The hepatic clearance of recombinant tissue-type plasminogen activator decreases after an inflammatory stimulus

We have shown that tissue-type plasminogen activator (tPA) and plasma kalli krein share a common pathway for liver clearance and that the hepatic clear ance rate of plasma kallikrein increases during the acute-phase (AP) respon se. We now report the clearance of tPA from the circulation and by the isol ated, exsanguinated and in situ perfused rat liver during the AP response ( 48-h ex-turpentine treatment). For the sake of comparison, the hepatic clea rance of a tissue kallikrein and thrombin was also studied. We verified tha t, in vivo, the clearance of I-125-tpA from the circulation of turpentine-t reated rats (2.2 +/- 0.2 ml/ min, N = 7) decreases significantly (P = 0.016 ) when compared to normal rats (3.2 +/- 0.3 ml/min, N = 6). The AP response does not modify the tissue distribution of administered I-125-tpA and the liver accounts for most of the I-125-tpA (>80%) cleared from the circulatio n. The clearance rate of tPA by the isolated and perfused liver of turpenti ne-treated rats (15.5 +/- 1.3 mu g/min, N = 4) was slower (P = 0.003) than the clearance rate by the liver of normal rats (22.5 +/- 0.7 mu g/ min, N = 10). After the inflammatory stimulus and additional Kupffer cell ablation (GdCl3 treatment), tPA was cleared by the perfused liver at 16.2 +/- 2.4 mu g/min (N = 5), suggesting that Kupffer cells have a minor influence on the hepatic tPA clearance during the AP response. In contrast, hepatic clearan ce rates of thrombin and pancreatic kallikrein were not altered during the AP response. These results contribute to explaining why the thrombolytic ef ficacy of tPA does not correlate with the dose administered.