Liver regeneration is transiently impaired in urokinase-deficient mice

Abstract

To test the hypothesis that urokinase-type plasminogen activator (uPA) plays an important role in liver regeneration in vivo, partial hepatectomy was performed on wild-type and uPA-deficient (uPA−/−) mice. Mice were studied at 24, 44, and 96 h and at 8 days and 4 wk post-partial hepatectomy for evidence of regeneration, as measured by mitotic indexes and [3H]thymidine incorporation. In wild-type mice, thymidine incorporation peaked at 44 h and this index was reduced by 47% in uPA−/− mice ( P= 0.02). By 8 days, however, liver mass was comparable in both groups. Histological analysis revealed the presence of focal areas of fibrin deposition and cellular loss by 24 h that were more severe and prevalent in uPA−/− mice than in wild-type mice (62 and 23%, respectively; χ2 = 3.939, P = 0.047). In contrast, regeneration was not impaired in uPA receptor (uPAR)-deficient mice at 24 and 44 h. Taken together, these data indicate that uPA, independent of its interaction with the uPAR, plays an important role in liver regeneration in vivo.

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice

“…As shown in Fig. 6, liver proliferation peaked at 48 hours after PH, both in PBS-and Flt3L-pretreated animals, as described previously [30][31][32] ; at 12, 24, 48, and 72 hours after PH the PCNA LI was 45% to 50% higher in Flt3L-pretreated animals than in PBSinjected mice (12 hours: 26 Ϯ 6 vs. 13 Ϯ 6, P Ͻ .006; 24 hours: 30 Ϯ 6 vs. 17 Ϯ 4, P Ͻ .007; 48 hours: 34 Ϯ 2 vs. 22 Ϯ 3, P Ͻ .005; 72 hours: 14 Ϯ 2 vs. 8 Ϯ 2, P Ͻ .009). The PCNA LI in liver tissue from Flt3L-treated, shamoperated, non-hepatectomized animals, at each time point, was very low, ruling out a direct effect of Flt3L on Fig.…”

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

“…The impairment is moderate and is accompanied by a delayed onset of peak DNA synthesis and several changes in gene transcription. Other genetically modified mice, including those carrying homozygous deletions for UPA, 20 iNos, 13 CREM, 21 TNFR1, 22,23 IL-6, 24 and C/ebp␤, 25 have been previously tested for hepatic regenerative capacity. In these models, DNA synthesis was decreased in mice lacking IL-6, UPA, C/ebp␤, TNFR1, iNos, and CREM but not in mice lacking TNFR2.…”

Cell Surface-Bound Plasminogen Regulates Hepatocyte Proliferation Through a uPA-Dependent Mechanism

“…29) The possible role of the uPA/plasminogen system in liver regeneration has been studied using knockout mice, but the regeneration profiles observed in them were different among the models, which were injured in different ways. Hepatocyte proliferation was impaired in uPA and plasminogen-deficient mice after two-thirds partial hepatectomy, 22,23,30) and in those with anti-Fas antibodyinduced hepatic apoptosis, 4) but not in CCl 4 -induced acute liver injury. 31,32) The liver regeneration model with CCl 4 -induced liver injury is more inflammatory than that with partial hepatectomy or anti-Fas antibody-induced apoptosis.…”

“…[1][2][3]21) These proteases are also known to play important roles in liver regeneration, and the evidence for this has been supported by animal studies using the knockout mice for these factors. [22][23][24] Furthermore, an activation network connecting uPA/plasmin and MMPs has been found to be a mechanism in which they exhibit their respective functions efficiently; e.g., in an experiment with mice, inhibition of uPA by a specific inhibitor suppressed MMP-2 activity. uPA activity was measured by zymography to determine that of the conditioned media cultured hepatocytes for 24 h in the presence or absence of plasminogen, EGF, and TXA (A), or CPB (B), at various concentrations as shown under the pictures of gels.…”