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Ehrhardt, H.* ; Pritzke, T. ; Oak, P. ; Kossert, M. ; Biebach, L.* ; Forster, K.* ; Koschlig, M. ; Alvira, C.M.* ; Hilgendorff, A.

Absence of TNF-α enhances inflammatory response in the newborn lung undergoing mechanical ventilation.

Am. J. Physiol. Lung Cell Mol. Physiol. 310, L909-L918 (2016)

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RATIONALE: 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 pro-inflammatory 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 Methods: Neonatal TNF-α null (TNF-α(-/-)) and wild type (TNF-α(+/+)) mice received MV-O2for 8h; 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 (TA) from preterm infants were determined by ELISA. RESULTS: Although MV-O2induced 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 pro-inflammatory mediator expression (IL-1β, CXCL-1, MCP-1) in TNF-α(-/-)mice. These differences were associated with increased pulmonary 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. CONCLUSION: 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.

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