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

## TL;DR

Stimulating lung fibroblasts with TNF-α and IL-4 improves their ability to reduce lung fibrosis and promote tissue repair in rats.

## Contribution

Cytokine-stimulated fibroblasts show antifibrotic and lymphangiogenic potential as a novel cell therapy for lung fibrosis.

## Key findings

- Cytokine-stimulated fibroblasts upregulated ADM and VEGFC and formed more tubes in vitro.
- Allogeneic fibroblast treatment reduced fibrosis and SP-D levels in a rat model.
- Fibrosis-related gene markers were downregulated following treatment.

## Abstract

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.

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.

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.

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.