The dual impact of TNFα on lung regeneration: divergent effects on epithelial cells and fibroblasts

Chronic obstructive pulmonary disease (COPD) is marked by persistent inflammation. Paradoxically, inflammation is required for epithelial repair, yet chronic inflammation in COPD is associated with emphysema and senescence. TNFα is a major cytokine in COPD pathogenesis, but how persistent inflammation triggers changes in epithelial repair remains unclear. We used transgenic mice overexpressing TNFα in alveolar type-II (AT2) cells. To assess regenerative capacity, we cultured lung epithelial cells and fibroblasts from TNFα+ and wild-type (WT) mice in organoid cultures. RNA-seq was performed on epithelial cells and fibroblasts to elucidate underlying mechanisms. TNFα+ mice showed emphysema, fibrosis, and immune cell infiltration. Epithelial cells from TNFα+ mice displayed enhanced organoid growth, suggesting increased regenerative potential. In contrast, lung fibroblasts from TNFα+ mice failed to support organoid formation in combination with Epcam+ cells from either WT or TNFα+ mice. Transcriptomic analysis further revealed that TNFα+ Epcam+ cells upregulated several inflammatory pathways, whereas fibroblasts from TNFα+ mice showed a reduction in expression of factors such as Wnts and FGFs, and a shift towards a pro-fibrotic myofibroblast phenotype. Our findings suggest that TNFα overexpression in AT2 cells promotes epithelial progenitor survival <italic>in vitro</italic> but has negative effects on the mesenchymal support, explaining emphysema development <italic>in vivo</italic>. This indicates that TNFα-driven inflammation shifts from supportive to detrimental depending on the cellular context and highlights the resilience of epithelial cells, yet the vulnerability of fibroblasts in response to chronic inflammation.