Endogenous protease inhibitor uptake within the graft during reperfusion in human liver transplantation

In experimental liver transplantation, endogenous protease inhibitors alleviate ischemia-reperfusion (I/R) injury by inhibiting proteolysis and by direct anti-inflammatory actions. We described the kinetics of endogenous protease inhibitors and explored their anti-inflammatory potential during reperfusion and their effects on graft function in human liver transplantation.

We measured circulating levels of protease inhibitors (secretory leukocyte proteinase inhibitor, SLPI; tissue inhibitor of metalloproteinases-1, TIMP-1) and proteolytic enzymes (elastase; matrix metalloproteinase-9, MMP-9) with ELISA, and neutrophil and monocyte CD11b and L-selectin expression with flow cytometry during liver transplantation in ten patients. To assess changes within the graft during reperfusion, blood samples from portal and hepatic veins were obtained simultaneously.

Circulating SLPI and TIMP-1 levels decreased during surgery. During initial reperfusion, the transhepatic SLPI gradient was -27 (-35 to -22) ng/ml, P = 0.005, and TIMP-1 -510 (-636 to -362) ng/ml, P = 0.005, indicating graft protease inhibitor uptake. Concomitantly, hepatic phagocyte activation and sequestration as well as elastase and MMP-9 release into the circulation occurred. The transhepatic SLPI gradient correlated with postoperative liver enzymes (ALT R = -0.648, P = 0.043; ALP R = -0.661, P = 0.038; bilirubin R = -0.821, P = 0.004; GGT R = -0.648, P = 0.043).

The results suggest a relative shortage of protease inhibitors within the liver during reperfusion, which may contribute to the development of graft injury.