Radiation Induces Pulmonary Fibrosis by Promoting the Fibrogenic Differentiation of Alveolar Stem Cells

Abstract

The lung is a radiosensitive organ, which imposes limits on the therapeutic dose in thoracic radiotherapy. Irradiated alveolar epithelial cells promote radiation-related pneumonitis and fibrosis. However, the role of lung stem cells (LSCs) in the development of radiation-induced lung injury is still unclear. In this study, we found that both LSCs and LSC-derived type II alveolar epithelial cells (AECII) can repair radiation-induced DNA double-strand breaks, but the irradiated LSCs underwent growth arrest and cell differentiation faster than the irradiated AECII cells. Moreover, radiation drove LSCs to fibrosis as shown with the elevated levels of markers for epithelial-mesenchymal transition and myofibroblast (α-smooth muscle actin (α-SMA)) differentiation in in vitro and ex vivo studies. Increased gene expressions of connective tissue growth factor and α-SMA were found in both irradiated LSCs and alveolar cells, suggesting that radiation could induce the fibrogenic differentiation of LSCs. Irradiated LSCs showed an increase in the expression of surfactant protein C (SP-C), the AECII cell marker, and α-SMA, and irradiated AECII cells expressed SP-C and α-SMA. These results indicated that radiation induced LSCs to differentiate into myofibroblasts and AECII cells; then, AECII cells differentiated further into either myofibroblasts or type I alveolar epithelial cells (AECI). In conclusion, our results revealed that LSCs are sensitive to radiation-induced cell damage and may be involved in radiation-induced lung fibrosis.

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1

“…However, in recent years, researchers found that BMMSCs could differentiate into myo broblasts which is the key effector cell in brosis, in particular microenvironment including irradiation injury [37,38]. This brogenic differentiation phenomenon makes MSCs a potential danger to aggravate brosis stimulated by irradiation or other factors [39]. In this study, we found that X-ray irradiation suppressed the proliferation of BMMSCs in a dose-dependent manner.…”

Brahma-related gene 1 regulates the proliferation of alveolar type II epithelial cells via the JAK1/2-PI3K/AKT signaling pathway

“…Through in vitro experiments, we found that the increased number of AEC s was related to the increased proliferation ability of Brg1 gene knockdown cells. The increase in the number and function of AECIIs in lung tissue can enable the lung to repair the injury in time [50] . The results of this study can provide new targets and directions for the study and treatment of respiratory diseases such as pulmonary brosis, asthma, and acute lung injury.…”

Tolerogenic dendritic cells in radiation-induced lung injury

“…Type I alveolar epithelial cells, which lack the ability to proliferate, undergo direct necrosis or apoptosis following irradiation. Damage to type II alveolar epithelial cells can trigger excessive proliferation of fibroblasts, leading to fibrosis ( 39 – 41 ). Moreover, the abnormal proliferation of type II alveolar epithelial cells reduces the secretion of alveolar surface-active substances, resulting in decreased alveolar surface tension and causing pulmonary tissue edema and atelectasis ( 42 , 43 ).…”