Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats.
Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II 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 control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and 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 expression and reduced proliferation of vascular smooth muscle cells.
Price
L C
LC
Faculté de Médecine, Université Paris-Sud, Paris, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Clamart, France.
Montani
D
D
Tcherakian
C
C
Dorfmüller
P
P
Souza
R
R
Gambaryan
N
N
Chaumais
M-C
MC
Shao
D M
DM
Simonneau
G
G
Howard
L S
LS
Adcock
I M
IM
Wort
S J
SJ
Humbert
M
M
Perros
F
F
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D049109:Cell Proliferation; D003907:Dexamethasone / Q000494:pharmacology*; D065627:Familial Primary Pulmonary Hypertension; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D007150:Immunohistochemistry / Q000379:methods; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects*; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D016686:Monocrotaline; D003907:Dexamethasone; D052004:Bone Morphogenetic Protein Receptors