Mesenchymal stem cells-derived exosomes alleviate radiation induced pulmonary fibrosis by inhibiting the protein kinase B/nuclear factor kappa B pathway

Abstract

BACKGROUND

Radiation induced pulmonary fibrosis (RIPF) is a long-term lung condition with a bleak outlook and few treatment possibilities. Mesenchymal stem cells (MSCs)-derived exosomes (MSCs-exosomes) possess tissue repair and regenerative properties, but their exact mechanisms in RIPF remain unclear. This study explores whether MSCs-exosomes can alleviate RIPF by modulating inflammation, extracellular matrix (ECM) accumulation, and epithelial-mesenchymal transition (EMT) via the protein kinase B (Akt)/nuclear factor kappa B (NF-κB) pathway.

AIM

To assess the therapeutic potential and mechanisms of MSCs-exosomes in RIPF.

METHODS

Sprague-Dawley rats were received 30 Gy X-ray radiation on the right chest to induce RIPF, while RLE-6TN and BEAS-2B cell lines were exposed to 10 Gy X-rays. Using differential centrifugation, MSCs-exosomes were isolated, and their protective effects were examined both in vivo and in vitro. Inflammatory cytokine concentrations were measured using Luminex liquid chip detection and enzyme linked immunosorbent assay. ECM and EMT-related proteins were analyzed using immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction. Western blotting and immunohistochemistry were also used to investigate the mechanisms underlying MSCs-exosomes’ effects in RIPF.

RESULTS

Administration of MSCs-exosomes significantly mitigated RIPF, reduced collagen deposition, and decreased levels of various inflammatory cytokines. Additionally, MSCs-exosomes prevented radiation-induced ECM accumulation and EMT. Treatment with MSCs-exosomes notably promoted cell proliferation, suppressed inflammation, and reversed ECM deposition and EMT in radiation-exposed alveolar epithelial cells. Mechanistic analysis further revealed that MSCs-exosomes exerted their anti-RIPF effects by inhibiting the Akt/NF-κB pathway, as shown in both in vivo and in vitro models.

CONCLUSION

MSCs-exosomes mitigate RIPF by suppressing inflammation, ECM deposition, and EMT through Akt/NF-κB inhibition, highlighting their potential as a therapeutic strategy.

Keywords: Mesenchymal stem cells; Exosomes; Radiation induced pulmonary fibrosis; Protein kinase B; Nuclear factor kappa B

Core Tip: Mesenchymal stem cells-derived exosomes were demonstrated protective properties against radiation induced pulmonary fibrosis in rat models and lung epithelial cell models. Moreover, these exosomes were shown to reverse the expression of key components involved in the buildup of extracellular matrix and epithelial-mesenchymal transition due to radiation by inhibiting the protein kinase B/nuclear factor kappa B pathway. This inhibition prevented fibrosis progression and facilitated the recovery and proliferation of damaged lung epithelial cells. These findings offer new insights into potential treatment strategies for radiation-induced pulmonary fibrosis.