IFN-γ and TNF-α Impair Lung Development by Upregulating SMAD7 to Inhibit TGF-β Signaling Pathway and ECM Dysregulation

Abstract Inflammation plays a pivotal role in neonatal lung injury and is closely associated with the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants, although the underlying molecular mechanisms remain incompletely understood. Our study detected elevated serum levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in preterm neonates as early as postnatal day 1 among those who later developed moderate-to-severe BPD. In pulmonary fibroblasts, co-treatment with IFN-γ and TNF-α significantly downregulated α-smooth muscle actin (α-SMA) and disrupted extracellular matrix (ECM) homeostasis, evidenced by reduced collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and elastin expression, but elevated fibronectin 1 (FN1) and matrix metalloproteinase-1. Furthermore, dual-cytokine exposure attenuated SMAD2/3 phosphorylation and nuclear translocation, while upregulating SMAD7. Parallel experiments using E16.5 fetal rat lung explants recapitulated these changes, showing decreased COL1A1, elevated SMAD7, and BPD-like histopathological alterations, including alveolar simplification and enlarged airspaces. Mechanistically, IFN-γ and TNF-α synergistically promoted SMAD7 overexpression, which competitively bound to SMAD2/3 and suppressed TGF-β signaling, ultimately leading to ECM dysregulation. These data delineate a novel inflammatory axis impairing lung development, highlighting SMAD7 and TGF-β pathways as promising intervention targets.