title: Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Regulates LPS-Induced Inflammation and Alveolar Remodeling in the Developing Lung.
abstract: In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsis-induced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2+/+and NOX2-/-mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2+/+mice was decreased by >50% in NOX2-/-mice. LPS-induced TLR4 signaling evident by inhibitor of NF-κB kinase-β and mitogen-activated protein kinase phosphorylation, and nuclear factor-κB/AP-1 translocation were attenuated in NOX2-/-mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX2+/+mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX2-/-mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2-/-mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Menden
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xia
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Mabry
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Angels
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Nyp
authors.affiliation: Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Sampath
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000254:growth & development* / Q000473:pathology; D018805:Sepsis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Toll-like receptor signaling; bronchopulmonary dysplasia; neonatal lung injury; nicotinamide adenine dinucleotide phosphate oxidase; sepsis