Background: There is an urgent need to inhibit endothelin (ET)-1 induced chronic inflammatory processes in early stages of lung diseases in order to prevent untreatable irreversible stages often accompanied by lung fibrosis and pulmonary hypertension. Nothing is known about the airway inflammation inducing and/or maintaining role of ET-1 in human airway smooth muscle cells (HASMCs).
Objective: We investigated ET-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in response to tumor necrosis factor-α (TNFα) and ET-1 stimulation, and studied the impact of mitogen-activated protein (MAP) kinase pathways in this context. To elucidate the anti-inflammatory properties of the dual endothelin receptor antagonist Bosentan that targets both endothelin receptor subtypes A (ETAR) and B (ETBR), we investigated its effect on the TNFα/ET-1/GM-CSF network.
Methods: ET-1 and GM-CSF expression and activation of MAP-kinases were investigated via quantitative RT-PCR, Western blotting and ELISA.
Main results: Both, TNFα and ET-1 activated p38MAPK and ERK-1/-2 signalling. ET-1 expression was induced by TNFα and by ET-1 itself. Both effects were inhibited by Bosentan and by specific ETAR or p38MAPK blockade. ET-1- and TNFα-induced GM-CSF expression were both reduced by Bosentan as well as by specific inhibition of either ETAR, ETBR, p38MAPK or ERK-1/-2.
Conclusion: TNFα activates an ETAR- and p38MAPK–dependent ET-1 autoregulatory positive feedback loop to maintain GM-CSF release from HASMCs. Since Bosentan impairs ET-1 autoregulation and TNFα-induced ET-1 release as well as TNFα- and ET-1-induced GM-CSF release our data suggest therapeutic utility for Bosentan in treating particularly early stages of chronic inflammatory airway diseases.