The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension.
Bottom Line: Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod).Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod.This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6.
Affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom; email@example.com.Show MeSH
Related in: MedlinePlus
Mentions: Exposure of RPAF to hypoxia for up to 48 h led to upregulation of IL-6 and release of IL-6 from the cells. Secreted levels of IL-6 were significantly increased at 48 h of exposure. Treatment of cells with SB203580 prevented the release of the IL-6 from hypoxia-exposed fibroblasts (Fig. 6, A and B). This was time dependent with peak mRNA effect observed at 12 h after hypoxic exposure (Fig. 6C). This was reduced in the presence of p38 inhibition (data not shown). Further studies showed that pulmonary artery fibroblasts proliferate in response to IL-6, which was not significantly increased in the presence of the soluble IL-6R-α subunit (testing transactivation of the IL-6 pathway) but was more pronounced under hypoxic conditions (Fig. 6D). In PASMCs, the addition of IL-6 also proved to be a strong mitogen (Fig. 6E) and incubation with anti-IL-6 blocked the PASMC proliferation (Fig. 6F). In addition, the proliferation via IL-6 seemed to be mediated by the classical STAT-3 pathway with increased phosphorylation in a time-dependent manner as shown (Fig. 6, G and H).
Affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom; firstname.lastname@example.org.