Summary
Hepatic fibrinogen (FBG) is upregulated during an acute phase response (APR) induced
by glucocorticoids and interleukin (IL)-6. Furthermore, intestine and lung epithelium
synthesize FBG after exposure to inflammatory mediators, and both plasma and lung
cell-derived FBG, along with fibronectin, assemble in detergent-insoluble extracellular
matrices (ECM) of pneumocytes and fibroblasts independent of thrombin or plasmin cleavage.
An epitope cryptic in soluble FBG (β15-21) but exposed in matrix-FBG and fibrin induces cell proliferation and actin cytoskeleton
reorganization during wound repair and angiogenesis. Although fibrin(ogen) is involved
in hemostasis and homeostasis, mechanisms regulating extrahepatic FBG expression remain
unexplored. Herein we examined FBG production by lung compared to liver epithelial
cell lines in response to dexamethasone (DEX)+IL-6. Regulated synthesis of HepG2-FBG
follows the pathway shown for constitutive synthesis by liver epithelium. Constitutive
A549-FBG expression was not detectable, however, intracellular FBG precursors in DEX+IL-6-treated
A549 lung cells were similar to HepG2 cells with two notable exceptions. The relative
rate of chain synthesis in HepG2 cells was unequal, whereas nascent synthesis of all
three chains occurred at equivalent rates in stimulated A549 cells. Unlike HepG2 cells,
which rapidly secreted intact FBG, nascent dimeric FBG accumulated in the A549 cell-associated
fraction prior to release into medium. Furthermore, soluble A549-FBG was susceptible
to thrombin and plasmin cleavage. Interestingly, many functionally diverse proteins
possess FBG-related domains that direct cell-fate determination during development
or wound repair, suggesting that extrahepatic FBG biosynthesis evoked only during
inflammation plays such a role during localized injury and repair to restore tissue
homeostasis.
Keywords
Extrahepatic fibrinogen - wound repair - lung epithelium - thrombin - extracellular
matrix