show abstract] [Hide abstract]
ABSTRACT: Asthma is a chronic airway inflammatory disease with functional and structural changes, leading to bronchial hyperresponsiveness and airflow obstruction. Airway structural changes or airway remodelling consist of epithelial injury, goblet cell hyperplasia, subepithelial layer thickening, airway smooth muscle hyperplasia and angiogenesis. These changes were previously considered as a consequence of chronic airway inflammation. Even though inhaled corticosteroids can suppress airway inflammation, the natural history of asthma is still unaltered after inhaled corticosteroid treatment. As such there is increasing evidence for the role of mechanical forces within the asthmatic airway contributing to airway structural changes.01/2014; 4(1):19-24. DOI:10.5415/apallergy.2014.4.1.19
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ABSTRACT: Epiregulin is a 46-amino acid protein that belongs to the epidermal growth factor (EGF) family of peptide hormones. Epiregulin binds to the EGF receptor (EGFR/ErbB1) and ErbB4 (HER4) and can stimulate signaling of ErbB2 (HER2/Neu) and ErbB3 (HER3) through ligand-induced heterodimerization with a cognate receptor. Epiregulin possesses a range of functions in both normal physiologic states as well as in pathologic conditions. Epiregulin contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation. Deregulated epiregulin activity appears to contribute to the progression of a number of different malignancies, including cancers of the bladder, stomach, colon, breast, lung, head and neck, and liver. Therefore, epiregulin and the elements of the EGF/ErbB signaling network that lie downstream of epiregulin appear to be good targets for therapeutic intervention.Seminars in Cell and Developmental Biology 04/2014; DOI:10.1016/j.semcdb.2014.03.005 · 5.97 Impact Factor
Article: Asthma.[Show abstract] [Hide abstract]
ABSTRACT: Asthma is a heterogeneous group of conditions that result in recurrent, reversible bronchial obstruction. Although the disease can start at any age, the first symptoms occur during childhood in most cases. Asthma has a strong genetic component, and genome-wide association studies have identified variations in several genes that slightly increase the risk of disease. Asthma is often associated with increased susceptibility to infection with rhinoviruses and with changes in the composition of microbial communities colonising the airways, but whether these changes are a cause or consequence of the disease is unknown. There is currently no proven prevention strategy; however, the finding that exposure to microbial products in early life, particularly in farming environments, seems to be protective against asthma offers hope that surrogates of such exposure could be used to prevent the disease. Genetic and immunological studies point to defective responses of lung resident cells, especially those associated with the mucosal epithelium, as crucial elements in the pathogenesis of asthma. Inhaled corticosteroids continue to be the mainstay for the treatment of mild and moderate asthma, but limited adherence to daily inhaled medication is a major obstacle to the success of such therapy. Severe asthma that is refractory to usual treatment continues to be a challenge, but new biological therapies, such as humanised antibodies against IgE, interleukin 5, and interleukin 13, offer hope to improve the quality of life and long-term prognosis of severe asthmatics with specific molecular phenotypes.The Lancet 08/2013; · 39.21 Impact Factor