Ra. Panettieri et al., ENDOTHELIN-1-INDUCED POTENTIATION OF HUMAN AIRWAY SMOOTH-MUSCLE PROLIFERATION - AN ETA-RECEPTOR-MEDIATED PHENOMENON, British Journal of Pharmacology, 118(1), 1996, pp. 191-197
1 In this study the mitogenic effects in human cultured tracheal smoot
h muscle cells of endothelin-l (ET-I), ET-3, and sarafotoxin S6c (S6c)
, the ET(B) receptor-selective agonist, were explored either alone or
in combination with the potent mitogen, epidermal growth factor(EGF).
2 In confluent, growth-arrested human airway smooth, neither ET-1 (0.0
1 nM - 1 mu M) nor ET-3 (0.001 nM - 1 mu M) Or S6c (0.01 nM - 1 mu M)
induced cell proliferation, as assessed by [H-3]-thymidine incorporati
on. In contrast, EGF (1.6 pM - 16 nM) produced concentration-dependent
stimulation of DNA synthesis (EC(50) of about 0.06 nM). The maximum i
ncrease of about 60 fold above control, elicited by 16 nM EGF, was sim
ilar to that obtained with 10% foetal bovine serum (FBS). EGF (0.16 -
16 nM) also produced a concentration-dependent increase in cell counts
, whereas ET-1 (1 - 100 nM) was without effect on this index of mitoge
nesis. 3 ET-1 (1 - 100 nM) potentiated EGF-induced proliferation of hu
man tracheal smooth muscle cells. For example, ET-I (100 nM), which al
one was without significant effect, increased by 3.0 to 3.5 fold the m
itogenic influence of EGF (0.16 nM). The potentiating effect of ET-1 o
n EGF-induced proliferation was antagonized by BQ-123 (3 mu M), the ET
(A) receptor antagonist, but was unaffected by the ET(B) receptor anta
gonist BQ-788 (10 mu M). 4 Neither ET-3 (1 - 100 nM) nor S6c (1 - 100
nM) influenced the mitogenic effects of EGF (0.16 - 1.6 nM). 5 [I-125]
-ET-1 binding studies revealed that on average the ratio of ET(A) to E
T(B) receptors in human cultured tracheal smooth muscle cells was 35:6
5 (+/- 3; n = 4), confirming the predominance of the ET(B) receptor su
btype in human airway smooth muscle. 6 These data indicate that ET-1 a
lone does not induce significant human airway smooth muscle cell proli
feration. However, it potently potentiated mitogenesis induced by EGF,
apparently via an ET(A) receptor-mediated mechanism. These findings s
uggest that ET-l, a mediator detected in increased amounts in patients
with acute asthma, may potentiate the proliferative effects of mitoge
ns and contribute to the airway smooth muscle hyperplasia associated w
ith chronic severe asthma.