Haidaris P J
Department of Medicine/Hematology Unit, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Blood. 1997 Feb 1;89(3):873-82.
Although the liver is the primary site of fibrinogen (FBG) synthesis, epithelial cells from diverse tissues have been shown to express one or more of the FBG A alpha, B beta, and gamma chain genes. In contrast, marrow megakaryocytes, which store FBG in the alpha-granules, are thought not to express the FBG genes. Our earlier studies have shown that epithelial cells in a variety of extrahepatic tissues express the gamma chain gene ubiquitously, while the mRNAs for the A alpha and B beta chain genes are essentially undetectable. During systemic inflammation, the liver secretes increased levels of FBG into the circulation, and lung epithelium responds to local inflammation during pulmonary infection by increased transcription of the gamma-FBG gene. Therefore, to determine whether extrahepatic epithelial cells express the A alpha, B beta, and gamma chain genes in response to proinflammatory mediators, cultured lung epithelial cells were treated with interleukin-6 (IL-6) and dexamethasone (DEX). Northern blot analysis demonstrated that the levels of gamma-FBG mRNA in cultured lung (A549) and liver (HepG2) epithelial cells increased 2- to 10-fold in response to treatment. Reverse-transcriptase-polymerase chain reaction amplification demonstrated increased accumulation of steady state levels of FBG A alpha, B beta, and gamma chain mRNAs in lung epithelial cells after treatment. The basal level of lung cell gamma-FBG gene transcription was not accompanied by appreciable levels of A alpha and B beta chain gene transcription; however, nuclear run-on analysis suggested that the increase in lung cell FBG mRNAs in response to DEX +/- IL-6 was due to new transcription. Furthermore, stimulation of lung epithelial cells with IL-6 + DEX resulted in maximal secretion of intact FBG (340 kD) composed of the characteristic A alpha, B beta, and gamma chain polypeptides. The data suggest that basal expression of the gamma-FBG gene in extrahepatic tissue occurs ubiquitously in the absence of detectable levels of A alpha- and B beta-FBG gene expression, which are then upregulated on induction of an inflammatory response. This would result in local synthesis and secretion of FBG in the injured tissue, supporting the hypothesis that production of FBG by extrahepatic epithelial cells in response to inflammation plays a role in wound repair.
虽然肝脏是纤维蛋白原（FBG）合成的主要部位，但已表明来自不同组织的上皮细胞可表达FBG的Aα、Bβ和γ链基因中的一种或多种。相比之下，在α颗粒中储存FBG的骨髓巨核细胞被认为不表达FBG基因。我们早期的研究表明，各种肝外组织中的上皮细胞普遍表达γ链基因，而Aα和Bβ链基因的mRNA基本检测不到。在全身炎症期间，肝脏会向循环系统中分泌更多的FBG，并且肺上皮细胞在肺部感染期间通过增加γ-FBG基因的转录来应对局部炎症。因此，为了确定肝外上皮细胞是否会响应促炎介质而表达Aα、Bβ和γ链基因，我们用白细胞介素-6（IL-6）和地塞米松（DEX）处理培养的肺上皮细胞。Northern印迹分析表明，培养的肺（A549）和肝（HepG2）上皮细胞中的γ-FBG mRNA水平在处理后增加了2至10倍。逆转录聚合酶链反应扩增表明，处理后肺上皮细胞中FBG Aα、Bβ和γ链mRNA的稳态水平积累增加。肺细胞γ-FBG基因的基础转录水平并未伴随着Aα和Bβ链基因的明显转录水平；然而，细胞核转录分析表明，肺细胞FBG mRNA对DEX +/- IL-6的反应增加是由于新的转录。此外，用IL-6 + DEX刺激肺上皮细胞会导致由特征性Aα、Bβ和γ链多肽组成的完整FBG（340 kD）的最大分泌。数据表明，在没有可检测到的Aα-和Bβ-FBG基因表达水平的情况下，肝外组织中γ-FBG基因的基础表达普遍存在，然后在炎症反应诱导时上调。这将导致受损组织中FBG的局部合成和分泌，支持了肝外上皮细胞响应炎症产生FBG在伤口修复中起作用的假设。
