阳离子纳米载体诱导细胞坏死和引起体内炎性反应的机理研究
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- 英文论文题名：Cationic Nanocarriers Induce Cell Necrosis and Mitochondrial Damage-Associated Molecular Patterns in the Regulation of Inflammatory Response
- 论文作者：魏霞蔚
- 英文论文作者：Xiawei Wei ; State Key Laboratory of Biotherapy ; Sichuan University
- 年：2016
- 作者机构：四川大学华西医院生物治疗国家重点实验室;
- 论文关键词：阳离子纳米载体 ; 细胞坏死 ; 炎性毒性 ; 损伤相关分子模式 ; 线粒体DNA
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第三十八分会：纳米生物效应与纳米药物化学
- 语种：中文
- 分类号：R450
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第三十八分会 ; 纳米生物效应与纳米药物化学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：193k
- 原文格式：D
- 会议级别：全国
摘要
阳离子纳米载体在基因治疗中作为非病毒载体具有许多应用。近年来,也有多例基于阳离子脂质体复合物的治疗基因药物进入了临床试验,然而,阳离子脂质的炎性毒性反应仍是阻碍其更广泛应用的重要原因。但是,阳离子载体在体内引起炎性毒性的分子机理尚不清楚。本研究针对该问题,提出了两个重要发现。一方面,研究发现阳离子纳米载体能直接诱导细胞坏死,其机理是通过与细胞膜上的钠钾ATP酶(Na/K-ATPase)相互作用,并且鉴定出阳离子纳米载体是与Na/K-ATPase上特定亚基的阳离子结合位点相结合,降低其活性,细胞内离子浓度失衡,从而诱导细胞坏死。另一方面,这种阳离子纳米载体引起的坏死细胞能释放线粒体相关物质,如甲酰肽和线粒体DNA(mtDNA),它们能通过刺激中性粒细胞上的TLR9受体,激活p38MAPK通路,从而激活中性粒细胞释放各种炎性因子,进一步诱导体内的炎性反应。以此阐明了阳离子纳米载体的细胞毒性及其引起体内炎性毒性的机理,为今后设计更安全、有效的纳米载体提供参考。
To understand the mechanisms for nanoparticle toxicity is important for human health and the design of optimized nanocarriers. Surface charge is one of the important characteristics of nanoparticles. Nanocarriers with positive surface charge are known for toxicity which confined their clinical applications, and the mechanisms for their toxicity, such as inducing inflammatory response, remain largely unknown. In the present study we found that cationic nanocarriers could induce acute cell necrosis through the specific inhibition of Na+/K+-ATPase. The subsequent release of mtD NA could further trigger inflammation response in animal model, which is mediated by a pathway involving TLR9 and MyD 88 signaling. Our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na+/K+-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. These findings have important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.
To understand the mechanisms for nanoparticle toxicity is important for human health and the design of optimized nanocarriers. Surface charge is one of the important characteristics of nanoparticles. Nanocarriers with positive surface charge are known for toxicity which confined their clinical applications, and the mechanisms for their toxicity, such as inducing inflammatory response, remain largely unknown. In the present study we found that cationic nanocarriers could induce acute cell necrosis through the specific inhibition of Na+/K+-ATPase. The subsequent release of mtD NA could further trigger inflammation response in animal model, which is mediated by a pathway involving TLR9 and MyD 88 signaling. Our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na+/K+-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. These findings have important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.
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