title: Moderate oxygen augments lipopolysaccharide-induced lung injury in mice.
abstract: Despite the associated morbidity and mortality, underlying mechanisms leading to the development of acute lung injury (ALI) remain incompletely understood. Frequently, ALI develops in the hospital, coinciding with institution of various therapies, including the use of supplemental oxygen. Although pathological evidence of hyperoxia-induced ALI in humans has yet to be proven, animal studies involving high oxygen concentration reproducibly induce ALI. The potentially injurious role of lower and presumably safer oxygen concentrations has not been well characterized in any species. We hypothesized that in the setting of a preexisting insult to the lung, the addition of moderate-range oxygen can augment lung injury. Our model of low-dose intratracheal LPS (IT LPS) followed by 60% oxygen caused a significant increase in ALI compared with LPS or oxygen alone with increased alveolar neutrophils, histological injury, and epithelial barrier permeability. In the LPS plus oxygen group, regulatory T cell number was reduced, and macrophage activation markers were increased, compared with LPS alone. Antibody-mediated depletion of neutrophils significantly abrogated the observed lung injury for all measured factors. The enhanced presence of alveolar neutrophils in the setting of LPS and oxygen is due, at least in part, to elevated chemokine gradients signaling neutrophils to the alveolar space. We believe these results strongly support an effect of lower concentrations of oxygen to augment the severity of a mild preexisting lung injury and warrants further investigation in both animals and humans.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Aggarwal
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsushima
authors.forename: D Clark
authors.initials: DC
authors.lastname: Files
authors.forename: Mahendra
authors.initials: M
authors.lastname: Damarla
authors.forename: Venkataramana K
authors.initials: VK
authors.lastname: Sidhaye
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Fraig
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002463:Cell Membrane Permeability / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D047589:Leukocyte Reduction Procedures; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010100:Oxygen