MITOGENIC ACTIONS OF ENDOTHELIN-1 AND EPIDERMAL GROWTH-FACTOR IN CULTURED AIRWAY SMOOTH-MUSCLE

1. Hyperplasia of airway smooth muscle contributes to the increase in bronchomotor responsiveness that characterizes asthma. We have investigated the mitogenic potential of endothelin-1 (ET-1) and epidermal growth factor (EGF) in guinea-pig cultured airway smooth muscle and the relationship of these actions to tyrosine phosphorylation and increases in intracellular calcium (Ca-i(2+)). 2. ET-1 stimulated DNA and protein synthesis and also increased cell number, but these mitogenic actions were small compared with those of EGF. 3. ET-1 and EGF increased the level of tyrosine phophorylation of a range of proteins with apparent molecular weights between 80 and 100 kDa and also increased phosphorylation of a single protein of 33 kDa. 4. Ca-i(2+) levels were increased by both ET-1 and EGF. However, concentrations of EGF three orders of magnitude higher than those having mitogenic actions or increasing protein tyrosine phosphorylation were required. ET-1 was a more potent stimulant of increases in intracellular calcium than of mitogenesis. 5. We conclude that elevation of Ca-i(2+) is unlikely to be an important signal for the mitogenic action of EGF. It is suggested that stimulants at the EGF receptor (EGF and transforming growth factor alpha) may play a role in the airway smooth muscle hyperplasia in asthma.