Effects of explosive brain death on cytokine activation of peripheral organs in the rat
Effects of explosive brain death on cytokine activation of peripheral organs in the rat
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DOI：
10.1097/00007890-199806270-00001
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发表时间：
1998-06-27
期刊：
影响因子：
6.2
通讯作者：
Tilney, NL
中科院分区：
文献类型：
--
作者：
Takada, M;Nadeau, KC;Tilney, NL
背景从脑死亡的尸体捐赠者移植器官的成功率一直低于活体来源。由于尸体和活着的无关捐赠者与给定的受体在遗传上是完全不同的，所以差异一定在于捐赠者本身和/或器官保存和储存的影响。我们假设不可逆的中枢神经系统损伤可能上调要移植的外周器官中的促炎介质和细胞表面分子，使它们更容易发生宿主炎症和免疫应答。大鼠手术诱导急性颅内压增高（爆炸性脑死亡），随后6小时，他们的外周组织进行了检查，通过逆转录聚合酶链反应和免疫组织化学，血清因子进行了评估，并通过与正常动物的交叉循环实验，确定炎症分子在血流中的影响。血清中的类似因子同时增加;通过与正常动物的交叉循环显示这些因子在体内具有活性。所有对照组（包括严重缺血性损伤和出血性休克动物）的器官均为阴性。MHC I类和II类抗原以及共刺激分子B7的上调表明外周器官的免疫原性增加。这些变化可被抑制：（i）给予重组可溶性P-选择素糖蛋白配体-Ig，一种P-和E-选择素拮抗剂;和（ii）融合蛋白，细胞毒性T淋巴细胞抗原4-IG，其阻断B7介导的T细胞共刺激。结论，爆炸性脑死亡后外周器官的激活可能由各种相关事件引起，包括大面积急性中枢损伤的影响，低血压和循环因素。生物制剂几乎可以完全抑制这些变化。这种干预措施如果在人类身上重现，可以提高“边缘”捐赠者的器官质量，扩大捐赠者接受的标准。
Background. The success rate of transplanted organs from brain-dead cadaver donors is consistently inferior to that of living sources. As cadaver and living unrelated donors are equally genetically disparate with a given recipient, the difference must lie within the donor himself and/or the effects of organ preservation and storage. We have hypothesized that irreversible central nervous system injury may up-regulate proinflammatory mediators and cell surface molecules in peripheral organs to be engrafted, making them more prone to host inflammatory and immunological responses,Methods. Rats undergoing surgically :induced acutely increased intracranial pressure (explosive brain death) were followed for 6 hr, Their peripheral tissues were examined by reverse transcriptase polymerase chain reaction and immunohistology, serum factors were assessed by enzyme-linked immunosorbent assay, and the influence of inflammatory molecules in the blood stream was determined by cross-circulation experiments with normal animals.Results, mRNA expression of both lymphocyte- and macrophage-associated products increased dramatically in all tissues. Similar factors in serum were coincidentally increased; these were shown to be active in vivo by cross-circulation with normal animals, The organs of all control groups, including animals with important ischemic injury and with hemorrhagic shock, were negative. Up-regulation of MHC class I and II antigens and the co-stimulatory molecule B7 suggests increased immunogenicity of the peripheral organs. These changes could be inhibited by: (i) administration of a recombinant soluble P-selectin glycoprotein ligand-Ig, a P- and E-selectin antagonist; and (ii) a fusion protein, cytotoxic T lymphocyte antigen 4-Ig, which blocks B7-mediated T-cell co-stimulation,Conclusions, Activation of peripheral organs following explosive brain death may be caused by various interrelated events, including the effects of massive acute central injury, hypotension, and circulating factors. Almost complete suppression of these changes could be produced by biological agents. Such interventions, if reproducible in humans, could improve the quality off organs from "marginal" donors, broadening the criteria for donor acceptance.