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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/L568    most recent 00066.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Komissarov, A. A. Articles by Idell, S. PubMed PubMed Citation Articles by Komissarov, A. A. Articles by Idell, S.

Regulation of intrapleural fibrinolysis by urokinase--macroglobulin complexes in tetracycline-induced pleural injury in rabbits

¹The Texas Lung Injury Institute of The University of Texas Health Science Center at Tyler, Tyler, Texas; and ; ²Attenuon Limited Liability Company, Evanston, Illinois

Submitted 27 February 2009 ; accepted in final form 19 June 2009

The proenzyme single-chain urokinase plasminogen activator (scuPA) more effectively resolved intrapleural loculations in rabbits with tetracycline (TCN)-induced loculation than a range of clinical doses of two-chain uPA (Abbokinase) and demonstrated a trend toward greater efficacy than single-chain tPA (Activase) (Idell S et al., Exp Lung Res 33: 419, 2007.). scuPA more slowly generates durable intrapleural fibrinolytic activity than Abbokinase or Activase, but the interactions of these agents with inhibitors in pleural fluids (PFs) have been poorly understood. PFs from rabbits with TCN-induced pleural injury treated with intrapleural scuPA, its inactive Ser195Ala mutant, Abbokinase, Activase, or vehicle, were analyzed to define the mechanism by which scuPA induces durable fibrinolysis. uPA activity was elevated in PFs of animals treated with scuPA, correlated with the ability to clear pleural loculations, and resisted (70–80%) inhibition by PAI-1. -macroglobulin (M) but not urokinase receptor complexes immunoprecipitated from PFs of scuPA-treated rabbits retained uPA activity that resists PAI-1 and activates plasminogen. Conversely, little plasminogen activating or enzymatic activity resistant to PAI-1 was detectable in PFs of rabbits treated with Abbokinase or Activase. Consistent with these findings, PAI-1 interacts with scuPA much slower than with Activase or Abbokinase in vitro. An equilibrium between active and inactive scuPA (k_on = 4.3 h^–1) limits the rate of its inactivation by PAI-1, favoring formation of complexes with M. These observations define a newly recognized mechanism that promotes durable intrapleural fibrinolysis via formation of M/uPA complexes. These complexes promote uPA-mediated plasminogen activation in scuPA-treated rabbits with TCN-induced pleural injury.

single-chain urokinase; tissue plasminogen activator