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.

FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy

“…The middle right lobe was collected for RNA and protein, while the remaining right lobes, cranial, caudal and accessory, were imbedded for immunostaining. Alterations in lung volume and function following PNX were assessed using the Flexivent small animal ventilator (SCIREQ) as previously described 17 . Protein extracts were used for either Western blot analysis as previously described 18 – 20 or gel zymography.…”

Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway

“…Inflammatory cells were analyzed from bleomycin-treated lungs of myFoxm1 -/and Foxm1 fl/fl mice by flow cytometry as described previously [55]. The following antibodies were used to stain inflammatory cells: anti-F4/80 (clone BM8; eBiosciences), anti-CD11b (clone M1/70; eBiosciences), anti-Ly-6C (clone HK1.4; BioLegend), anti-Ly-6G (clone 1A8; BioLegend), anti-CD68 (clone FA-11; Biolegend), anti-CD45 (clone 30-F11; BD Pharmingen), anti-CD3 (Clone 17A2; eBioscience), anti-B220 (Clone RA3-6B2; eBioscience).…”

β‐catenin and Kras/Foxm1 signaling pathway are critical to restrict Sox9 in basal cells during pulmonary branching morphogenesis

“…Expression of an activated Kras G12D in respiratory epithelial cells impaired branching lung morphogenesis, increased MAPK activity and induced expression of Sprouty-2, a Ras/ERK antagonist (Shaw et al, 2007). Foxm1 transcription factor is a key downstream target of the Kras/ERK signaling pathway and an important regulator of cellular proliferation during embryonic development, organ injury and carcinogenesis (Bolte et al, 2011(Bolte et al, , 2012Balli et al, 2012;Sengupta et al, 2013;Cheng et al, 2014;Xia et al, 2015). Kras downstream kinases, including ERK, Cdk1, and Cdk2, directly phosphorylate Foxm1 and induce its transcriptional activity (Major et al, 2004;Ma et al, 2005).…”