Mechanisms of epidermal growth factor-induced contraction of guinea pig

We investigated the functional effects of epidermal growth factor (EGF) on guinea pig airways in vitro. EGF (3 ng/ml to 1 !-tg/ml) induced a concentration-dependent contraction in epithelium-denuded strips. The average of maximal contractions was 0.64±0.1 g (mean±S.E., for n=27), which was 72.0±9.5% of 100 mM KCI-induced contraction. The ECso was 12.3±1.6 ng/ml. The presence of epithelium significantly suppressed EGF-induced contraction (P<O.Ol). EGF-induced contraction was abolished by cyclooxygenase inhibitors (indomethacin and ibuprofen) and a 5-lipoxygenase inhibitor, 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6tri-methyl-1,4-benzoquinone (AA-861). It was also inhibited by a leukotriene-receptor antagonist, 8-fp-( 4-phenylbutyloxy) benzoyl] amino2-(tetrazol-5-yl)-4-oxo-4H-1-benzopyran hemihydrate (ONO-1078) but not affected by a thromboxane A2-synthetase inhibitor, (E)-3-[ 4-(1imidazolylmethyl) phenyl]-2-propenoic acid (OKY -046) or a thromboxane A2-receptor antagonist, 9, 11-epithio-11, 12-methanothromboxane A2 (ONO-3708). A phospholipase A2 inhibitor (mepacrine) inhibited EGF-induced contraction but a diacylglycerol-lipase inhibitor, 1,6-di(O-(carbamoyl)cyclohexanone oxime)hexane (V-57908) and a phospholipase D inhibitor (wortmannin) did not affect it. A tyrosine kinase inhibitor (genistein) abolished it. In the measurement of prostanoids, EGF (300 ng/ml) did not increase the prostaglandin F2u level in either epithelium-intact or epithelium-denuded strips. In epithelium-intact strips, EGF significantly increased the prostaglandin E2 concentration (P<O.Ol). These results suggest that EGF causes contraction of guinea pig airway smooth muscle by activating tyrosine