Journal
EUROPEAN RESPIRATORY JOURNAL
Volume 39, Issue 4, Pages 927-938Publisher
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/09031936.00021411
Keywords
Bosentan; cigarette smoke; endothelin receptor; human pulmonary artery smooth muscle cells; precision-cut lung slice
Categories
Funding
- Ministry of Science and Innovation and Health Institute Carlos III of the Spanish Government [SAF2008-03113, SAF2009-08913, CB06/06/0027]
- Regional Government (Generalitat Valenciana'') [Prometeo/2008/045, Emerging Groups GE-029/10]
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The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients. This study examined the effect of cigarette smoke (CS) on ET receptor A (ETA) and B (ETB) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences. CS extract (CSE) increased ETA and ETB expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ETA antagonist BQ123 and the ETB antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ETA and ETB than those of nonsmoker patients. These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.
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