Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Abstract

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 ) 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.

Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension

“…The effect of inflammation in PH development has been further confirmed by the fact that clinical improvements have been observed in patients after steroid treatment or immunosuppressor administration (5,44). However, the potential benefit of anti-inflammatory therapies in PH still remains to be confirmed and requires further investigation.…”

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

“…In addition to both the Kv/calcium axis and DYm, other pathways are known to be implicated in PAH-PASMC proliferation and resistance to apoptosis, including: BMPR2 protein and mRNA expression [39]; ROCK1 activation [40]; and mRNA interleukin (IL)-6 expression [41]. Although the importance of each pathway in the aetiology of PAH remains to be established (and is likely to be different among the different forms of PAH), we provide evidence that PLB can affect all of them.…”

Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

“…Concentrations of proinflammatory cytokines, including IL-1 and IL-6, are elevated in both human idiopathic pulmonary artery hypertension (PAH) (8) and in the monocrotaline (MCT) model of PH (9,10). Depletion of the circulating pool of macrophages is sufficient to prevent hypoxia-driven PH (11), and dexamethasone treatment reverses MCT PH (12). Taken together, these studies suggest that PH is a syndrome characterized by the complex disturbance of innate and acquired immune cells, and of mediators and effectors of inflammation.…”