Molecular mechanisms and treatment of radiation-induced lung fibrosis

Abstract

Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients.

Fig. (1)

Numerous cell types are involved in RILF. Irradiation causes delayed damage to resident lung cells, leading primarily to the injury and apoptosis of bronchiolar epithelial cells. Via EMT, injured epithelial cells provide a source of myofibroblasts, which produce collagens (especially types I and III), fibronectins and other matrix molecules. Myofibroblasts can originate from resident fibroblasts and circulating fibroblast-like cells called fibrocytes, which are derived from bone marrow stem cells. The alveolar type II epithelial cells (AE2) in patients with RILF express high levels of EMT-associated protein markers, suggesting that the AE2 cells had acquired a mesenchymal phenotype. After lung injury, AE2 cells can convert to alveolar type I epithelial cells to re-establish a functional alveolar epithelium. Thorax irradiation can also trigger the recruitment of various immune cells into the lung, such as monocytic cells, neutrophils, basophils and lymphocytes, which are associated with the characteristic changes in the local and systemic expression of cytokines and chemokines.

Fig. (2)

Signaling pathways in RILF. Irradiation induces TGF-β expression. Ligand binding to TGF-β activates type II TGF-β receptor serine/threonine kinases. TGF-β stimulation results in the induction of Smad proteins, which are transcription factors that also induce other transcription factors, including Slug, Snail, Scatter, lymphoid enhancing factor-1, and β-catenin. FoxM1 binds to and increases the promoter activity of the Snail1 gene. NRF2 binding to a Smad Binding Element (SBE) suppresses TGF-β target gene expression. TGF-β1 also activates non-Smad-mediated signaling pathways, which are associated with occludin at tight junctions, to phosphorylate Par6. Phosphorylated Par6 recruits Smurf1, resulting in the ubiquitination and degradation of RhoA, which is responsible for stress fiber formation and the maintenance of apical-basal polarity and junctional stability. Radiation activates the MEK/ERK signaling pathway by increasing ROS generation. Activated ERK1/2 phosphorylates GSK3β, resulting in its inactivation and leading to the disassociation of GSK3β and Snail. Unbound Snail then migrates to the nucleus and represses E-cadherin, leading to a mesenchymal-like phenotypic change.