Bronchial epithelial compression regulates MAP kinase signaling and HB-EGF-like growth factor expression
Airway smooth muscle constriction leads to the development of compressive stress on bronchial epithelial cells. Normal human bronchial epithelial cells exposed to an apical-to-basal transcellular pressure difference equivalent to the computed stress in the airway during bronchoconstriction demonstrate enhanced phosphorylation of extracellular signal-regulated kinase (ERK). The response is pressure dependent and rapid, with phosphorylation increasing 14-fold in 30 min, and selective, since p38 and c-Jun NH(2)-terminal kinase phosphorylation remains unchanged after pressure application. Transcellular pressure also elicits a ninefold increase in expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF) after 1 h, followed by prominent immunostaining for pro-HB-EGF after 6 h. Inhibition of the ERK pathway with PD-98059 results in a dose-dependent reduction in pressure-induced HB-EGF gene expression. The magnitude of the HB-EGF response to transcellular pressure and tumor necrosis factor (TNF)-alpha (1 ng/ml) is similar, and the combined mechanical and inflammatory stimulus is more effective than either stimulus alone. These results demonstrate that compressive stress is a selective and potent activator of signal transduction and gene expression in bronchial epithelial cells.
Keywords: Bronchi/cytology ; Cells ; Cultured ; Compressive Strength ; Enzyme Inhibitors/pharmacology ; Epidermal Growth Factor/*genetics/metabolism ; Flavonoids/pharmacology ; Gene Expression/physiology ; Humans ; MAP Kinase Signaling System/*physiology ; Mitogen-Activated Protein Kinases/metabolism ; Osmotic Pressure ; Phosphorylation ; RNA ; Messenger/analysis ; Research Support ; U.S. Gov't ; P.H.S. ; Respiratory Mucosa/cytology/*metabolism
Record created on 2006-08-09, modified on 2016-08-08