Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models
Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models
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DOI：
10.1016/j.ejphar.2013.08.019
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发表时间：
2013-10-15
影响因子：
5
通讯作者：
McLeod, Robbie L.
中科院分区：
文献类型：
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作者：
Lieber, Gissela B.;Fernandez, Xiomara;McLeod, Robbie L.
越来越多的证据表明，盐皮质激素拮抗剂(MR拮抗剂)对心血管病理具有保护作用，包括钝化血管炎症和心肌纤维化。我们研究了MR拮抗剂在啮齿动物呼吸道模型中的抗炎和抗纤维化作用。在卵蛋白过敏和激发的棕色挪威大鼠模型中，鼻腔灌洗液中的细胞总数为29348+/-5451，螺内酯(0.3-60 mg/kg，P.O.)可阻断这一作用。依普利酮(0.3~30 mg/kg，P.O.我们还发现MR拮抗剂减轻了棕色挪威大鼠的肺部炎症。为探讨MR阻滞剂在急、慢性肺损伤模型中的作用，进行了一系列实验。(1)体外肺切片实验发现，依普利酮(0.01和10mU M)和螺内酯(10mM)可使肺组织羟脯氨酸浓度分别降低55.5%、122.9%和83+/-8%。(2)在体内实验中，MR拮抗剂可减轻博莱霉素所致的BAL中性粒细胞和巨噬细胞的增加。在单独的研究中，博莱霉素(4.0U/kg，it.)经螺内酯(10-60 mg/kg，P.O.)阻断后，肺组织羟脯氨酸水平增加约155%。在大鼠脂多糖(LPS)模型中，螺内酯抑制BAL细胞因子的急剧增加，对中性粒细胞的影响中等。最后，我们发现，慢性内毒素暴露显著增加了小鼠的呼气末肺活量，降低了肺弹性。MR拮抗剂可改善慢性内毒素的上述功能效应。我们的结果表明，MR拮抗剂在呼吸系统具有显著的药理作用。爱思唯尔出版公司(Elsevier B.V.)
Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 +/- 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 mu M) and spironolactone (10 mu M) diminished lung hydroxyproline concentrations by 55 5, 122 9, and 83 +/- 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, it.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system. Published by Elsevier B.V.