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首页> 外文期刊>Journal of endotoxin research >Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression.
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Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression.

机译:重组腺病毒对内毒素中毒肝损伤的影响及其对IL-10表达的调节作用。

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Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNF-alpha-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-alpha-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (10(5) particles) protects, while high-dose adenovirus (10(10) particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF-alpha dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNF-alpha appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-alpha responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.
机译:基于腺病毒的基因治疗提供了独特的机会,可以通过全身性递送将基因表达靶向肝脏。然而,第一代腺病毒构建体的全身给药引起炎症反应,导致TNF-α依赖性肝损伤。这项研究的目的是评估全身施用重组腺病毒是否会加剧随后由D-半乳糖胺和脂多糖诱导的TNF-α依赖性肝损伤。出人意料的是,低剂量腺病毒给药(10(5)颗粒)可提供保护,而高剂量腺病毒(10(10)颗粒)与随后的D-半乳糖胺和脂多糖攻击引起的肝炎反应过度有关。这种恶化是TNF-α依赖性的,因为用TNF抑制剂治疗可以完全预防肝损伤。而且,静脉内施用表达抗炎蛋白白细胞介素10的腺病毒构建体可减少TNF-α的出现并减轻增加的肝细胞损伤。两者合计,该报告证明了由腺病毒和其他炎症信号诱导的TNF-α反应的潜在加性效应,并表明该反应可通过相对腺病毒颗粒剂量或抑制剂(例如TNF结合蛋白或白介素10)减轻。

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