Published ahead of print on February 10, 2005, doi:10.1165/rcmb.2004-0266OC Am. J. Respir. Cell Mol. Biol., Volume 32, Number 5, May 2005, 373-380 A more recent version of this article appeared on May 1, 2005
Submitted on August 18, 2004 Bronchial Epithelial Compression Regulates EGFR Family Ligand Expression in an Autocrine MannerEric K Chu1*,1 Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA, 2 Physiology Program, Harvard School of Public Health, Boston, MA, USA * To whom correspondence should be addressed. E-mail: echu{at}partners.org.
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, 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: i) continuous compressive stress over 8 hours, ii) compression with and without EGFR inhibitor (AG1478), or iii) time limited compression (3.75, 7.5, 15, 30, and 60 minutes). Compressive stress produced a sustained upregulation of the EGFR ligands HB-EGF, epiregulin, and amphiregulin, but not transforming growth factor-
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. 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.
