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Single-Chain Urokinase Alone or Complexed to Its Receptor in Tetracycline-induced Pleuritis in Rabbits

Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas; Attenuon, La Jolla, California; Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania; Louisiana State University Health Sciences Center, Shreveport, Louisiana; and Department of Surgery, North Shore-LIJ Research Institute, Manhasset, New York

Correspondence and requests for reprints should be addressed to Steven Idell, M.D., Ph.D., Chairman, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U.S. HWY 271, Tyler, TX 75708. E-mail: steven.idell{at}uthct.edu

Intrapleural loculation can increase morbidity in hemothoraces or parapneumonic effusions. Intrapleural fibrin precedes visceral–parietal pleural adhesions. We speculated that single-chain urokinase plasminogen activator alone or bound to its receptor could prevent these adhesions by their relative resistance to local inhibition by plasminogen activator inhibitors. We found that recombinant human single-chain urokinase-bound rabbit pleural mesothelial cells or lung fibroblasts with kinetics similar to that reported for human cells (kD of approximately 5 nM). The receptor-bound fibrinolysin maintained in vitro fibrinolytic activity in the presence of pleural fluids from rabbits with tetracycline-induced pleural injury over 24 hours. In rabbits given intrapleural single-chain urokinase 24 and 48 hours after intrapleural tetracycline (n = 10 animals), adhesions were prevented, whereas the receptor-complexed form (n = 12) attenuated adhesions versus vehicle/tetracycline-treated rabbits (n = 22, p 0.005 in both cases). There were more adhesions in the complex than the single-chain urokinase group (p = 0.02). Residual antigenic but not functional evidence of the interventional agents remained in pleural fluids at 72 hours after tetracycline. No local or systemic bleeding occurred because of either interventional agent. The data demonstrate that single-chain urokinase inhibits, whereas lysin–receptor complexes attenuate, adhesion formation in tetracycline-induced pleural injury in rabbits.

Key Words: urokinase • fibrinolysis • pleural scarring

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