Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator
Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator
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DOI：
10.1172/jci118691
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发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Loskutoff, DJ
中科院分区：
文献类型：
--
作者：
Yamamoto, K;Loskutoff, DJ
这份报告的主要假设是，在病理过程中特定组织中纤维蛋白的形成和随后的去除反映了关键的促凝和纤溶基因局部表达的时间变化。为了开始验证这一假设，我们使用定量PCR分析和原位杂交分析来检测内毒素对小鼠组织中特定基因表达的影响，并使用免疫组织化学方法将这些变化与纤维蛋白沉积/溶解联系起来，在所研究的大多数组织中，内毒素导致纤溶酶原激活物抑制物-1 mRNA的大量增加和组织因子mRNA的适度增加。然而，纤维蛋白只在内毒素处理的小鼠的肾脏和肾上腺中检测到，而且是短暂的。出乎意料的是，尿激酶型纤溶酶原激活物mRNA的变化，而不是组织型纤溶酶原激活物mRNA的变化，与这些组织中纤维蛋白的沉积/溶解有关。在内毒素之前，用纤溶抑制剂epsilon-氨基己酸对小鼠进行预处理，可以增加纤维蛋白阳性组织的数量，并延长纤维蛋白在肾脏和肾上腺中沉积的时间。这些结果表明，某些组织中纤维蛋白的缺乏反映了正在进行的局部纤溶反应，纤溶酶原激活物抑制物-1和组织因子基因表达的增加以及尿激酶型纤溶酶原激活物的表达减少是组织特异性纤维蛋白沉积所必需的。在这种脓毒症小鼠模型中，组织型纤溶酶原激活物基因表达的变化似乎不是纤维蛋白沉积/溶解的关键。
The primary hypothesis of this report is that the formation and subsequent removal of fibrin in specific tissues during pathologic processes reflects temporal changes in the local expression of key procoagulant and fibrinolytic genes. To begin to test this hypothesis, we have used quantitative PCR assays and in situ hybridization analysis to examine the effects of endotoxin on the expression of specific genes in murine tissues, and to relate these changes to fibrin deposition/dissolution using immunohistochemical approaches, Endotoxin caused large increases in plasminogen activator inhibitor-1 mRNA and modest increases in tissue factor mRNA in most tissues examined. However, fibrin was only detected in the kidneys and adrenals of endotoxin-treated mice, and it was transient. Unexpectedly, changes in urokinase-type plasminogen activator mRNA but not tissue-type plasminogen activator mRNA correlated with fibrin deposition/dissolution in these tissues. Pretreatment of mice with the fibrinolytic inhibitor epsilon-aminocaproic acid before endotoxin increased both the number of fibrin-positive tissues and the duration of fibrin deposition in the kidneys and adrenals. These results suggest that the absence of fibrin in some tissues reflects ongoing local fibrinolysis, and that increases in plasminogen activator inhibitor-1 and tissue factor gene expression and decreases in urokinase-type plasminogen activator expression are necessary for tissue-specific fibrin deposition. Changes in tissue-type plasminogen activator gene expression do not appear to be essential for fibrin deposition/dissolution in this murine model of sepsis.