title: Resolution of neutrophilic inflammation by H2O2 in antigen-induced arthritis.
abstract: OBJECTIVE
  Neutrophil accumulation contributes to the pathogenesis of rheumatoid arthritis. This study was undertaken to examine the ability of H2O2 to influence neutrophilic inflammation in a model of antigen-induced arthritis (AIA) in mice.
  
  
  METHODS
  AIA was induced by administration of antigen into the knee joints of previously immunized mice. Neutrophil accumulation was measured by counting neutrophils in the synovial cavity and assaying myeloperoxidase activity in the tissue surrounding the mouse knee joint. Apoptosis was determined by morphologic and molecular techniques. The role of H2O2 was studied using mice that do not produce reactive oxygen species (gp91phox-/- mice) and drugs that enhance the generation or enhance the degradation of H2O2.
  
  
  RESULTS
  Antigen challenge of immunized mice induced neutrophil accumulation that peaked at 12-24 hours after challenge. H2O2 production peaked at 24 hours, after which time, the inflammation resolved. Neutrophil recruitment was similar in wild-type and gp91phox-/- mice, but there was delayed resolution in gp91phox-/- mice or after administration of catalase. In contrast, administration of H2O2 or superoxide dismutase (SOD) resolved neutrophilic inflammation. The resolution of inflammation induced by SOD or H2O2 was accompanied by an increase in the number of apoptotic neutrophils. Apoptosis was associated with an increase in Bax and caspase 3 cleavage and was secondary to phosphatidylinositol 3-kinase (PI3K)/Akt activation.
  
  
  CONCLUSIONS
  Our findings indicate that levels of H2O2 increase during neutrophil influx and are necessary for the natural resolution of neutrophilic inflammation. Mechanistically, enhanced levels of H2O2 (endogenous or exogenous) inhibit p-Akt/NF-κB and induce apoptosis of migrated neutrophils. Modulation of H2O2 production may represent a novel strategy for controlling neutrophilic inflammation in the joints.
authors.affiliation: Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopes
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Coelho
authors.forename: Vivian V
authors.initials: VV
authors.lastname: Costa
authors.forename: Érica L M
authors.initials: ÉL
authors.lastname: Vieira
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
authors.forename: Tarcília A
authors.initials: TA
authors.lastname: Silva
authors.forename: Leda Q
authors.initials: LQ
authors.lastname: Vieira
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D006861:Hydrogen Peroxide