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Title: Hepatic clearance of tissue plasminogen activator (t-PA) : the role of PAI-1
Author: Wing, Luman R.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1991
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The clearance of t-PA and the role of protease inhibitors in this process was examined by comparing the rate of t-PA and pre-formed t-PA-PAI-1 complex in an isolated rat liver perfusion system. Pharmacokinetic analysis of the effluent concentration vs. time curves revealed that t-PA-PAI-1 complex is cleared twice as fast as t-PA; free PAI-1 is cleared slowly. The rate constants derived from these curves demonstrated that the binding of t-PA-PAI-1 complex was four-fold faster than t-PA. The data indicated that the binding of t-PA-PAI-1 was the most important factor in the faster clearance compared to free-t-PA, suggesting the presence of a specific receptor for t-PA-PAI-1. The project then focussed on the specific binding of 125I-t-PA-PAI-1 complex to human hepatocytes and the hepatocellular cell line Hep G2. These studies indicated that t-PA-PAI-1 binds specificially to human hepatocytes after 2h at 4oC with a Kd &'61 0.87 0.09. The number of binding sites/cell was 76,000 10,000. The only other competitor for this interaction was plasmin-2-antiplasmin. No competition with t-PA, PAI-1, u-PA, u-PA-PAI-1 complex, plasminogen, 2-antiplasmin or vitronectin was observed. The fate of bound 125I-t-PA-PAI-1 was followed at 37oC after binding of the complex to hepatocytes for 2h at 4oC. These experiments demonstrated that the cell-surface receptor-ligand complex was internalized after 30 minutes. Uptake and degradation of t-PA-PAI-1 by hepatocytes was inhibited by chloroquine, a known inhibitor of the lysosomal degradation pathway, indicating that receptor-mediated endocytosis and lysosomal degradation of the complex occurs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available