NF-κB Signaling in Fetal Lung Macrophages Disrupts Airway Morphogenesis
Year: 2011
Type: article
Abstract: Bronchopulmonary dysplasia is a common pulmonary complication of extreme prematurity. Arrested lung development leads to bronchopulmonary dysplasia, but the molecular pathways that cause this arrest are unclear. Lung injury and inflammation increase disease risk, but the cellular site of the inflammatory response and the potential role of localized inflammatory signaling in inhibiting lung morphogenesis are not known. In this study, we show that tissue macrophages present in the fetal mouse lung mediate the inflammatory response to LPS and that macrophage activation inhibits airway morphogenesis. Macrophage depletion or targeted inactivation of the NF-κB signaling pathway protected airway branching in cultured lung explants from the effects of LPS. Macrophages also appear to be the primary cellular site of IL-1β production following LPS exposure. Conversely, targeted NF-κB activation in transgenic macrophages was sufficient to inhibit airway morphogenesis. Macrophage activation in vivo inhibited expression of multiple genes critical for normal lung development, leading to thickened lung interstitium, reduced airway branching, and perinatal death. We propose that fetal lung macrophage activation contributes to bronchopulmonary dysplasia by generating a localized inflammatory response that disrupts developmental signals critical for lung formation.
Source: The Journal of Immunology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G102869925, Eunice Kennedy Shriver Intellectual and Developmental Disability Research Center, G1344704808, G150953014, G1600742463, G2019238319, G247096544, G2940777275, G3137495633, G35732448, G3722609264, G3872320933, G3886521569, G3989539122, Vanderbilt Mouse Metabolic Phenotyping Center, G4513176822, G4562270770, G5559228156, G7234576704, G725763919, G7850988048, Role of Fetal Lung Macrophages in Bronchopulmonary Dysplasia, Molecular and Cellular Basis for Digestive Diseases, Vanderbilt Diabetes Research Center, Core Grant in Vision Research
OpenAlex ID: W2167802097