Urokinase-like plasminogen activator (uPA), initially recognised by its ability to convert plasminogen to plasmin and to participate in the fibrinolytic cascade, is now considered to have a wider role, which encompasses metastatic invasion by tumour cells and liver regeneration. 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 matrix (ECM). In vitro uPA and tissue-like plasminogen activator (tPA) have been shown to convert single chain inactive HGF into the active two chain form  in cultures of hepatocytes. In normal rodent liver, both the inactive and active forms of HGF can be detected, with the predominance of the inactive form . 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 . This implies an early proteolytic conversion, possibly mediated by the plasminogen activators. The importance of the uPA-plasminogen system to liver repair has been further demonstrated by the inability of plasminogen deficient animals to form regenerative nodules in response to acute liver injury . As discussed by Mangnall et al. , uPA may also activate a signalling pathway leading to mitosis of the hepatocyte.
Increases in uPA activity are amongst the earliest documented changes following partial hepatectomy in rats . Raised uPA activity was detected in the remnant liver at one-minute post-hepatectomy and continued to increase for at least one hour, although there were no changes in the total amount of uPA protein detectable by Western blotting. The binding of uPA to the uPA receptor (uPAR) is also associated with an increase in uPA enzymatic activity . In the rat partial hepatectomy model, the increase in uPA activity is thought to be due to an increase in the level of uPAR and subsequent binding and activation of uPA. In the remnant liver, increases in the amount of uPAR have been detected by Western blotting also as early as 1 min post hepatectomy and more clearly at 1 hour. This had decreased by 6 h and was back to basal levels by 24 h . The mechanism underlying these changes remains unclear.
Additional support for a role for uPA in the hepatic regenerative process comes from studies of uPA-deficient (uPA-/-) mice. In these animals, uptake of [3H]-thymidine into DNA and mitotic index were reduced by almost half at 44 h post-hepatectomy (the peak time for control mice), suggesting a slower hepatocyte growth response . In a separate study uPA-/-mice were treated with anti-Fas monoclonal antibody to induce extensive hepatocyte apoptosis. Fas (a member of the TNF-receptor superfamily) is present in the inactive state as a monomer, but on binding the appropriate ligand (in this case the antibody) the receptors aggregate and activate apoptosis leading to cell destruction. In these uPA-deficient animals, the regeneration response following anti-Fas treatment was delayed relative to normal control animals . Generation of mature HGF and time of peak levels were delayed in the uPA-/-mice and peak levels of proliferating cell nuclear antigen at 96 h were also delayed relative to controls, which peaked at 48 h. Treatment of the uPA-/-mice with the uPA gene by lipofection reversed these effects. The results support a role for uPA in the generation of mature HGF and in the regeneration after Fas-mediated liver damage.
More recently, studies with uPA or plasminogen deficient mice confirmed the requirement for plasminogen activation in liver regeneration and also showed a need for plasminogen in regeneration-associated hepatic angiogenesis . Collectively, these studies strongly suggest that a very early increase in uPA activity is a key feature of the liver regenerative response in rodents. It is generally assumed that regeneration in the human liver follows a similar course but the relative paucity of studies in humans means that, at present, it is unclear whether a similar role for uPA exists in the regeneration of human liver.
Though not necessarily identical, it is clear from the literature that regeneration in humans and rodents share similar mechanisms. Many of the cytokines and growth factors essential for regeneration in rodents [reviewed in ] are also found in increased amounts in the regenerating human liver, implying once more similar mechanisms.
However, clear differences between species do exist; a notable example being the differences in the time at which DNA synthesis peaks in the remnant liver. In rats, this is at about 24 h; in mice, at about 40 h; and in man, at 180–200 h following hepatectomy. In the case of the human studies, this may partially reflect the relatively greater age of the patients since the rate of regeneration slows with age. Such age related effects are less likely in the rodent studies where the timing of hepatocyte entry into DNA synthesis following partial hepatectomy has been shown to be an intrinsic, cell-autonomous, feature . Thus, although the basic mechanisms may be fundamentally similar, there are inherent differences between species (such as the timing of the cell cycle clock) which underscores the need not to assume that all aspects of regeneration operate identically in all mammals.
The unique sensitivity of the human hepatocyte to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)  likewise emphasises the need for caution when extrapolating from rodent liver to human liver.
The vast majority of the literature concerns regeneration in rats and mice and much less information is available from human studies since the opportunity to study liver regeneration in humans is generally limited to units specialising in liver surgery and is necessarily constrained by ethical considerations. Surgical removal of liver metastases affords the opportunity to obtain small samples of liver at the start, time of resection and time of wound closure approximating to the early sampling times in the animal studies. In this vein, the aim of the present study was to determine whether very early increases in uPA activity occur in the remnant liver following resection in man.