Influence of the endothelin receptor antagonists Ambrisentan and Bosentan on TNFa induced GM-CSF expression in human airway smooth muscle cells

Background: Human airway smooth muscle cells (HASMCs) have an important part in chronic inflammatory airway diseases and lung fibrosis for whose establishment TNFα and GM-CSF have a key role. We were able to show TNFα induced GM-CSF expression is regulated by endothelin-1 (ET-1) (Thorax, 2009;64:1044–52). This hints at an anti-inflammatory effect of endothelin receptor antagonists (ERA). Their efficacy in idiopathic pulmonary fibrosis is the subject of ongoing clinical trials. So far, few studies comparing the efficacy of a selective blockade of the endothelin receptor subtype A (ETAR) against the dual blockade of both subtypes (ETAR and ETBR) exist. Ambrisentan (ETAR blocker) and Bosentan (dual blocker) have been approved for the therapy of pulmonary arterial hypertension.

Aim: To investigate the anti-inflammatory effect of ERA in HASMCs and to compare the efficacy of selective against dual ERA in this. Methods: HASMC culture, qRT-PCR, ELISA.

Results: TNFα (20ng/ml) and ET-1 (100 nM) induce transcription and expression of ET-1 (p<0.01) or precursor ET-1 (p<0.05) or GM-CSF (p<0.01). Ambrisentan and Bosentan each reduce ET-1 induced ET-1 transcription (p<0.05) or TNFα induced GM-CSF expression (p<0.001). Regression analyses with sigmoidal dose-response-curves show Bosentan (EC50 4.5*10–8M, EMAX –63.7%) leads to a significantly greater reduction (p<0.001) of GM-CSF expression than Ambrisentan (EC50 11*10–8M, EMAX –54.8%).

Discussion: Our data support the hypothesis that ERA have an anti-inflammatory effect. Both selective as well as dual endothelin receptor antagonist cause a significant reduction of TNFα induced GM-CSF expression. However, Bosentan shows a higher effectiveness suggesting a potentially higher anti-inflammatory efficacy in comparison to Ambrisentan.