Transduction of compressive stress by bronchial epithelium

Abstract

The epithelial lining of the asthmatic airway is exposed to compressive stress as a consequence of smooth muscle constriction. We have shown previously that in vitro compression of bronchial epithelial cells stimulates extracellular signal-regulated kinase (ERK) phosphorylation and downstream gene expression. Here we show that inhibition of signaling through the epidermal growth factor receptor (EGFR) with a tyrosine kinase inhibitor (AG1478) or a neutralizing antibody to the ligand-binding domain of the EGFR blocks compression-induced ERK phosphorylation. A metalloprotease inhibitor (Galardin) and a neutralizing antibody to heparin binding epidermal growth factor (HB-EGF), but not EGF, also attenuates the compression-induced ERK activation. Our results demonstrate that compressive activation of the ERK signaling pathway requires signaling through the EGFR, and involves metalloprotease-dependent shedding of HB-EGF.