Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.

The lung has raised significant concerns because of its radiosensitivity. Radiation-induced lung injury (RILI) has a serious impact on the quality of patients\' lives and limits the effect of radiotherapy on chest tumors. In clinical practice, effective drug intervention for RILI remains to be fully elucidated. Therefore, an in-depth understanding of the biological characteristics is essential to reveal the mechanisms underlying the complex biological processes and discover novel therapeutic targets in RILI. In this study, Wistar rats received 0, 10, 20 or 35 Gy whole-thorax irradiation (WTI). Lung and plasma samples were collected within 5 days post-irradiation. Then, these samples were processed using liquid chromatography-mass spectrometry (LC-MS). A panel of potential plasma metabolic markers was selected by correlation analysis between the lung tissue and plasma metabolic features, followed by the evaluation of radiation injury levels within 5 days following whole-thorax irradiation (WTI). In addition, the multiple metabolic dysregulations primarily involved amino acids, bile acids and lipid and fatty acid β-oxidation-related metabolites, implying disturbances in the urea cycle, intestinal flora metabolism and mitochondrial dysfunction. In particular, the accumulation of long-chain acylcarnitines (ACs) was observed as early as 2 d post-WTI by dynamic plasma metabolic data analysis. Our findings indicate that plasma metabolic markers have the potential for RILI assessment. These results reveal metabolic characteristics following WTI and provide new insights into therapeutic interventions for RILI.

The biological roles of epithelial-mesenchymal transition (EMT) in the pathogenesis of radiation-induced lung injury (RILI) have been widely demonstrated, but the mechanisms involved have been incompletely elucidated. N6 -methyladenosine (m6 A) modification, the most abundant reversible methylation modification in eukaryotic mRNAs, plays vital roles in multiple biological processes. Whether and how m6 A modification participates in ionizing radiation (IR)-induced EMT and RILI remain unclear. Here, significantly increased m6 A levels upon IR-induced EMT are detected both in vivo and in vitro. Furthermore, upregulated methyltransferase-like 3 (METTL3) expression and downregulated α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5) expression are detected. In addition, blocking METTL3-mediated m6 A modification suppresses IR-induced EMT both in vivo and in vitro. Mechanistically, forkhead box O1 (FOXO1) is identified as a key target of METTL3 by a methylated RNA immunoprecipitation (MeRIP) assay. FOXO1 expression is downregulated by METTL3-mediated mRNA m6 A modification in a YTH-domain family 2 (YTHDF2)-dependent manner, which subsequently activates the AKT and ERK signaling pathways. Overall, the present study shows that IR-responsive METTL3 is involved in IR-induced EMT, probably by activating the AKT and ERK signaling pathways via YTHDF2-dependent FOXO1 m6 A modification, which may be a novel mechanism involved in the occurrence and development of RILI.

Radiotherapy (RT) is an effective treatment option for multiple thoracic malignant tumors, including lung cancers, thymic cancers, and tracheal cancers. Radiation-induced lung injury (RILI) is a serious complication of radiotherapy. Radiation causes damage to the pulmonary cells and tissues. Multiple factors contribute to the progression of Radiation-induced lung injury, including genetic alterations, oxidative stress, and inflammatory responses. Especially, radiation sources contribute to oxidative stress occurrence by direct excitation and ionization of water molecules, which leads to the decomposition of water molecules and the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS). Subsequently, reactive oxygen species and reactive nitrogen species overproduction can induce oxidative DNA damage. Immune cells and multiple signaling molecules play a major role in the entire process. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple differentiation potentials, which are under investigation to treat radiation-induced lung injury. Mesenchymal stem cells can protect normal pulmonary cells from injury by targeting multiple signaling molecules to regulate immune cells and to control balance between antioxidants and prooxidants, thereby inhibiting inflammation and fibrosis. Genetically modified mesenchymal stem cells can improve the natural function of mesenchymal stem cells, including cellular survival, tissue regeneration, and homing. These reprogrammed mesenchymal stem cells can produce the desired products, including cytokines, receptors, and enzymes, which can contribute to further advances in the therapeutic application of mesenchymal stem cells. Here, we review the molecular mechanisms of radiation-induced lung injury and discuss the potential of Mesenchymal stem cells for the prevention and treatment of radiation-induced lung injury. Clarification of these key issues will make mesenchymal stem cells a more fantastic novel therapeutic strategy for radiation-induced lung injury in clinics, and the readers can have a comprehensive understanding in this fields.

[This corrects the article DOI: 10.3389/fimmu.2022.875152.].

UNASSIGNED: Radiation-induced lung injury (RILI) occurs after chest radiation therapy, which ranges from acute radiation pneumonia to subsequent radiation pulmonary fibrosis. However, they are difficult to predict. The study aimed to examine the predictive utility of serum levels of transforming growth factor-beta (TGF-β) for radiation-induced lung injury.
UNASSIGNED: This single-center prospective observational study enrolled 21 patients with locally advanced lung cancer who underwent chest radiation therapy. We measured the serum levels of TGF-β, Krebs von Denlungen-6, and granulocyte colony-stimulating factor (GCSF) eight times immediately before irradiation.
UNASSIGNED: Seven, four, eight, and one patient had Grade 0, 1, 2, and 3 radiation-induced lung injury, respectively. Compared with the Grade 0 and 1 RILI groups (RP- group), the Grade 2 and 3 RILI groups (RP+ group) had a significantly higher relative ratio of TGF-β values from immediately before irradiation to the time of 30-48 Gy irradiation (P=0.011). The cut-off value of the TGF-β relative ratio of the RP+ group measured from the receiver operating characteristic curve was 1.31; moreover, the sensitivity, specificity, and positive predictive value were 75%, 100%, and 75%, respectively. There was no significant between-group difference in the levels of the other cytokines.
UNASSIGNED: For patients undergoing radiation therapy for locally advanced lung cancer, the ratio of TGF-β levels before and after 30-48 Gy irradiation may predict the onset of RILI. Our findings may facilitate the identification of predictors of the onset of radiation-induced lung injury.

UNASSIGNED: Persistent inflammation and immune activation in the lungs are associated with adverse outcomes such as radiation pneumonitis (RP) and poor survival in non-small-cell lung cancer (NSCLC) patients. However, it is unknown how this is reflected by leukocyte activation markers in serum.
UNASSIGNED: The aim was to evaluate the serum levels of activation of different leukocyte subsets and to examine those in relation to the pathogenesis of RP and survival in NSCLC.
UNASSIGNED: We analyzed the serum levels of MPO, sCD25, sTIM-3, sPD-L1, sCD14, sCD163, CCL19 and CCL21 in 66 inoperable NSCLC patients with stage IA-IIIA disease. The patients were treated with stereotactic body radiation therapy (SBRT) or concurrent chemoradiation therapy (CCRT), followed by regular blood sampling for 12 months after treatment and for 5 years for survival.
UNASSIGNED: Nineteen (29%) patients developed RP, which occurred more frequently and earlier in patients receiving CCRT than in those receiving SBRT. Increases in sCD25, sTIM-3 and CCL21 levels were observed at the last 6 months of follow-up in patients who had RP after SBRT. Patients who had RP after CCRT had higher sTIM-3 levels during the first 3 months of follow-up. Baseline sCD25 was independently associated with both 2- and 5-year mortality outcomes, while baseline sTIM-3 was independently associated with 2-year mortality.
UNASSIGNED: We showed that T cell activation and exhaustion markers such as sCD25 and sTIM-3 are enhanced in patients developing RP and are associated with poor survival in NSCLC.

UNASSIGNED: Radiation-induced lung injury (RILI) is often found in thoracic tumor patients after thoracic radiation therapy, and influences patient quality of life. However, systematic exploration of RILI, including its molecular biological mechanisms and standardized treatment, has not yet been fully elucidated. The main objective of the narrative review was to describe the available evidence concerning RILI, from the biological mechanism to the clinical management. The underlying causes of RILI are multifactorial, including gene-level changes, the influence of signaling pathways, the convergence of various cells, as well as the expression of cytokines and chemokines. Based on the various mechanisms of RILI, several novel treatment strategies have been proposed and gradually applied in clinical practice.
UNASSIGNED: PubMed was used to collect articles about RILI from 1995 to 2021. The papers included clinical trials, reviews, as well as systematic reviews and meta-analyses. Based on the mechanism, diagnosis, and treatment, we synthesized and analyzed these papers to form a clearly logical and normative suggestion to guide clinical application.
UNASSIGNED: RILI is a constantly developing and changing process including radiation pneumonitis and radiation lung fibrosis. Different kinds of inflammatory and immune cells such as macrophages, fibroblasts, and T cells play key roles in the development of RILI, and transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-13, and interferon-γ (IFN-γ) are also participants in this process. At present, glucocorticoids are mainly therapeutic drugs for the early stage of RILI, and drugs treatment should abide early period, sufficient doses, and the individual principles. Other novel drugs such as Azithromycin also have been tried in clinical application. radiation dose, combination therapy modality, the condition of the tumor, and the age and underlying conditions of patients all effect the occurrence of RILI. Importantly, RILI has a relatively higher incidence in patients who received radiotherapy combined with other treatments, especially immunotherapy.
UNASSIGNED: The occurrence of RILI after radiotherapy will greatly affect the prognosis and quality of life of patients. In clinical practice, early intervention, active treatment, and more effective therapeutic drugs should be found.

BACKGROUND: To investigate the enhancement of autophagy by ulinastatin for protecting against radiation-induced lung injury (RILI) in mice.
METHODS: Forty C57BL/6 mice were equally divided into (I) control (C), (II) irradiation (R), (III) ulinastatin (U), (IV) 3-methyladenine (3-MA) (M), and (V) ulinastatin plus 3-MA (U+M) groups. Three mice in each group were infected with adeno-associated virus (AAV) carrying green fluorescent protein (GFP)-1A/1B-light chain 3 (GFP-LC3) in the lung for the marker of autophagy. All mice in R, U, M and U+M groups were given chest irradiation (1 Gy/min, 12 min), following injection with normal saline in C and U groups, ulinastatin (500,000 IU/kg·d, i.p., 7 d) in U group, 3-MA (10 mg/kg·d, i.p., 7 d) in M group, and ulinastatin plus 3-MA in U+M group. The effects of ulinastatin on lung injury and autophagy were evaluated by electron microscope (EM), immunohistochemistry, mRNA expression levels of collagen alpha-1 (COL1A1), collagen alpha-2 (COL1A2), α-smooth muscle actin (α-SMA) and transforming growth factor β1 (TGF-β1), and protein levels of LC3, α-SMA, COL1A2, TGF-β1, matrix metalloproteinase-2 (MMP-2) and MMP-9.
RESULTS: EM observation revealed that the radiation caused the injury of type I and II alveolar epithelial cells, which was improved by ulinastatin treatment associated with increased the numbers of autophagosomes. GFP-LC3 signals was significantly enhanced by ulinastatin detected by immune histochemical tests. At transcriptional and/or translational levels, ulinastatin significantly enhanced the expression levels of TGF-β1 and LC3 but reduced COL1A1, COL1A2, α-SMA, MMP-2 and MMP-9 after radiation-induced RILI.
CONCLUSIONS: Ulinastatin reduces RILI by enhancing autophagy, which might be a potential therapeutic drug in the protection against RILI.

BACKGROUND: Radiation-induced lung injury (RILI) often occurs in patients with non-small cell lung cancer (NSCLC) after radiotherapy, and the prognosis of patients with RILI is usually poor. This work plan to investigate the expression patterns of microRNA-21(miR-21) in NSCLC patients with RILI and the protective effects of miR-21 over-expressed bone marrow mesenchymal stem cells (BMSCs) against RILI in rat model.
METHODS: MiR-21 expressions were determined in both serum samples and bronchoalveolar lavage fluid (BALF) samples from NSCLC patients after radiation therapy. The correlation between miR-21 expression and the follow-up clinical characterizations were determined. Further, miR-21 over-expressed BMSCs were transplanted into RILI rats and the protective effects were evaluated. BMSCs and alveolar macrophages (AMs) were co-cultured in vitro and the macrophage M1 polarization markers were determined by ELISA and qRT-PCR assays.
RESULTS: Expression of miR-21 was significantly increased in NSCLC patients with RILI compared with control group, especially before or at 4 weeks after radiation therapy commenced. The miR-21 levels were highly correlated with IL-12, TNF-α, and IL-6 expressions and the severity of RILI. Animal based experiments demonstrated that BMSCs treatment had a remarkable effect on alleviating alveolitis in RILI rats, and miR-21 over-expression could enhance this effect significantly. Cell based experiments demonstrated that BMSCs notably inhibited M1 polarization of AMs and this inhibition is in a miR-21 dependent manner.
CONCLUSIONS: These results indicated that BMSCs could blocked the proinflammatory pathway of macrophage through miR-21 over-expression, thus could be a potential therapeutic strategy for RILI.