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

• Published in: Journal of hepato-biliary-pancreatic sciences 2010-03, Vol.17 (2), p.158-165
• Main Authors: Ilmakunnas, Minna, Höckerstedt, Krister, Mäkisalo, Heikki, Siitonen, Sanna, Repo, Heikki, Pesonen, Eero J.
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; CD11 Antigens - biosynthesis; Disease Progression; Enzyme-Linked Immunosorbent Assay; Enzymes; Female; Flow Cytometry; Follow-Up Studies; Gastroenterology; Graft Rejection - enzymology; Graft Rejection - pathology; Hepatology; HIV; Human immunodeficiency virus; Humans; Intraoperative Period; L-Selectin - biosynthesis; Leukocyte Count; Liver Transplantation - physiology; Male; Medicine; Medicine & Public Health; Middle Aged; monocyte; Monocytes - metabolism; neutrophil; Neutrophils - metabolism; Original Article; Peptide Hydrolases - blood; Prognosis; Protease inhibitors; Protease Inhibitors - blood; reperfusion; Reperfusion Injury - enzymology; Secretory Leukocyte Peptidase Inhibitor - blood; SLPI; Surgical Oncology; TIMP‐1; Tissue Inhibitor of Metalloproteinase-1 - blood; Transplants & implants; Young Adult
• ISSN: 1868-6974; 1868-6982
• DOI: 10.1007/s00534-009-0125-3

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