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A more recent version of this article appeared on June 1, 2004
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Submitted on December 17, 2003
Revised on March 9, 2004
Accepted on March 16, 2004
1 Centre for Rheumatology, Royal Free and University College Medical School, London NW3 2PF, UK
2 Centre for Tissue Engineering Research, University of Westminster, 115 New Cavendish St. London W1W 6UM
3 Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College School of Medicine, London SW3 6LR, U.K.
4 Dept. of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN
5 Centre for Cardiovascular Biology & Medicine, GKT School of Biomedical Sciences, King’s College London, Guy’s Campus, London, SE1 1UL, UK
6 Department of Molecular Pathology, Royal Free and University College Medical School, London NW3 2PF, UK
* Corresponding author. E-mail address: a.leask{at}rfc.ucl.ac.uk.
The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair, and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including 
-smooth muscle actin (-SMA), ezrin, moesin and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/PI-3 kinase pathway with Ly294002 and wortmannin prevents the ability of ET-1 to induce -SMA, ezrin, paxillin and moesin, and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of -SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma; SSc) show enhanced ET-1 expression and binding. SSc lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins -SMA, ezrin, paxillin and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI-3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis.
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