title: RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB.
abstract: The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-kappaB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-alpha and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death-promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.
authors.affiliation: Division of Liver Diseases and Transplantation, Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY 10032, USA.
authors.forename: Guellue
authors.initials: G
authors.lastname: Cataldegirmen
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Nikki
authors.initials: N
authors.lastname: Feirt
authors.forename: Nikalesh
authors.initials: N
authors.lastname: Ippagunta
authors.forename: Hao
authors.initials: H
authors.lastname: Dun
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Rong
authors.forename: Marion A
authors.initials: MA
authors.lastname: Hofmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.forename: Sophia I
authors.initials: SI
authors.lastname: Pachydaki
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Jenkins
authors.forename: Alan
authors.initials: A
authors.lastname: Weinberg
authors.forename: Jay
authors.initials: J
authors.lastname: Lefkowitch
authors.forename: Xavier
authors.initials: X
authors.lastname: Rogiers
authors.forename: Shi Fang
authors.initials: SF
authors.lastname: Yan
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Jean C
authors.initials: JC
authors.lastname: Emond
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha