A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells.
A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells.
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DOI：
10.1089/104303403322542275
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发表时间：
2003-11
影响因子：
4.2
通讯作者：
G. Schiedner;W. Bloch;S. Hertel;M. Johnston;A. Molojavyi;V. Dries;G. Varga;N. Van Rooijen;S. Kochanek
中科院分区：
文献类型：
--
作者：
G. Schiedner;W. Bloch;S. Hertel;M. Johnston;A. Molojavyi;V. Dries;G. Varga;N. Van Rooijen;S. Kochanek
腺病毒载体的血管内注射可能导致毒性和潜在的致命反应，其机制知之甚少。我们注意到，小鼠在静脉注射相对低剂量的腺病毒载体（包括高容量无肠载体）后几分钟内表现出短暂的行为变化，其特征是不活动和嗜睡。此外，在载体注射后立即测量到血压的显著下降，这最可能是由内皮细胞的全身活化引起的，如通过检测磷酸化Akt/PKB激酶、活化的内皮一氧化氮合酶（eNOS）和硝基酪氨酸所监测的。内皮的激活是病毒颗粒与枯否细胞相互作用的结果，枯否细胞是肝脏的常驻巨噬细胞，代表先天免疫系统的第一道防线。令人惊讶的是，库普弗细胞对载体颗粒的摄取不仅导致它们的强烈活化，而且还导致它们几乎完全从肝脏中消失。我们的研究结果表明，静脉注射腺病毒载体的毒性可能直接与库普弗细胞的激活和破坏。
Intravascular injection of adenoviral vectors may result in a toxic and potentially lethal reaction, the mechanism of which is poorly understood. We noted that mice demonstrated a transient change in behavior that was characterized by inactivity and lethargy within minutes after intravenous injection of relatively low doses of adenoviral vectors (including high-capacity gutless vectors). Moreover, immediately after vector injection a significant drop in blood pressure was measured that most probably was caused by the systemic activation of endothelial cells as monitored by detection of phosphorylated Akt/PKB kinase, activated endothelial nitric oxide synthase (eNOS), and nitrotyrosine. The activation of the endothelium was the result of the interaction of viral particles with Kupffer cells, which are resident macrophages of the liver representing the first line of defense of the innate immune system. Surprisingly, the uptake of vector particles by Kupffer cells not only resulted in their strong activation, but also in their nearly complete disappearance from the liver. Our results suggest that the toxicity of intravenously injected adenoviral vectors may be directly linked to the activation and destruction of Kupffer cells.