RT Journal Article SR Electronic T1 Endothelin receptor B (ETBR) dependent GM-CSF mRNA stabilization explains the higher efficacy of bosentan vs. ambrisentan in the reduction of GM-CSF release from human airway smooth muscle cells (HASMCs) JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP p4103 VO 38 IS Suppl 55 A1 David Jungck A1 Juergen Knobloch A1 Katja Urban A1 Erich Stoelben A1 Justus Strauch A1 Juergen Behr A1 Andrea Koch YR 2011 UL http://erj.ersjournals.com/content/38/Suppl_55/p4103.abstract AB Introduction: TNFα and GM-CSF are pivotal in chronic inflammatory airway diseases and lung fibrosis. TNFα-induced Endothelin-1 (ET-1) release is required for full TNFα induced GM-CSF transcription in HASMCs suggesting anti-inflammatory potential of endothelin receptor antagonists (ERA). The MAP-Kinase ERK protects GM-CSF mRNA from degradation. Ambrisentan (ETAR blocker) and bosentan (dual blocker) are available for PAH therapy.Aim: We compared the anti-inflammatory potential of bosentan vs. ambrisentan.Methods: HASMC culture, qRT-PCR, ELISA.Results: TNFα and ET-1 induce transcription and release of ET-1 and GM-CSF (each p<0.05). Bosentan reduces GM-CSF release more efficiently than ambrisentan (p<0.01; EC50: 4.5 vs. 11×10-8M; EMAX: 63.7 vs. 54.8% reduction; n=9) but both block GM-CSF transcription similarly. Specific ETBR inhibition (BQ 788) also reduces GM-CSF mRNA. Combined blocking of ETAR (ambrisentan) and ERK activity (PD 098059) leads to a greater reduction of GM-CSF release than single inhibition (each p<0.05). In the presence of actinomycin D which blocks gene transcription bosentan leads to a significantly greater reduction of GM-CSF mRNA than ambrisentan (p<0.01).Conclusion: Following TNFa-induced ET-1 release, ETAR induces GM-CSF transcription and ETBR signals via ERK to protect GM-CSF mRNA from degradation. This can explain why bosentan reduces TNFα induced GM-CSF release more effectively than ambrisentan. Thus, bosentan may be superior in the therapy of early stages of chronic airway diseases by preventing the establishment of inflammation.