title: Activation of the nuclear factor-κB pathway during postnatal lung inflammation preserves alveolarization by suppressing macrophage inflammatory protein-2.
abstract: A significant portion of lung development is completed postnatally during alveolarization, rendering the immature lung vulnerable to inflammatory stimuli that can disrupt lung structure and function. Although the NF-κB pathway has well-recognized pro-inflammatory functions, novel anti-inflammatory and developmental roles for NF-κB have recently been described. Thus, to determine how NF-κB modulates alveolarization during inflammation, we exposed postnatal day 6 mice to vehicle (PBS), systemic lipopolysaccharide (LPS), or the combination of LPS and the global NF-κB pathway inhibitor BAY 11-7082 (LPS + BAY). LPS impaired alveolarization, decreased lung cell proliferation, and reduced epithelial growth factor expression. BAY exaggerated these detrimental effects of LPS, further suppressing proliferation and disrupting pulmonary angiogenesis, an essential component of alveolarization. The more severe pathology induced by LPS + BAY was associated with marked increases in lung and plasma levels of macrophage inflammatory protein-2 (MIP-2). Experiments using primary neonatal pulmonary endothelial cells (PEC) demonstrated that MIP-2 directly impaired neonatal PEC migration in vitro; and neutralization of MIP-2 in vivo preserved lung cell proliferation and pulmonary angiogenesis and prevented the more severe alveolar disruption induced by the combined treatment of LPS + BAY. Taken together, these studies demonstrate a key anti-inflammatory function of the NF-κB pathway in the early alveolar lung that functions to mitigate the detrimental effects of inflammation on pulmonary angiogenesis and alveolarization. Furthermore, these data suggest that neutralization of MIP-2 may represent a novel therapeutic target that could be beneficial in preserving lung growth in premature infants exposed to inflammatory stress.
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California;
authors.forename: Yanli
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California;
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California; Department of Biochemistry, Faculty of Medicine, University of Nevada/Reno, Reno, Nevada; and.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Husted
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California;
authors.forename: Chihhsin
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California;
authors.forename: Kavitha
authors.initials: K
authors.lastname: Thiagarajan
authors.affiliation: Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Johns
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California;
authors.forename: Shailaja P
authors.initials: SP
authors.lastname: Rao
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California; calvira@stanford.edu.
authors.forename: Cristina M
authors.identifier: http://orcid.org/0000-0002-6921-0001
authors.initials: CM
authors.lastname: Alvira
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054426:Chemokine CXCL2; D018031:Connexin 43; C404915:Cxcl2 protein, mouse; C543076:GJA1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse
keywords: angiogenesis; bronchopulmonary dysplasia; endothelial migration; proliferation