title: Regulation of type I plasminogen activator inhibitor by fibrin degradation products in rat lung fibroblasts.
abstract: Persistent fibrin deposition in tissues characterizes the early pathology of many types of injury. In an animal model of bleomycin-induced lung fibrosis, increased expression of type 1 plasminogen activator inhibitor (PAI-1) is associated with accumulation of fibrin in fibroproliferative lesions. Plasmin proteolysis of cross-linked fibrin generates fibrin degradation products (FDPs) with multiple biological activities in several cell types. We reasoned that fibrin fragments may also regulate fibroblast-mediated fibrinolysis. In this study, we describe induction of PAI-1 mRNA, protein, and activity by soluble FDPs and fibrinogen in rat lung fibroblast monolayers. FDPs are more potent than fibrinogen, inducing a concentration-dependent, maximal 3.7 (+/- 0.9)-fold increase in PAI-1 mRNA as measured by northern blotting and a 9.0 (+/- 1.3)-fold induction of PAI-1 antigen levels. Active PAI-1 is demonstrated in fibrinogen- and FDP-stimulated conditioned media. Further characterization of this response shows that PAI-1 expression is induced by the DD/D fragments, but not by immunopurified fragment E. Experiments using Actinomycin D and puromycin indicate that the induction appears to be transcriptionally regulated and is not dependent on new protein synthesis. FDP induction of PAI-1 suggests a matrix-cell feedback process in which a fibrin fragment modulates expression of an important regulator of fibrinolysis.
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham 35294, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Hagood
authors.forename: M A
authors.initials: MA
authors.lastname: Olman
authors.forename: J A
authors.initials: JA
authors.lastname: Godoy
authors.forename: K E
authors.initials: KE
authors.lastname: Rivera
authors.forename: G M
authors.initials: GM
authors.lastname: Fuller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger