Faculté de Médecine, Université Paris-Sud, Paris, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Clamart, France.
Eur Respir J. 2011 Apr;37(4):813-22. doi: 10.1183/09031936.00028310. Epub 2010 Aug 6.
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.
肺动脉高压（PAH）与骨形态发生蛋白受体（BMPR）-II 信号传导失调和肺血管炎症有关。我们评估了地塞米松对野百合碱（MCT）诱导的 PAH 大鼠的影响，以期在晚期逆转 PAH。在 MCT 后第 28 天和第 35 天，对生理盐水处理的对照组、MCT 暴露组、MCT 暴露和地塞米松处理组（5mg·kg⁻¹·day⁻¹、1.25mg·kg⁻¹和 2.5mg·kg⁻¹·48h⁻¹）进行血流动力学参数、右心室肥厚、形态计量学、免疫组织化学以及 IL6 和 BMPR2 表达的评估。地塞米松改善了血流动力学和肺血管重构，预防了早期（MCT 后第 1-14 天和第 1-28 天）和晚期（MCT 后第 14-28 天和第 21-35 天）PAH 的发展，并提高了 MCT 暴露大鼠的存活率与对照组相比。MCT 诱导的肺 IL6 过表达和间质炎症细胞浸润都减少了。这与 MCT 后肺 BMPR2 下调有关，地塞米松增加了肺 BMPR2 的表达，在整个肺和对照肺动脉平滑肌细胞中均如此。地塞米松还减少了大鼠肺动脉平滑肌细胞在体外的增殖。实验性 PAH 可被地塞米松预防和逆转，并提高了存活率。在该模型中，机制可能涉及减少表达 IL-6 的炎症细胞、恢复肺 BMPR2 表达和减少血管平滑肌细胞增殖。
