Alterations in fibrinolytic system proteins PAI-1, MMP-3, MMP-8, TIMP-1 and TIMP-2 in post-cholecystectomy bile duct injury

Abstract

Introduction: In bile duct injuries (BDI), cholestasis and cholangitis can alter the fibrinolytic system by promoting an increase of extracellular matrix depositions which favor an imbalance between metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Materials and Methods: Levels of PAI-1, MMP-3, MMP-8, TIMP-1 and TIMP-2 in 35 patients with post-cholecystectomy BDI by complete biliary obstruction were measured and compared to a healthy control group. Sirius red staining and immune staining for MMP-3 and MMP-8 were also undertaken in liver biopsies. Results: Levels of PAI-1, TIMP-1, TIMP-2 and MMP-8 were higher in BDI than healthy controls: 15 ± 2 ng/mL vs 7.1 ± 2 ng/mL ( p < 0.024); 539 ± 64 ng/mL vs 256 ± 13 ng/mL ( p < 0.003); 178.4 ± 79.8 ng/mL vs 98.6 ± 2 ng/mL; and 90 ± 10 ng/mL vs 6.8 ± 2 ng/mL ( p < 0.002), respectively. However, serum levels of MMP-3 expression in BDI were decreased 9.0 ± 1 vs. healthy controls 20.3 ± 6 ng/mL ( p < 0.001). Morphometric analysis showed that Sirius red staining in BDI was increased 121548.6 ± 20545.4 μm 2 vs. 22865.7 ± 3865 μm 2 in healthy controls ( p < 0.0001), MMP-8 deposition in liver was higher in BDI compared to controls: 233015.2 ± 32953.3 μm 2 vs. 30744.2 ± 5810.2 μm 2 ( p < 0.0001). MMP-3 liver staining in BDI compared to healthy controls was not significant 130837.9 ± 17,484 μm 2 vs. 116337.9 ± 24803.3 μm 2 ( p < 0.55). These results suggest an imbalance between fibrogenic/fibrinolytic protein levels. Interestingly, expression of the fibrinolytic protein MMP-8 was increased in serum and liver biopsies in BDI. Conclusion: We found an imbalance of profibrogenic molecules which promote extracellular matrix deposition. The over-expression of fibrinolytic proteins such as MMP-8 could limit liver fibrosis, preventing hepatic dysfunction in post-cholecystectomy BDI.