title: Protective role of reactive oxygen species in endotoxin-induced lung inflammation through modulation of IL-10 expression.
abstract: Reactive oxygen species (ROS) generated by NADPH oxidase are generally known to be proinflammatory, and it seems to be counterintuitive that ROS play a critical role in regulating the resolution of the inflammatory response. However, we observed that deficiency of the p47(phox) component of NADPH oxidase in macrophages was associated with a paradoxical accentuation of inflammation in a whole animal model of noninfectious sepsis induced by endotoxin. We have confirmed this observation by interrogating four separate in vivo models that use complementary methodology including the use of p47(phox-/-) mice, p47(phox-/-) bone marrow chimera mice, adoptive transfer of macrophages from p47(phox-/-) mice, and an isolated perfused lung edema model that all point to a relationship between excessive acute inflammation and p47(phox) deficiency in macrophages. Mechanistic data indicate that ROS deficiency in both cells and mice results in decreased production of IL-10 in response to treatment with LPS, at least in part, through attenuation of the Akt-GSK3-β signal pathway and that it can be reversed by the administration of rIL-10. Our data support the innovative concept that generation of ROS is essential for counterregulation of acute lung inflammation.
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Stephen
authors.initials: S
authors.lastname: Vogel
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Ravi
authors.initials: R
authors.lastname: Ranjan
authors.forename: Hyesuk
authors.initials: H
authors.lastname: Park
authors.forename: Manjula
authors.initials: M
authors.lastname: Karpurapu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Gye Young
authors.initials: GY
authors.lastname: Park
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D004731:Endotoxins; C508609:IL10 protein, human; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016753:Interleukin-10; D008156:Luciferases; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1