title: Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms.
abstract: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation, and matrix degradation. This study tests the hypothesis that macrophage-produced high mobility group box 1 (HMGB1) production is dependent on nicotinamide adenine dinucleotide phosphate oxidase (Nox2), which leads to increase in interleukin (IL)-17 production resulting in AAA formation and that treatment with human mesenchymal stem cells (MSCs) can attenuate this process thereby inhibiting AAA formation.
  
  
  
  Human aortic tissue demonstrated a significant increase in HMGB1 expression in AAA patients when compared with controls. An elastase-perfusion model of AAA demonstrated a significant increase in HMGB1 production in C57BL/6 (wild-type [WT]) mice, which was attenuated by MSC treatment. Furthermore, anti-HMGB1 antibody treatment of WT mice attenuated AAA formation, IL-17 production, and immune cell infiltration when compared with elastase-perfused WT mice on day 14. Elastase-perfused Nox2(-/y) mice demonstrated a significant attenuation of HMGB1 and IL-17 production, cellular infiltration, matrix metalloproteinase activity, and AAA formation when compared with WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not from Nox2(-/y) mice, produced HMGB1, which was attenuated by MSC treatment. The production of macrophage-dependent HMGB1 involved Nox2 activation and superoxide anion production, which was mitigated by MSC treatment.
  
  
  
  These results demonstrate that macrophage-produced HMGB1 leads to aortic inflammation and acts as a trigger for CD4(+) T-cell-produced IL-17 during AAA formation. HMGB1 release is dependent on Nox2 activation, which can be inhibited by MSCs leading to attenuation of proinflammatory cytokines, especially IL-17, and protection against AAA formation.
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Salmon
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Pope
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Smith
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.).
authors.forename: Mark L
authors.initials: ML
authors.lastname: Weiss
authors.affiliation: From the Department of Surgery, University of Virginia, Charlottesville (A.K.S., M.D.S., G.L., G.S., N.H.P., G.R.U.); and Department of Anatomy and Physiology, Kansas State University, Manhattan (J.R.S., M.L.W.). gru6n@virginia.edu.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010196:Pancreatic Elastase; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010196:Pancreatic Elastase
keywords: HMGB1 protein; aortic aneurysms, abdominal; inflammation; interleukins; stem cells