Immune Activation and Target Organ Damage Are Consequences of Hydrodynamic Treatment but Not Delivery of Naked siRNAs in Mice
Immune Activation and Target Organ Damage Are Consequences of Hydrodynamic Treatment but Not Delivery of Naked siRNAs in Mice
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DOI：
10.1089/nat.2010.0248
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发表时间：
2011-06-01
影响因子：
4
通讯作者：
Hamar, Peter
中科院分区：
文献类型：
--
作者：
Racz, Zsuzsanna;Godo, Maria;Hamar, Peter
短链干扰RNA(SiRNAs)是RNA干扰的关键媒介，是一种很有前途的治疗工具，但干扰素(IFN)反应等副作用仍不完全清楚。此外，向目标器官递送是一个重大挑战，可能与免疫激活或器官损伤等副作用有关。我们研究了双链RNA诱导的干扰素反应(Jak/STAT通路激活或细胞因子产生)或靶器官损伤所导致的免疫激活是否由体内低容量(LV)或高容量(HV)流体输送或裸露siRNA处理所诱导。NMRI小鼠注射裸siRNA或生理盐水(HDI)，阳性对照小鼠注射多聚肌苷多胞苷(PolyI：C)。比较LV(1ml/只)和HV(10%体重)HDI。观察LV HDI后STAT1、OAS1基因表达、炎性细胞因子血浆水平及靶器官损伤情况。LV HDI可引起丙氨酸氨基转移酶轻度升高和轻度肝细胞损伤，而HV HDI可导致ALAT升高和肝细胞广泛坏死。LV siRNA不能诱导STAT1或OAS1基因的表达，但HV生理盐水诱导的基因表达呈时间依赖性的轻微增加。无论是否使用siRNA，LV HDI后炎性细胞因子、血浆水平、器官组织学和功能参数均未见损害。我们的数据表明，裸露的siRNAs可以在不诱导干扰素反应或免疫激活的情况下被利用，而且LV HDI更可取，因为HV HDI可能会导致器官损伤。
Short-interfering RNAs (siRNAs), key mediators of RNA interference comprise a promising therapeutic tool, although side effects such as interferon (IFN) response are still not perfectly understood. Further, delivery to target organs is a major challenge, possibly associated with side effects including immune activation or organ damage. We investigated whether immune activation as a consequence of double-stranded RNA induced IFN response (Jak/STAT pathway activation or cytokine production) or target organ damage is induced by in vivo low-volume (LV) or high-volume (HV) hydrodynamic delivery or treatment with naked siRNA. NMRI mice were injected with naked siRNAs or saline by hydrodynamic injection (HDI) and positive control mice received polyinosinic-polycytidilic acid (poly I: C). LV (1mL/mouse) and HV (10% of body weight) HDI were compared. After LV HDI, STAT1 and OAS1 gene expression inflammatory cytokine plasma levels and target organ injury were assessed. LV HDI induced slight alanine aminotransferase elevation and mild hepatocyte injury, whereas HV HDI resulted in high ALAT level and extensive hepatocyte necrosis. STAT1 or OAS1 was not induced by LV siRNA; however, HV saline led to a time-dependent slight increase in gene expression. Inflammatory cytokine plasma level and organ histology and functional parameters demonstrated no damage following LV HDI with or without siRNA. Our data demonstrate that naked siRNAs may be harnessed, without the induction of IFN response or immune activation, and that LV HDI is preferable, because HV HDI may cause organ damage.