title: Tenascin-C: a novel mediator of hepatic ischemia and reperfusion injury.
abstract: Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability of Tnc(-/-) mice to express Tnc significantly reduced the levels of active caspase-3/transferase-mediated dUTP nick end-labeling (TUNEL) apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of interleukin (IL)-1β, IL-6, and CXCL2 after liver reperfusion. Tnc-deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly down-regulated in the absence of Tnc. We also show that Tnc is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4. Therefore, our data suggest that Tnc is a relevant mediator of the pathogenic events underlying liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as Tnc, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI.
authors: 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: Naohisa
authors: N
authors: Kuriyama
authors: Sergio
authors: S
authors: Duarte
authors: Takashi
authors: T
authors: Hamada
authors: Ronald W
authors: RW
authors: Busuttil
authors: Ana J
authors: AJ
authors: Coito
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000473:pathology / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000276:immunology*; D019063:Tenascin / Q000172:deficiency* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019063:Tenascin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9