| First Author | Menden HL | Year | 2016 |
| Journal | Am J Respir Cell Mol Biol | Volume | 55 |
| Issue | 6 | Pages | 767-778 |
| PubMed ID | 27438994 | Mgi Jnum | J:250864 |
| Mgi Id | MGI:6101280 | Doi | 10.1165/rcmb.2016-0006OC |
| Citation | Menden HL, et al. (2016) Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Regulates LPS-Induced Inflammation and Alveolar Remodeling in the Developing Lung. Am J Respir Cell Mol Biol 55(6):767-778 |
| abstractText | 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-kappaB kinase-beta and mitogen-activated protein kinase phosphorylation, and nuclear factor-kappaB/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. |
