Mitogenic actions of endothelin-1 and epidermal growth factor in cultured airway smooth muscle

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 (Ca2+(i)). ET-1 stimulated DNA and protein synthesis and also increased cell number, but these mitogenic actions were small compared with those of EGF. ET-1 and EGF increased the level of tyrosine phosphorylation 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. Ca2+(i) 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. We conclude that elevation of Ca2+(i) 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 a) may play a role in the airway smooth muscle hyperplasia in asthma.