Conclusion: These results support a critical protective function for TIMP-1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver Gefitinib concentration IRI. (HEPATOLOGY 2012;56:1074–1085) Hepatic ischemia/reperfusion injury (IRI) occurs during trauma, shock, orthotopic liver transplantation (OLT), and other surgical procedures where the blood supply to the liver is temporarily interrupted.1

Hepatic IR-related damage is the result of various factors that include leukocyte migration, release of cytokines, and free radicals.1, 2 Leukocytes migration across endothelial and extracellular matrix (ECM) barriers is dependent on cellular adhesion-release and focal matrix degradation mechanisms.3 Although adhesion molecules are important for the successful leukocyte transmigration by providing leukocyte attachment

to the endothelium, there is a growing body of evidence suggesting that matrix metalloproteinases (MMP) are critical for facilitating leukocyte movement across vascular barriers.3 In this regard, our previous studies showed an important role for leukocyte-expressed MMP-9, or gelatinase B, as a key mediator of leukocyte transmigration leading to liver injury.4 Tissue inhibitors of metalloproteinases (TIMPs) are a family Ribonucleotide reductase of naturally occurring inhibitors of MMPs. Alterations in the MMP-TIMP balance Galunisertib concentration have been linked to pathological conditions that require disruption of the basement membrane, such as tumor invasion, angiogenesis, and wound healing.5 There are at least four identified members (TIMP 1-4)

in the TIMP family, varying in tissue-specific expression and in their ability to inhibit various MMPs.6 Among the different TIMPs, TIMP-1 is of particular interest; TIMP-1 is a 28.5-kDa soluble glycoprotein known to inhibit MMP-9 with high affinity, without interacting with MMP-2, or gelatinase A (the other member of the gelatinase family), as it lacks the required C-terminal MMP-2-interacting residues.7, 8 In addition to its ability to inhibit MMP activity, TIMP-1 possesses other biological activities, such as cell growth regulation, that are just beginning to be recognized and characterized.9 The specific effects of TIMPs likely depend on the cell context and on the pathological condition. Although TIMP-1 has been detected in the plasma of patients after liver transplantation,10 and in rat liver grafts after IRI,11 its role in liver IRI, or in OLT, remains to be established. Therefore, in the present study we used mice lacking TIMP-1 to examine the significance of TIMP-1 expression in hepatic IRI.