EFFECTS OF TGF-BETA AND TNF-ALPHA ON PROCOAGULANT AND FIBRINOLYTIC PATHWAYS OF HUMAN TRACHEAL EPITHELIAL-CELLS

The epithelial lining of the airways is subject to injury through seve ral processes, including infections, bronchiolitis, and fume exposures . Because airway fibrin deposition influences the course of local inju ry, we examined how two inflammatory cytokines influenced fibrin forma tion and clearance in human tracheal epithelial cells (TEC). TEC were treated with transforming growth factor-beta (TGF-beta) and tumor necr osis factor-alpha (TNF-alpha). TNF-alpha increased release of tissue f actor (TF)-related procoagulant activity that, through generation of f actor Xa, promotes assembly of the prothrombinase complex at the cell surface. Fibrinolytic activity was plasminogen dependent and due to bo th urokinase (uPA) and tissue plasminogen activator (tPA). The cells e xpressed plasminogen activator inhibitor 1 (PAI-1), but relatively lit tle PAI-2. Depression of fibrinolysis by TGF-beta correlated with incr eased PAI-1. Conversely, TNF-alpha increased plasminogen activator (PA ) activity due to increased uPA. Fibrinolytic activity was inhibited b y actinomycin D and cyclohexamide, but changes in mRNAs for uPA, tPA, PAI-1, and TF by either cytokine were not appreciable. PAI-2 mRNA was not found. The data indicate that TGF-beta decreases the fibrinolytic capacity of TEC, suggesting that this cytokine promotes fibrin retenti on. TNF-alpha increases expression of both procoagulant and fibrinolyt ic activities; this differential regulation could favor both pericellu lar fibrin formation and dissolution.