Mesenchyme-derived inflammation during the saccular stage recruits macrophages and alters lung development

Fibroblasts in the lung mesenchyme produce growth factors and extracellular matrix components that guide formation of distal airspaces during the saccular stage of lung development. Inflammation in preterm infants disrupts this process, leading to bronchopulmonary dysplasia (BPD). To examine how mesenchymal inflammation contributes to BPD pathogenesis, we developed a transgenic mouse model (IKKβTbx4) in which expression of activated human IκB kinase β (IKKβ), an upstream activator of NF-κB, was induced in Tbx4 lung enhancer-positive mesenchymal cells during the saccular stage of lung development (P0-P5). Saccular-stage IKKβTbx4 mice exhibited a BPD-like phenotype with interstitial thickening and reduced distal airspaces at P5, progressing to emphysematous enlargement of the distal lung at 2 months of age. Mesenchymal NF-κB activity upregulated the chemokines CCL2 and CCL7, recruiting CCR2pos monocyte-derived macrophages to the lung. Recruited macrophages disrupted the elastin scaffold and impaired microvascular organization with reductions in CAP2 endothelial cells and pericytes. Blocking CCR2-dependent monocyte recruitment with a small-molecule CCR2 antagonist rescued the abnormal lung phenotype. These findings identify mesenchyme-macrophage crosstalk as a mechanism by which inflammation disrupts saccular-stage lung development, suggesting a role for this signaling axis in BPD pathogenesis.