Background Pulmonary arterial hypertension (PAH) is associated with pulmonary vascular inflammation and dysregulated bone morphogenetic protein receptor type 2 (BMPR2) signalling in both human and experimental PAH. We evaluated the effects of dexamethasone on established monocrotaline-induced PAH in rats for potential reversal of PAH, at time points when pulmonary vascular remodelling has already developed (from day 14 after a single injection of monocrotaline at day 0), and for the effects on pulmonary IL6 and BMPR2 expression.
Methods Saline-treated controls, monocrotaline-exposed, monocrotaline-exposed and dexamethasone-treated rats (5 mg/kg/day, 1.25 mg/kg and 2.5 mg/kg/48 h given from day 14–28 and day 21–35) were evaluated at day 28 and day 35 following monocrotaline for pulmonary vascular haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, whole lung IL-6 and BMPR2 expression by quantitative real-time PCR (qRT-PCR).
Results Dexamethasone significantly improved pulmonary haemodynamics and morphometric indices of pulmonary vascular remodelling, reversing PAH when given at day 14–28, day 21–35 following monocrotaline, as well as improving survival in monocrotaline-exposed rats compared to controls (log rank p<0.0001). Dexamethasone reduced both monocrotaline-induced whole lung IL-6 overexpression (p<0.05), as well as reducing IL-6-expressing adventitial inflammatory cell infiltration as assessed by immunohistochemistry. This was associated with pulmonary BMPR2 down-regulation (p<0.01) following monocrotaline, which was significantly increased following day 14–28 dexamethasone treatment in whole lung (p<0.05) (Abstract S152 Figure 1). Cellular BMPR2 was also increased following in vitro treatment of control pulmonary artery smooth muscle cells (PASMC) with ×10−8 molar dexamethasone (p<0.05), but not in PASMC isolated from pulmonary hypertensive rats. Dexamethasone (×10−8 and 10−7 molar) also reduced proliferation of PASMC isolated from both control and pulmonary hypertensive rats (p<0.05 for both doses).
Conclusion PAH in this well-characterised experimental model can be reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, reduced proliferation of vascular smooth muscle cells, and restoration of pulmonary BMPR2 expression may be important.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.