Down-regulation of murine tissue factor pathway inhibitor mRNA by endotoxin and tumor neerosis factor-alpha In vitro and In vivo.

组织因子途径抑制剂（Tissue factor pathway inhibitor， TFPI）是一种蛋白酶抑制剂，可调节由VIIa/TF因子复合物引发的外源性凝血途径。在本研究中，我们首先研究了TFPI mRNA在小鼠中的组织分布，发现TFPI mRNA在肺组织中的表达水平最高，其次是心脏、肾上腺和脂肪组织。由于对TFPI基因在体内的表达调控知之甚少，我们进一步分析了腹腔注射脂多糖（LPS）、肿瘤坏死因子- α (tnf - α)和白细胞介素-1 （IL-1）后小鼠组织中TFPI mRNA水平的变化。LPS和tnf - α显著降低了四种组织（如肺、心脏、肾脏和脂肪组织，其中观察到纤维蛋白沉积）中TFPI mRNA的表达，而IL-1对TFPI mRNA的抑制作用有限。LPS和tnf - α对培养的小鼠内皮细胞和心肌细胞系中TFPI mRNA的表达也有下调作用。LPS和tnf - α在组织和特定细胞类型中的TFPI基因表达的降低可能导致局部促凝潜能的增加，从而导致脓毒症和/或炎症条件下的血栓形成倾向。

Tissue factor pathway inhibitor (TFPI) is the protease inhibitor that regulates the extrinsic coagulation pathway initiated by the factor VIIa/TF complex. In this study, we first investigated tissue distribution of TFPI mRNA in the mouse and found that TFPI mRNA expression level was by far the highest in the lung, followed by the heart, adrenal, and adipose tissue. Since little has been known concerning the regulation of TFPI gene expression in vivo, we further analyzed the changes in the TFPI mRNA level in murine tissues after intraperitoneal injection of lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 (IL-1). LPS and TNF-alpha dramatically decreased TFPI mRNA expression in four tissues examined (e.g., lung, heart, kidney, and adipose tissue, in which fibrin deposition were observed), whereas the suppressive effect of IL-1 on TFPI mRNA was limited. The down-regulation of TFPI mRNA expression by LPS and TNF-alpha was also observed in cultured mouse endothelial cells and in cardiomyocyte cell lines. The decreased TFPI gene expression by LPS and TNF-alpha in tissues and in the specific cell types may contribute to an increase in the local procoagulant potential, resulting in the thrombotic tendency under septic and/or inflammatory conditions.