Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: primary pulmonary hypertension (PPH); vasoactive intestinal peptide (VIP); pulmonary artery smooth muscle cells (PASMCs); mean pulmonary arterial pressure (MPAP).

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: primary pulmonary hypertension (PPH); vasoactive intestinal peptide (VIP); pulmonary artery smooth muscle cells (PASMCs); mean pulmonary arterial pressure (MPAP).

Lefamulin may be an addition to the therapeutic armamentarium for the treatment of infections. Simultaneous measurements of unbound drug concentration can guide target attainment for future therapeutic trials.

BackgroundPulmonary arterial hypertension is characterized by increased thickness of pulmonary vessel walls due to both increased proliferation of pulmonary arterial smooth muscle cell (PASMC) and deposition of extracellular matrix. In patients suffering from pulmonary arterial hypertension, endothelin-1 (ET-1) synthesis is up-regulated and may increase PASMC activity and vessel wall remodeling through transforming growth factor beta-1 (TGF-β1) and connective tissue growth factor.ObjectiveTo assess the signaling pathway leading to ET-1 induced proliferation and extracellular matrix deposition by human PASMC.MethodsPASMC were serum starved for 24 hours before stimulation with either ET-1 and/or TGF-β1. ET-1 was inhibited by Bosentan, ERK1/2 mitogen activated protein kinase (MAPK) was inhibited by U0126 and p38 MAPK was inhibited by SB203580.ResultsET-1 increased PASMC proliferation when combined with serum. This effect involved the mitogen activated protein kinases (MAPK) ERK1/2 MAPK and was abrogated by Bosentan which caused a G1- arrest through activation of p27(Kip). Regarding the contribution of extracellular matrix deposition in vessel wall remodeling, TGF-β1 increased the deposition of collagen type-I and fibronectin, which was further increased when ET-1 was added mainly through ERK1/2 MAPK. In contrast, collagen type-IV was not affected by ET-1. Bosentan dose-dependently reduced the stimulatory effect of ET-1 on collagen type-I and fibronectin, but had no effect on TGF-β1.Conclusion and Clinical RelevanceET-1 alone does not induce PASMC proliferation and extracellular matrix deposition. However, ET-1 significantly up-regulates serum induced proliferation and TGF-β1 induced extracellular matrix deposition, specifically of collagen type-I and fibronectin. The synergistic effects of ET-1 on serum and TGF-β1 involve ERK1/2 MAPK and may thus present a novel mode of action in the pathogenesis of pulmonary arterial hypertension.

In patients with COPD, abnormal pulmonary artery pressure impairs gas exchange, decreases maximum oxygen uptake during exercise and impairs exercise capacity.