摘要
急性肺损伤(ALI)及其最严重的表现为急性呼吸窘迫综合征(ARDS),是一种临床综合征,定义为急性低氧性呼吸衰竭和肺部水肿。AL住院死亡率为38.5%,ARDS 为41.1%。供肺者的肺泡巨噬细胞激活会导致促炎性趋化因子和细胞因子如TNF-α的释放。测定TNF-α的相关性α破坏支气管内皮细胞功能,用脂多糖(LPS)刺激人THP-1巨噬细胞和使用所产生的细胞因子补充媒介来扰乱正常的内皮细胞功能。在LPS激活THP-1条件培养液的情况下,内皮管道形成过程被打乱,依那西普为0.1µg/ml时发生逆转效果,表明TNF-α是抑制内皮管道形成的主要血清成分。为加强肺癌的调理,我们测试了脂质体和多孔硅(pSi)给药系统,并使用RNA干扰TNFR1选择性地沉默。在测试的三类脂质体中,仅阳离子脂质体具有相当大的内皮细胞摄取能力,与猪细胞作为对照, 人类细胞摄取的脂质体是猪细胞的10倍以上,但是,非特异性细胞激活,阻止其作为免疫抑制剂发挥作用。另一方面,与用积累®LTX的标准转染相比,在无内皮细胞非特异性激活的情况下,PSI微粒可使大量的内皮细胞中siRNA累积。αTNFR1沉默可降低TNF-α介导的内皮管形成的抑制作用,以及TNF-α诱导的人肺微血管内皮细胞中肿瘤坏死因子-αICAM-1,VCAM, E-选择等。
关键词: 内皮细胞,脂质体,肺,多孔硅,siRNA,肿瘤坏死因子受体1
图形摘要
Current Drug Targets
Title:Silencing of Tumor Necrosis Factor Receptor-1 in Human Lung Microvascular Endothelial Cells Using Particle Platforms for siRNA Delivery
Volume: 16 Issue: 13
Author(s): Litao Bai, Helen A. Andersson, Kellie I. McConnell, Diana L. Chan, Michael Hernandez, Javier Gonzalez, Xuewu Liu and , Saverio La Francesca, Jason H. Sakamoto and Rita E. Serda
Affiliation:
关键词: 内皮细胞,脂质体,肺,多孔硅,siRNA,肿瘤坏死因子受体1
摘要: Acute lung injury (ALI) and its most severe manifestation, acute respiratory distress syndrome (ARDS), is a clinical syndrome defined by acute hypoxemic respiratory failure and bilateral pulmonary infiltrates consistent with edema. In-hospital mortality is 38.5% for AL, and 41.1% for ARDS. Activation of alveolar macrophages in the donor lung causes the release of pro-inflammatory chemokines and cytokines, such as TNF-α. To determine the relevance of TNF-α in disrupting bronchial endothelial cell function, we stimulated human THP-1 macrophages with lipopolysaccharide (LPS) and used the resulting cytokine-supplemented media to disrupt normal endothelial cell functions. Endothelial tube formation was disrupted in the presence of LPS-activated THP- 1 conditioned media, with reversal of the effect occurring in the presence of 0.1µg/ml Enbrel, indicating that TNF-α was the major serum component inhibiting endothelial tube formation. To facilitate lung conditioning, we tested liposomal and porous silicon (pSi) delivery systems for their ability to selectively silence TNFR1 using siRNA technology. Of the three types of liposomes tested, only cationic liposomes had substantial endothelial uptake, with human cells taking up 10-fold more liposomes than their pig counterparts; however, non-specific cellular activation prohibited their use as immunosuppressive agents. On the other hand, pSi microparticles enabled the accumulation of large amounts of siRNA in endothelial cells compared to standard transfection with Lipofectamine® LTX, in the absence of non-specific activation of endothelia. Silencing of TNFR1 decreased TNF-α mediated inhibition of endothelial tube formation, as well as TNF-α-induced upregulation of ICAM-1, VCAM, and E-selection in human lung microvascular endothelial cells.
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Cite this article as:
Litao Bai, Helen A. Andersson, Kellie I. McConnell, Diana L. Chan, Michael Hernandez, Javier Gonzalez, Xuewu Liu and , Saverio La Francesca, Jason H. Sakamoto and Rita E. Serda , Silencing of Tumor Necrosis Factor Receptor-1 in Human Lung Microvascular Endothelial Cells Using Particle Platforms for siRNA Delivery, Current Drug Targets 2015; 16 (13) . https://dx.doi.org/10.2174/1389450115666140828105507
DOI https://dx.doi.org/10.2174/1389450115666140828105507 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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