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Induction of fibrinogen biosynthesis and secretion from cultured pulmonary
epithelial cells
PJ Haidaris
Department of Medicine/Hematology Unit, University of Rochester School of
Medicine and Dentistry, NY 14642, USA.
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.
Volume 89,
Issue 3,
pp. 873-882,
02/01/1997
Copyright © 1997 by The American Society of Hematology
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