吡格列酮、PPARγ激动剂和合成表面活性剂B-YL联合应用可预防高氧诱导的成年小鼠肺外植体肺损伤

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Chie Kurihara , Reiko Sakurai , Tsai-Der Chuang , Alan J. Waring , Frans J. Walther , Virender K. Rehan
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引用次数: 0

摘要

引言低氧诱导的肺损伤以急性肺泡损伤、上皮-间充质信号传导中断、氧化应激和表面活性剂功能障碍为特征,但目前尚无有效的治疗方法。尽管雾化吡格列酮(PGZ)和合成肺表面活性剂(B-YL肽,表面活性剂蛋白B模拟物)的组合可以预防高氧诱导的新生大鼠肺损伤,但它是否也能有效预防高氧诱发的成人肺损伤尚不清楚。方法采用成年小鼠肺外植体,研究高氧暴露24和72小时对1)肺损伤关键介质Wingles/Int(Wnt)和转化生长因子(TGF)-β信号通路的干扰,以及3)这些高氧诱导的像差是否可以通过PGZ和B-YL组合的联合治疗来阻断。结果我们的研究表明,暴露于成年小鼠肺外植体的高氧会导致Wnt(关键Wnt信号中间体β-catenin和LEF-1的上调)和TGF-β(关键TGF-β信号中间体TGF-βI型受体(ALK5)和SMAD3的上调)信号通路的激活,并伴随着肌生成蛋白(钙蛋白和纤连蛋白)和炎症细胞因子(IL-6、IL-1β和TNFα),以及关键内皮细胞(VEGF-A及其受体FLT-1和PECAM-1)标志物的改变。PGZ+B-YL组合在很大程度上缓解了所有这些变化。结论PGZ+B-YL联合应用能有效阻断高氧诱导的成年小鼠离体肺损伤,有望成为一种有效的体内治疗成年肺损伤的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Combination of pioglitazone, a PPARγ agonist, and synthetic surfactant B-YL prevents hyperoxia-induced lung injury in adult mice lung explants

Introduction

Hyperoxia-induced lung injury is characterized by acute alveolar injury, disrupted epithelial-mesenchymal signaling, oxidative stress, and surfactant dysfunction, yet currently, there is no effective treatment. Although a combination of aerosolized pioglitazone (PGZ) and a synthetic lung surfactant (B-YL peptide, a surfactant protein B mimic) prevents hyperoxia-induced neonatal rat lung injury, whether it is also effective in preventing hyperoxia-induced adult lung injury is unknown.

Method

Using adult mice lung explants, we characterize the effects of 24 and 72-h (h) exposure to hyperoxia on 1) perturbations in Wingless/Int (Wnt) and Transforming Growth Factor (TGF)-β signaling pathways, which are critical mediators of lung injury, 2) aberrations of lung homeostasis and injury repair pathways, and 3) whether these hyperoxia-induced aberrations can be blocked by concomitant treatment with PGZ and B-YL combination.

Results

Our study reveals that hyperoxia exposure to adult mouse lung explants causes activation of Wnt (upregulation of key Wnt signaling intermediates β-catenin and LEF-1) and TGF-β (upregulation of key TGF-β signaling intermediates TGF-β type I receptor (ALK5) and SMAD 3) signaling pathways accompanied by an upregulation of myogenic proteins (calponin and fibronectin) and inflammatory cytokines (IL-6, IL-1β, and TNFα), and alterations in key endothelial (VEGF-A and its receptor FLT-1, and PECAM-1) markers. All of these changes were largely mitigated by the PGZ + B-YL combination.

Conclusion

The effectiveness of the PGZ + B-YL combination in blocking hyperoxia-induced adult mice lung injury ex-vivo is promising to be an effective therapeutic approach for adult lung injury in vivo.

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来源期刊
CiteScore
6.20
自引率
0.00%
发文量
41
审稿时长
42 days
期刊介绍: Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.
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