The role of endogenous versus exogenous tPA on edema formation in murine ICH
The role of endogenous versus exogenous tPA on edema formation in murine ICH
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DOI：
10.1016/j.expneurol.2004.05.021
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Tsirka, SAE
中科院分区：
文献类型：
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作者：
Thiex, R;Mayfrank, L;Tsirka, SAE
为了最大限度地减少脑出血（ICH）后凝块衍生物质对周围脑组织的神经毒性损伤，微创神经外科手术方案已经发展为通过立体定位注射纤维蛋白溶解剂（如重组组织纤溶酶原激活剂（rtPA）），然后抽吸溶解的凝块来清除血肿。然而，外源性tPA本身的存在对血肿衍生因子的毒性作用的可能贡献使这种治疗方法的原理和有效性复杂化。为了阐明外源性rtPA对水肿发展的作用，我们检查了胶原酶诱导的ICH小鼠模型中水肿形成的程度，该模型包括tPA缺陷型（tPA（-/-））和野生型（wt）小鼠。在32只小鼠中的16只（7只tPA（-/-）和9只wt小鼠）中，在ICH诱导后5 h将1 mg/kg r-tPA注射到血肿中，然后在20 min后抽吸液化凝块。在对照组（8只tPA（-/-）和8只wt小鼠）中，仅注射胶原酶。在手术后24小时、3天和7天，使用SPOT软件在Luxol Fast Blue和甲酚紫染色的横截面上定量水肿体积。在ICH诱导后24小时，即使给予rtPA，tPA（-/-）小鼠的水肿体积也显著较小（P <0.01）。在ICH后第3天至第7天，外源性rtPA发挥其促水肿作用，与潜在的基因型无关，并在凝块附近表现出广泛的小胶质细胞活化。总之，内源性tPA的作用似乎仅限于水肿形成的早期阶段，而外源性rtPA是脑出血后3 - 7天之间的水肿促进。(C)2004年爱思唯尔公司All rights reserved.
To minimize the neurotoxic injury by clot-derived substances after intracerebral hemorrhage (ICH) on the surrounding brain tissue, minimally invasive neurosurgical protocols have evolved evacuating the hematoma by stereotaxic injection of a fibrinolytic agent such as recombinant tissue plasminogen activator (rtPA), followed by aspiration of the lysed clot. However, the possible contribution of the presence of exogenous tPA itself to the toxic effects of hematoma-derived factors complicates the rationale and efficacy of this therapeutic approach. To clarify the role of exogenous rtPA on edema development, we examined the extent of edema formation in a murine model of collagenase-induced ICH, which included tPA-deficient (tPA(-/-)) and wild-type (wt) mice. In 16 (7 tPA(-/-) and 9 wt mice) out of 32 mice, 1 mg/kg r-tPA was injected into the hematoma 5 h after ICH induction followed by aspiration of the liquefied clot 20 min later. In the control group (8 tPA(-/-) and 8 wt mice), only collagenase was injected. The edema volume was quantified using SPOT software on Luxol Fast Blue and Cresyl violet-stained cross-sections 24 h, 3, and 7 days post surgery. Twenty-four hours after ICH induction, tPA(-/-) mice had a significantly smaller edema volume (P < 0.0 1), even when rtPA was administered. Between days 3 and 7 after ICH, exogenous rtPA exerts its edema-promoting effect irrespective of the underlying genotype and exhibits an extensive microglial activation adjacent to the clot. In conclusion, the role of the endogenous tPA appears to be limited to the early phase of edema formation, whereas exogenous rtPA is edema-promoting between days 3 and 7 after ICH. (C) 2004 Elsevier Inc. All rights reserved.