title: NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome.
abstract: Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91(phox-/y) (NOX2-deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2-deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation.
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and Interdisciplinary Graduate Program in Molecular and Cellular Biology, the University of Iowa, Iowa City, Iowa.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Whitmore
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Goss
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Newell
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and.
authors.forename: Brieanna M
authors.initials: BM
authors.lastname: Hilkin
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Hook
authors.affiliation: Department of Pediatrics, Inflammation Program, the University of Iowa, Iowa City, Iowa; and Interdisciplinary Graduate Program in Molecular and Cellular Biology, the University of Iowa, Iowa City, Iowa jessica.moreland@utsouthwestern.edu.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Moreland
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000235:genetics* / Q000401:mortality / Q000517:prevention & control; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000235:genetics* / Q000401:mortality / Q000517:prevention & control; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D015054:Zymosan
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D015054:Zymosan; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: MODS; SIRS; chronic granulomatous disease; gp91phox; inflammation