Pulmonary fibroblasts activated by the addition of TNF-α and IL-4 enhance lymphangiogenic capacity and ameliorate lung fibrosis in an allogeneic rat model

BACKGROUND: Pulmonary fibrosis remains a major clinical challenge with limited treatment options. Recent studies have suggested that fibroblasts, when stimulated by specific cytokines, may acquire lymphangiogenic and antifibrotic properties contributing to tissue repair. METHODS: Human and rat pulmonary fibroblasts (PFs) were stimulated with TNF-α and IL-4 to induce lymphangiogenic and antifibrotic characteristics. In vitro analyses assessed gene expression, cytokine secretion, tube formation capacity, and immunogenicity. Therapeutic efficacy was evaluated in a rat model of bleomycin-induced pulmonary fibrosis following allogeneic PF transplantation. RESULTS: Cytokine-stimulated PFs exhibited upregulation of ADM and VEGFC, enhanced tube formation capacity, and minimal expression of immunogenic markers. In vivo, allogeneic PF transplantation significantly reduced fibrotic lesion and plasma SP-D levels compared to controls. Gene expression analyses demonstrated downregulation of fibrosis-associated markers after treatment. CONCLUSION: Cytokine-stimulated pulmonary fibroblasts may serve as a novel cell source for antifibrotic therapy by modulating lymphangiogenesis and tissue remodeling, providing a potential alternative to conventional stem cell-based approaches for fibrotic lung diseases.