title: Foxm1 regulates resolution of hyperoxic lung injury in newborns.
abstract: Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68(-)) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs.
authors.affiliation: 3 Division of Neonatology and Pulmonary Biology.
authors.forename: Hongping
authors.initials: H
authors.lastname: Xia
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Ren
authors.forename: Craig S
authors.initials: CS
authors.lastname: Bolte
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tushar A
authors.initials: TA
authors.lastname: Shah
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Kalin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
mesh_terms: D056151:Airway Remodeling; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism; D016022:Case-Control Studies; D056649:Cathepsin G / Q000378:metabolism; D004195:Disease Models, Animal; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D018345:Mice, Knockout; D053146:Myeloblastin / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D009195:Peroxidase; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D053146:Myeloblastin
keywords: Foxm1; bronchopulmonary dysplasia; hyperoxia; inflammation; macrophage