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

Abstract

We have shown that tissue-type plasminogen activator (tPA) and plasma kallikrein share a common pathway for liver clearance and that the hepatic clearance rate of plasma kallikrein increases during the acute-phase (AP) response. We now report the clearance of tPA from the circulation and by the isolated, exsanguinated and in situ perfused rat liver during the AP response (48-h ex-turpentine treatment). For the sake of comparison, the hepatic clearance of a tissue kallikrein and thrombin was also studied. We verified that, in vivo, the clearance of 125 I-tPA from the circulation of turpentine-treated 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 125 I-tPA and the liver accounts for most of the 125 I-tPA (>80%) cleared from the circulation. The clearance rate of tPA by the isolated and perfused liver of turpentine-treated rats (15.5 ± 1.3 µg/min, N = 4) was slower (P = 0.003) than the clearance rate by the liver of normal rats (22.5 ± 0.7 µg/ min, N = 10). After the inflammatory stimulus and additional Kupffer cell ablation (GdCl 3 treatment), tPA was cleared by the perfused liver at 16.2 ± 2.4 µg/min (N = 5), suggesting that Kupffer cells have a minor influence on the hepatic tPA clearance during the AP response. In contrast, hepatic clearance rates of thrombin and pancreatic kallikrein were not altered during the AP response. These results contribute to explaining why the thrombolytic efficacy of tPA does not correlate with the dose administered.

Hepatic clearance of tissue‐type plasminogen activator and plasma kallikrein in experimental liver fibrosis

“…Since all livers were analyzed by histological examination and produced the same profile with almost complete inactivation of the Kupffer cells, it is possible that the activation of the inflammatory cascade precedes the cell inactivation. With regard to the role of the acute-phase reaction in the hepatic clearance, we have already shown that after an inflammatory stimulus induced by turpentine oil, the hepatic clearance of RPK increased (20) whereas that of tPA decreased (19). Kupffer cells are not directly involved in RPK internalization (22), but we now confirm that the inflammatory stimulus evokes a higher receptor expression that mediates the hepatic internalization of RPK, independently of the initial stimulus.…”

“…With regard to the role of the acute‐phase reaction in the hepatic clearance, we have already shown that after an inflammatory stimulus induced by turpentine oil, the hepatic clearance of RPK increased (20) whereas that of tPA decreased (19). Kupffer cells are not directly involved in RPK internalization (22), but we now confirm that the inflammatory stimulus evokes a higher receptor expression that mediates the hepatic internalization of RPK, independently of the initial stimulus.…”

“…Fibrosis was induced by intraperitoneal injection of porcine serum, twice a week, for 10-12 weeks, whereas cirrhosis was induced by intragastric administration of CCl 4 for 18 weeks. Clearance of 125 I-tPA from the circulation and organ distribution was performed as described (19).…”

“…tPA iodination and the clearance of 125 I‐tPA from the circulation was performed as described (19). In brief, 0.7 μg 125 I‐tPA (2×10 6 cpm) plus 500 μg of unlabeled tPA was injected intravenously in bolus and flushed with 0.5 ml of 0.15 M NaCl solution.…”

Time‐ and dose‐related regional fluxes of tissue‐type plasminogen activator in anesthetized endotoxemic pigs

“…The hepatic uptake mechanism for tPA involves both endothelial and parenchymal cells (17). It has been reported previously that hepatic clearance of tPA is reduced during the acute‐phase response of inflammation (18). Our results indicate the contrary.…”