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Am J Physiol Lung Cell Mol Physiol (August 18, 2006). doi:10.1152/ajplung.00111.2006
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Submitted on March 26, 2006
Accepted on August 14, 2006

Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells

Ralph McWhinnie1, Dmitri V Pechkovsky2, Danyi Zhou3, David Lane3, Andrew j Halayko4, Daryl Knight3, and Tony R. Bai3*

1 Medicine, UBC, vancouver, Canada
2 Icapture, UBC, vancouver, Canada
3 Medicine, UBC, Vancouver, Canada
4 physiology, Umanitoba, vancouver, Canada

* To whom correspondence should be addressed. E-mail: tbai{at}mrl.ubc.ca.

Endothelin-1 (ET-1), a G protein coupled receptor activating peptide, is increased in airway epithelium, plasma and BAL fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10-11 - 10-7 M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ET-A and ET-B receptors, cell size, as well as increased expression of myosin heavy chain, {alpha}-smooth muscle actin and calponin. ET-1 induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK 1 / 2 by the MEK 1 / 2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M (OSM), and greater than that induced by cardiotrophin-1 (CT-1). ET-1 induced release of IL-6 but not IL-11, LIF, OSM, or CT-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.




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