MECHANISMS OF EPIDERMAL GROWTH FACTOR-INDUCED CONTRACTION OF GUINEA-PIG ALWAYS

We investigated the functional effects of epidermal growth factor (EGF ) on guinea pig airways in vitro. EGF (3 ng/ml to 1 mu g/ml) induced a concentration-dependent contraction in epithelium-denuded strips. The average maximal contraction was 0.64 +/- 0.1 g (mean +/- S.E., for n = 27), which was 72.0 +/- 9.5% of the 100 mM KCl-induced contraction. The EC(50) was 12.3 +/- 1.6 ng/ml. The presence of the epithelium sign ificantly suppressed the EGF-induced contraction (P<0.01). EGF-induced contraction was abolished by cyclooxygenase inhibitors (indomethacin and ibuprofen) and a 5-lipoxygenase inhibitor, deca-5,10-diynyl)-3,5,6 -trimethyl-1,4-benzoquinone (AA-861). It was also inhibited by a leuko triene-receptor antagonist, zoyl]amino-2-(tetrazol-5-yl)-4-oxo-4H-1-be nzopyran hemihydrate (ONO-1078) but not affected by a thromboxane A(2) -synthetase inhibitor, (E)-3-[4-(1-imidazolylrnethyl)phenyl]-2-propeno ic acid (OKY-046) or a thromboxane A(2)-receptor antagonist, 9,11-epit hio-11,12-methano-thromboxane A(2) (ONO-3708). A phospholipase A(2) in hibitor (mepacrine) inhibited the EGF-induced contraction but a diacyl glycerol-lipase inhibitor, 1,6-di-(O-(carbamoyl)cyclohexanone oxime)he xane (U-57908) and a phospholipase D inhibitor (wortmannin) did not af fect it. A tyrosine kinase inhibitor (genistein) abolished it. Measure ment of prostanoids showed that EGF (300 ng/ml) did not increase the p rostaglandin F-2 alpha level in either epithelium-intact or epithelium -denuded strips. In epithelium-intact strips, EGF significantly increa sed the prostaglandin E(2) concentration (P < 0.01). These results sug gest that EGF causes contraction of guinea pig airway smooth muscle by activating tyrosine kinase followed by phospholipase A(2) activation, and that arachidonic acid metabolites, especially leukotrienes, may h ave important roles in this contraction.