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

Abstract

<span style="font-size:10pt;"><span style="font-family:Verdana;">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 (</span><i><span style="font-family:Verdana;">p < </span></i><span style="font-family:Verdana;">0.024); 539 ± 64 ng/mL vs 256 ± 13 ng/mL (</span><i><span style="font-family:Verdana;">p </span></i><span style="font-family:Verdana;">< 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 (</span><i><span style="font-family:Verdana;">p </span></i><span style="font-family:Verdana;">< 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 (</span><i><span style="font-family:Verdana;">p </span></i><span style="font-family:Verdana;">< 0.001). Morphometric analysis showed that Sirius red staining in BDI was increased 121548.6 ± 20545.4 μm</span></span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-family:Verdana;font-size:10pt;">vs. 22865.7 ± 3865 μm</span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-size:10pt;"><span style="font-family:Verdana;">in healthy controls (</span><i><span style="font-family:Verdana;">p </span></i><span style="font-family:Verdana;">< 0.0001), MMP-8 deposition in liver was higher in BDI compared to controls: 233015.2 ± 32953.3 μm</span></span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-family:Verdana;font-size:10pt;">vs. 30744.2 ± 5810.2 μm</span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-size:10pt;"><span style="font-family:Verdana;">(</span><i><span style="font-family:Verdana;">p </span></i><span style="font-family:Verdana;">< 0.0001). MMP-3 liver staining in BDI compared to healthy controls was not significant 130837.9 ± 17,484 μm</span></span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-family:Verdana;font-size:10pt;">vs. 116337.9 ± 24803.3 μm</span><span style="font-family:Verdana;font-size:6.5pt;">2 </span><span style="font-size:10pt;"><span style="font-family:Verdana;">(</span><i><span style="font-family:Verdana;">p < </span></i><span style="font-family:Verdana;">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 imb...