Bronchial Epithelial Compression Regulates Epidermal Growth Factor Receptor Family Ligand Expression in an Autocrine Manner

Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 06/2005; 32(5):373-80. DOI: 10.1165/rcmb.2004-0266OC
Source: PubMed


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.

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    • "Savla and Waters [16] have shown that mechanical forces from cyclical mechanical strain and compressive stress to human and cat airway epithelium cells inhibited epithelial layer repair after wounded by scraping. A model of compressive stress on differentiated normal human bronchial epithelial cells cultured at air-liquid interface has been shown to promote airway remodelling by increasing the gene expression of transforming growth factor (TGF)-β, endothelin-1, and plasminogen activator gene [17, 18], enhancing the release of profibrotic cytokines: TGF-β2 and endothelin [17], increasing intracellular mucin-5AC (MUC5AC) levels [19], increasing expression of EGFR and EGFR ligand [20], enhancing the production of matrix metalloproteinase (MMP)-2 and MMP-9 [18], YKL-40 [21], a chitinase like protein which was recently shown to be associated with airway remodelling in children as well as tissue factor, a coagulation factor that was shown to enhance angiogenesis [22]. Cyclical mechanical strain of airway epithelium cells has also been shown to increase the production of reactive oxygen species (ROS) [23], and to down-regulate prostaglandin E2 synthesis (PGE2) [24]. "
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    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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    • "A similar hypertrophic effect can be seen in arteries as a result of hypertension (high blood pressure) [271]. Other tissues where development is affected by mechanical loading are cartilage [117], the airway [48] [177], and the endothelial lining of blood vessels [202]. "
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    SIAM Review 01/2012; 54(1):52-118. DOI:10.1137/080731785 · 2.91 Impact Factor
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    • "To investigate the different signaling pathways potentially implicated in the stretch-induced response, experiments were run in parallel (control and pretreated groups) in the absence or presence of drugs added immediately to the organ bath after the last change of fresh Krebs-Henseleit solution during the equilibration period: 1) a cyclooxygenase (COX) inhibitor: indomethacin (0.1 μM); 2) a leukotriene Cyst-LT1 receptor antagonist: MK476 (0.1 μM); 3) a nonspecific NOS inhibitor at high concentration and specific NOS3 inhibitor at low concentration = L-nitroarginine methyl ester (L-NAME, 1 mM and 1 μM, respectively) [11,18,19]; 4) a selective inhibitor of inducible NOS2: 1400 W (1 mM) [11]; 5) a selective inhibitor of constitutive NOS1: Nω-propyl-L-arginine (5 mM) [11]; 6) a mixture of the tachykinin NK1-, NK2-, and NK3-receptor antagonists: SR 140333 (0.1 μM), SR 48968 (0.1 μM), SR 142801 (0.1 μM) [20]; 7) a histamine H1-receptor antagonist: mepyramine (0.1 μM); 8) a mixture of the selective endothelin ETA- and ETB-receptor antagonists: BQ 123 (0.1 μM) and BQ 788 (0.1 μM); 9) a muscarinic ACh-receptor antagonist: atropine (0.1 μM); 10) a nonspecific blocker of acid-sensing ion and stretch-activated channels: gadolinium (Gd3+, 0.1 mM) [21,22]; 11) a selective Rho-kinase (ROCK1 and ROCK2) inhibitor: Y27632 (0.1 μM) [23,24]. ACh, indomethacin, L-NAME, mepyramine, BQ 123, BQ 788, atropine and gadolinium were purchased from Sigma-Aldrich (St. Louis, MO, USA). "
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    Critical care (London, England) 09/2011; 15(5):R208. DOI:10.1186/cc10443 · 4.48 Impact Factor
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