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.
Tschumperlin
Daniel J
DJ
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Harvard Medical School, Boston, Massachusetts 02115, USA.
Shively
Jonathan D
JD
Swartz
Melody A
MA
Silverman
Eric S
ES
Haley
Kathleen J
KJ
Raab
Gerhard
G
Drazen
Jeffrey M
JM
D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D019245:Compressive Strength; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009997:Osmotic Pressure; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one