title: Absence of TNF-α enhances inflammatory response in the newborn lung undergoing mechanical ventilation.
abstract: Bronchopulmonary dysplasia (BPD), characterized by impaired alveolarization and vascularization in association with lung inflammation and apoptosis, often occurs after mechanical ventilation with oxygen-rich gas (MV-O2). As heightened expression of the proinflammatory cytokine TNF-α has been described in infants with BPD, we hypothesized that absence of TNF-α would reduce pulmonary inflammation, and attenuate structural changes in newborn mice undergoing MV-O2 Neonatal TNF-α null (TNF-α(-/-)) and wild type (TNF-α(+/+)) mice received MV-O2 for 8 h; controls spontaneously breathed 40% O2 Histologic, mRNA, and protein analysis in vivo were complemented by in vitro studies subjecting primary pulmonary myofibroblasts to mechanical stretch. Finally, TNF-α level in tracheal aspirates from preterm infants were determined by ELISA. Although MV-O2 induced larger and fewer alveoli in both, TNF-α(-/-) and TNF-α(+/+) mice, it caused enhanced lung apoptosis (TUNEL, caspase-3/-6/-8), infiltration of macrophages and neutrophils, and proinflammatory mediator expression (IL-1β, CXCL-1, MCP-1) in TNF-α(-/-) mice. These differences were associated with increased pulmonary transforming growth factor-β (TGF-β) signaling, decreased TGF-β inhibitor SMAD-7 expression, and reduced pulmonary NF-κB activity in ventilated TNF-α(-/-) mice. Preterm infants who went on to develop BPD showed significantly lower TNF-α levels at birth. Our results suggest a critical balance between TNF-α and TGF-β signaling in the developing lung, and underscore the critical importance of these key pathways in the pathogenesis of BPD. Future treatment strategies need to weigh the potential benefits of inhibiting pathologic cytokine expression against the potential of altering key developmental pathways.
authors.affiliation: Department of General Pediatrics and Neonatology, University Hospital of Giessen and Marburg, Giessen, Germany;
authors.forename: Harald
authors.initials: H
authors.lastname: Ehrhardt
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, Munich, Germany;
authors.forename: Tina
authors.initials: T
authors.lastname: Pritzke
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, Munich, Germany;
authors.forename: Prajakta
authors.initials: P
authors.lastname: Oak
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, Munich, Germany;
authors.forename: Melina
authors.initials: M
authors.lastname: Kossert
authors.affiliation: Department of Neonatology, Dr. von Haunersches Children's Hospital, Ludwig-Maximilians University of Munich, Munich, Germany;
authors.forename: Luisa
authors.initials: L
authors.lastname: Biebach
authors.affiliation: Department of Neonatology, Dr. von Haunersches Children's Hospital, Ludwig-Maximilians University of Munich, Munich, Germany;
authors.forename: Kai
authors.initials: K
authors.lastname: Förster
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, Munich, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Koschlig
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California.
authors.forename: Cristina M
authors.identifier: 0000-0002-6921-0001
authors.initials: CM
authors.lastname: Alvira
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum Muenchen, Munich, Germany; Department of Neonatology, Dr. von Haunersches Children's Hospital, Ludwig-Maximilians University of Munich, Munich, Germany; anne.hilgendorff@med.uni-muenchen.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Hilgendorff
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012121:Respiration, Artificial; D014132:Trachea / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: TGF-β; TNF-α; apoptosis; bronchopulmonary dysplasia; lung; mechanical ventilation; neonatal chronic lung disease; newborn mice; tumor necrosis factor