Epithelial cells and fibroblasts are both activated via TGF-β1 and GSK-3β pathways differentially in the comorbidity of pulmonary fibrosis with lung adenocarcinoma

Aims: Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung Cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung Cancer resection and radiotherapy, the influence of lung Cancer itself on PF remains enigmatic.

Materials and methods: We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.

Key findings: We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.

Significance: This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

EMT; GSK-3β; Lung adenocarcinoma; Myofibroblast activation; Pulmonary fibrosis; TGF-β.