Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis.
Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis.
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DOI：
10.1111/bph.12694
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发表时间：
2014-07
影响因子：
7.3
通讯作者：
Hobbs AJ
中科院分区：
文献类型：
--
作者：
Baliga RS;Scotton CJ;Trinder SL;Chambers RC;MacAllister RJ;Hobbs AJ
特发性肺纤维化（IPF）是一种进行性纤维增殖性疾病，目前的治疗难以治愈，通常会并发肺动脉高压（PH）；相关的发病率和死亡率很高。利钠肽具有血管扩张和抗纤维化作用，其生物活性的药理学增强可改善肾脏和心肌纤维化。在这里，我们研究了利钠肽是否具有内在的细胞保护功能，可预防肺纤维化和相关肺PH的发展，以及针对利钠肽信号传导的治疗是否在这种危及生命的疾病中表现出疗效。在暴露于博莱霉素（1 mg·kg−1）的野生型（WT）和利钠肽受体（NPR）-A 敲除（KO）小鼠中测定肺血流动力学、右心室功能和肺纤维化标志物。在体外研究了人肌成纤维细胞的分化。与暴露于博莱霉素的 WT 小鼠相比，在 NPR-A KO 动物中观察到心脏、血管和纤维化病理恶化。使用提高循环利尿钠肽水平（依卡多曲）和增强利尿钠肽依赖性信号传导（西地那非）的药物组合治疗可降低疾病进展指数，无论是预防性给药还是对已患有肺部疾病的动物给药。这种积极的药效作用在 NPR-A KO 小鼠中减弱。心钠素和西地那非协同减少 TGFβ 诱导的人肌成纤维细胞分化，这是 IPF 患者重塑的关键驱动因素。这些数据强调了利钠肽在肺纤维化和肺PH中的内源性宿主防御能力。依卡曲利和西地那非的组合逆转了该疾病特征的肺血流动力学畸变和重塑，提倡对 IPF 患者的利尿钠肽生物活性进行治疗操作。
Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder. Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1 mg·kg−1). Human myofibroblast differentiation was studied in vitro. Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients. These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
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影响因子：
7.3
作者：
Alexander SP;Benson HE;Faccenda E;Pawson AJ;Sharman JL;Spedding M;Peters JA;Harmar AJ;CGTP Collaborators
通讯作者：
CGTP Collaborators
影响因子：
6
作者：
HULKS, G;JARDINE, AG;THOMSON, NC
通讯作者：
THOMSON, NC
影响因子：
9.6
作者：
Lettieri, CJ;Nathan, SD;Shorr, AF
通讯作者：
Shorr, AF
影响因子：
9.6
作者：
Klinger, JR;Thaker, S;Farber, HW
通讯作者：
Farber, HW
影响因子：
5
作者：
Behnes, Michael;Hoffmann, Ursula;Brueckmann, Martina
通讯作者：
Brueckmann, Martina