Endothelin-1-induced potentiation of human airway smooth muscle proliferation: an ETA receptor-mediated phenomenon
Article first published online: 19 JUL 2012
1996 British Pharmacological Society
British Journal of Pharmacology
Volume 118, Issue 1, pages 191–197, May 1996
How to Cite
Panettieri, R. A., Goldie, R. G., Rigby, P. J., Eszterhas, A. J. and Hay, D. W.P. (1996), Endothelin-1-induced potentiation of human airway smooth muscle proliferation: an ETA receptor-mediated phenomenon. British Journal of Pharmacology, 118: 191–197. doi: 10.1111/j.1476-5381.1996.tb15385.x
- Issue published online: 19 JUL 2012
- Article first published online: 19 JUL 2012
- Received September 15, 1995; Revised December 18, 1995; Accepted January 16, 1996
- Human cultured airway smooth muscle;
- airway smooth muscle proliferation;
- sarafotoxin S6c;
- endothelin receptor subtypes;
- ETA receptor;
- ETB receptor;
- epidermal growth factor
- 1. In this study the mitogenic effects in human cultured tracheal smooth muscle cells of endothelin-1 (ET-1), ET-3, and sarafotoxin S6c (S6c), the ETB 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 (0.01 nM-1μm) nor ET-3 (0.001 nM-1 μm) or S6c (0.01 nM-1 μm) induced cell proliferation, as assessed by [3H]-thymidine incorporation. In contrast, EGF (1.6 pM − 16 nM) produced concentration-dependent stimulation of DNA synthesis (EC50 of about 0.06 nM). The maximum increase of about 60 fold above control, elicited by 16nM EGF, was similar 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 mitogenesis.
- 3. ET-1 (1–100 nM) potentiated EGF-induced proliferation of human tracheal smooth muscle cells. For example, ET-1 (100 nM), which alone was without significant effect, increased by 3.0 to 3.5 fold the mitogenic influence of EGF (0.16 nM). The potentiating effect of ET-1 on EGF-induced proliferation was antagonized by BQ-123 (3 μm), the ETA receptor antagonist, but was unaffected by the ETB receptor antagonist BQ-788 (10 μm).
- 4. Neither ET-3 (1 − 100 nM) nor S6c (1 − 100 nM) influenced the mitogenic effects of EGF (0.16-1.6 nM).
- 5. [125I]-ET-1 binding studies revealed that on average the ratio of ETA to ETB receptors in human cultured tracheal smooth muscle cells was 35:65 (±3; n=4), confirming the predominance of the ETB receptor subtype in human airway smooth muscle.
- 6. These data indicate that ET-1 alone does not induce significant human airway smooth muscle cell proliferation. However, it potently potentiated mitogenesis induced by EGF, apparently via an ETA receptor-mediated mechanism. These findings suggest that ET-1, a mediator detected in increased amounts in patients with acute asthma, may potentiate the proliferative effects of mitogens and contribute to the airway smooth muscle hyperplasia associated with chronic severe asthma.