The Promising Therapeutic Approaches for Radiation-Induced Pulmonary Fibrosis: Targeting Radiation-Induced Mesenchymal Transition of Alveolar Type II Epithelial Cells

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a common consequence of radiation for thoracic tumors, and is accompanied by gradual and irreversible organ failure. This severely reduces the survival rate of cancer patients, due to the serious side effects and lack of clinically effective drugs and methods. Radiation-induced pulmonary fibrosis is a dynamic process involving many complicated and varied mechanisms, of which alveolar type II epithelial (AT2) cells are one of the primary target cells, and the epithelial-mesenchymal transition (EMT) of AT2 cells is very relevant in the clinical search for effective targets. Therefore, this review summarizes several important signaling pathways that can induce EMT in AT2 cells, and searches for molecular targets with potential effects on RIPF among them, in order to provide effective therapeutic tools for the clinical prevention and treatment of RIPF.

Keywords: alveolar type II epithelial cells; epithelial–mesenchymal transition; radiation-induced pulmonary fibrosis.

Figure 1

Radiation-induced EMT. Ionizing radiation induces epithelial–mesenchymal transition in AT2 cells, which lose their tight intercellular junctions and gradually lose their epithelial phenotype, eventually allowing them to acquire a mesenchymal phenotype and differentiate into fibroblasts. Thereafter, fibroblasts proliferate and activate in large numbers, further differentiating into myofibroblasts, which secrete large amounts of extracellular matrix components, leading to excessive deposition of extracellular matrix and promoting the development of RIPF. (AT1-alveolar type I epithelial, AT2-alveolar type II epithelial, ECM-extracellular matrix, ZO-1-zonula occludens-1).

Figure 2

Signaling pathways and targets of EMT, and its therapeutic approach in RIPF. ROS, TGF-β signaling pathway, growth factors and MicroRNA are promising targets for therapeutic and developmental applications in RIPF, and their targeted inhibitors have potent inhibitory effects on IR-induced EMT in AT2 cells, respectively, inhibiting further development of RIPF. (TGF-β- Transforming growth factor β, TβR1-TGF-β type I receptor, TβR2-TGF-β type II receptor, ROS- Reactive oxygen species, RTKs- receptor tyrosine kinases, PIP2-phosphatidylinositol-4,5-biphosphate, PIP3-phosphatidylinositol triphosphate, α-SMA-α-smooth muscle actin). All arrows indicate the transduction process and protein changes in the EMT signaling pathway, and the red crosses indicate that the above inhibitors can ultimately suppress the change of EMT-related marker proteins by inhibiting the elevation of transcription factors, ultimately inhibiting IR-induced EMT in AT2.