CHRONIC GLUCOCORTICOSTEROID ADMINISTRATION MODULATES THE RESPONSE OF THE FIBRINOLYTIC SYSTEM TO BACTERIAL LIPOPOLYSACCHARIDE

An in vivo rat model was used to study the effect of chronic glucocort icosteroid administration on the response of the fibrinolytic system t o lipopolysaccharide (LPS). Male Lewis rats were injected subcutaneous ly for 30 consecutive days with either saline or saline containing 0.1 mu g/g dexamethasone. On the thirty-first day, the rats were challeng ed with intraperitoneal injections of LPS (0.5 mu g/g). Plasma and sel ected tissues (liver, kidney, heart, lung, muscle, and fat) were remov ed for analysis at various times after LPS injection. LPS treatment ca used a rapid rise in plasma type 1 plasminogen activator inhibitor (PA I-1) activity in both groups. However, in the dexamethasone-pretreated animals a transient decline in PAI-1 activity was detected at 4h, coi nciding with a transient increase in plasma tissue plasminogen activat or (t-PA) activity and a marked elevation of t-PA messenger RNA (mRNA) levels in the lung. Plasma t-PA activity returned below basal levels by 8h and did not differ between the two groups at later times. At 24h , PAI-1 activity remained significantly elevated in the dexamethasone- pretreated rats while declining in the saline-pretreated rats. A great er induction of PAI-1 mRNA was evident in the dexamethasone-pretreated rats in all six tissues examined. Notably, a 3-fold greater increase in PAI-1 mRNA was detected in the liver at 24 h, corresponding with th e sustained elevation in plasma PAI-1 activity at this time. Collectiv ely, these data suggest that chronic glucocorticosteroid treatment pot entiates the induction of both t-PA and PAI-1 gene expression by LPS, resulting in an initial transient increase in plasma t-PA activity fol lowed by a more sustained elevation in plasma PAI-1 activity.