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Ehrhardt, Harald; Pritzke, Tina; Oak, Prajakta; Kossert, Melina; Biebach, Luisa; Förster, Kai; Koschlig, Markus; Alvira, Cristina M.; Hilgendorff, Anne (2016): Absence of TNF-alpha enhances inflammatory response in the newborn lung undergoing mechanical ventilation. In: American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol. 310, No. 10: L909-L918
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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-O-2). As heightened expression of the proinflammatory cytokine TNF-alpha has been described in infants with BPD, we hypothesized that absence of TNF-alpha would reduce pulmonary inflammation, and attenuate structural changes in newborn mice undergoing MV-O-2. Neonatal TNF-alpha null (TNF-alpha(-/-)) and wild type (TNF-alpha(+/+)) mice received MV-O-2 for 8 h;controls spontaneously breathed 40% O-2. Histologic, mRNA, and protein analysis in vivo were complemented by in vitro studies subjecting primary pulmonary myofibroblasts to mechanical stretch. Finally, TNF-alpha level in tracheal aspirates from preterm infants were determined by ELISA. Although MV-O-2 induced larger and fewer alveoli in both, TNF-alpha(-/-) and TNF-alpha(+/+) mice, it caused enhanced lung apoptosis (TUNEL, caspase-3/-6/-8), infiltration of macrophages and neutrophils, and proinflammatory mediator expression (IL-1 beta, CXCL-1, MCP-1) in TNF-alpha(-/-) mice. These differences were associated with increased pulmonary transforming growth factor-alpha (TGF-alpha) signaling, decreased TGF-beta inhibitor SMAD-7 expression, and reduced pulmonary NF-kappa B activity in ventilated TNF-alpha(-/-) mice. Preterm infants who went on to develop BPD showed significantly lower TNF-alpha levels at birth. Our results suggest a critical balance between TNF-alpha and TGF-beta 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.