REGULATION OF TYPE-I PLASMINOGEN-ACTIVATOR INHIBITOR BY FIBRIN DEGRADATION PRODUCTS IN RAT LUNG FIBROBLASTS

Persistent fibrin deposition in tissues characterizes the early pathol ogy of many types of injury. In an animal model of bleomycin-induced l ung fibrosis, increased expression of type 1 plasminogen activator inh ibitor (PAI-1) is associated with accumulation of fibrin in fibroproli ferative lesions. Plasmin proteolysis of cross-linked fibrin generates fibrin degradation products (FDPs) with multiple biological activitie s in several cell types. We reasoned that fibrin fragments may also re gulate fibroblast-mediated fibrinolysis. In this study, we describe in duction of PAI-1 mRNA, protein, and activity by soluble FDPs and fibri nogen in rat lung fibroblast monolayers. FDPs are more potent than fib rinogen, 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 demonstr ated in fibrinogen- and FDP-stimulated conditioned media, Further char acterization of this response shows that PAI-1 expression is induced b y the DD/D fragments, but not by immunopurified fragment E. Experiment s using Actinomycin D and puromycin indicate that the induction appear s to be transcriptionally regulated and is not dependent on new protei n synthesis. FDP induction of PAI-1 suggests a matrix-cell feedback pr ocess in which a fibrin fragment modulates expression of an important regulator of fibrinolysis. (C) 1996 by The American Society of Hematol ogy.