Abstract
BackgroundIncreases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. Remodelling of the extracellular matrix, conversion of single chain hepatocyte growth factor to the active two-chain form and a possible activation of a mitogenic signalling pathway have all been ascribed to the increased uPA activity. The present study aimed to determine whether similar early increases in uPA activity could be detected in the remnant liver following resection of metastatic tumours in surgical patients.ResultsEighteen patients undergoing partial hepatectomy for the removal of hepatic metastases secondary to primary colonic tumours were studied. Increased plasminogen activator activity was found in the final liver samples for the group of patients in whom the resection size was at least 50%. For smaller resections, the increased activity was not observed. The increased activity did not correlate with the age of the patient or with the time between the start of resection and the end of the operation. There was, however, a negative correlation between plasminogen activator activity and the time for which blood supply to the liver was clamped.ConclusionsOur findings are in accordance with those from experimental animal models and show, for the first time, that rapid increases in plasminogen activator activity can occur following similarly large liver resection in humans. Thus, increases in plasminogen activator activity are an early event in the remnant liver following major liver resection in man. Our observations provide support for the contention that increases in plasminogen activators play a key role in the initiation of hepatic regeneration in man.
Highlights
Increases in urokinase-like plasminogen activator activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response
We find that with purified urokinase-like plasminogen activator (uPA) and tissue-like plasminogen activator (tPA) proteins, an increase of about one order of magnitude is necessary before the bands produced in the gels are notably different
As proposed by Mars et al [5], increased uPA activity is an essential feature at the start of regeneration, these observations confirm the findings of animal studies that the magnitude of the regenerative response is dependent on the extent of the hepatectomy [14,15]
Summary
Increases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. In regeneration of the liver following partial hepatectomy, uPA has a number of potential roles These include initiating the remodelling of the extracellular matrix to allow cell division, activation of extra-cellular pro-metalloproteases and the release of the bound single-chain form of hepatocyte growth factor (HGF) from the extracellular (page number not for citation purposes). Following partial hepatectomy in the rat there is an early net decrease in the total amount of HGF in the liver, but the relative proportion of the single chain, inactive form, is decreased and the active two-chain form increased [2]. This implies an early proteolytic conversion, possibly mediated by the plasminogen activators. As discussed by Mangnall et al [4], uPA may activate a signalling pathway leading to mitosis of the hepatocyte
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