Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020 USA.
Drug Deliv Transl Res. 2011 Feb;1(1):13-24. doi: 10.1007/s13346-010-0003-1. Epub 2010 Dec 14.
Many pathological conditions and environmental impacts lead to the development of severe tissue hypoxia that aggravates the primary disorder, provokes cell death, and limits the patient's recovery. We hypothesized that suppression of Jun N-terminal kinase 1 (JNK1) will limit tissue damage induced by severe hypoxia. To test the hypothesis, antisense oligonucleotides (ASO) or small interfering RNA (siRNA) targeted to JNK1 mRNA were incorporated or complexed with neutral or cationic liposomes, respectively, and administered systemically to mice prior to hypoxia exposure. The animals were placed in a special chamber ventilated with room air (normoxia) or a gas mixture containing 6% O(2) and 94% N(2) (hypoxia). Liposomes, ASO, and siRNA were found to accumulate in the lungs, kidney, spleen, and heart. Only trace amounts of liposomes and their payloads (ASO and siRNA) were found in the brain. The down regulation of JNK1 protein limited activation of cell death signal, apoptotic, and necrotic tissue damage under hypoxic conditions. Consequently, we were able to verify our hypothesis and provide proof of concept of a unique approach to the prevention of cellular hypoxic damage by the suppression of JNK1 signaling pathways after the efficient delivery of ASO or siRNA.
许多病理状况和环境影响导致严重组织缺氧的发展，这会加重原发性疾病、引发细胞死亡，并限制患者的康复。我们假设抑制 Jun N-末端激酶 1（JNK1）将限制严重缺氧引起的组织损伤。为了验证这一假设，针对 JNK1 mRNA 的反义寡核苷酸（ASO）或小干扰 RNA（siRNA）分别与中性或阳离子脂质体结合或复合，并在缺氧暴露前系统地给予小鼠。将动物置于特殊的室中，用空气（常氧）或含有 6%O2 和 94%N2 的气体混合物（缺氧）通风。发现脂质体、ASO 和 siRNA 在肺部、肾脏、脾脏和心脏中积累。只有痕量的脂质体及其有效载荷（ASO 和 siRNA）存在于大脑中。在缺氧条件下，JNK1 蛋白的下调限制了细胞死亡信号、凋亡和坏死组织损伤的激活。因此，我们能够验证我们的假设，并通过在有效递送 ASO 或 siRNA 后抑制 JNK1 信号通路，为预防细胞缺氧损伤提供一种独特方法的概念验证。
