RT Journal Article
SR Electronic
T1 Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP erj00283-2010
DO 10.1183/09031936.00028310
A1 L.C. Price
A1 D. Montani
A1 C. Tcherakian
A1 P. Dorfmüller
A1 R. Souza
A1 N. Gambaryan
A1 M-C. Chaumais
A1 D.M. Shao
A1 G. Simonneau
A1 L.S. Howard
A1 I.M. Adcock
A1 S.J. Wort
A1 M. Humbert
A1 F. Perros
YR 2010
UL http://erj.ersjournals.com/content/early/2010/08/06/09031936.00028310.abstract
AB Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor type 2 (BMPRII) signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points.Saline-treated controls, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5mg·kg−1·day−1, 1.25mg·kg−1 and 2.5mg·kg−1/48-hourly) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, IL-6 and BMPR2expression.Dexamethasone improved haemodynamics and pulmonary vascular remodeling, preventing PAH development at early (day1–14, day1–28) and reversing PAH at late time points (day14–28, day21–35) following monocrotaline, as well as improving survival in MCT-exposed rats compared to controls. Both MCT-induced pulmonary IL-6 overexpression and IL-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 down-regulation following monocrotaline which was increased with dexamethasone, in whole lung, and in control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro.Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 and reduced proliferation of vascular smooth muscle cells.