title: TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury.
abstract: Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is the major endogenous regulator of matrix metalloproteinase-9 (MMP-9). In this study we investigated the functional significance of TIMP-1 expression in a well-established mouse model of partial liver IRI. Compared to wildtype mice, TIMP-1(-/-) mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP-1 deficiency led to lethal liver IRI, as over 60% of the TIMP-1(-/-) mice died postreperfusion, whereas all TIMP-1(+/+) mice recovered and survived surgery. Lack of TIMP-1 expression was accompanied by markedly high levels of MMP-9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP-1(-/-) livers were characterized by massive leukocyte infiltration and by up-regulation of proinflammatory mediators, including tumor necrosis factor alpha, interferon-gamma, and inducible nitric oxide synthase post-IRI. The inability of TIMP-1(-/-) mice to express TIMP-1 increased the levels of active caspase-3 and depressed the expression of Bcl-2 and the phosphorylation of Akt, emphasizing an important role for TIMP-1 expression on hepatocyte survival. Using independent parameters of regeneration, 5-bromodeoxyuridine incorporation, proliferating cell nuclear antigen expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP-1-deficient livers after IRI. Inhibition of the cell cycle progression by TIMP-1 deficiency was linked to depressed levels of cyclins-D1 and -E and to a disrupted c-Met signaling pathway, as evidenced by reduced phosphorylated c-Met expression and elevated c-Met ectodomain shedding postliver IRI.
  
  
  CONCLUSIONS
  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 IRI.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7054, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Duarte
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Naohisa
authors.initials: N
authors.lastname: Kuriyama
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
mesh_terms: D000818:Animals; D007511:Ischemia / Q000209:etiology* / Q000401:mortality; D008099:Liver / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000209:etiology* / Q000401:mortality; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency*
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1