Search

Background: Investigations on radiation‐induced lung injury (RILI) have predominantly focused on local effects, primarily those associated with radiation damage to lung parenchyma. However, recent studies from our group and others have revealed that radiation‐induced damage to branching serial structures such as airways and vessels may also have a substantial impact on post‐radiotherapy (RT) lung function. Furthermore, recent results from multiple functional lung avoidance RT trials, although promising, have demonstrated only modest toxicity reduction, likely because they were primarily focused on dose avoidance to lung parenchyma. These observations emphasize the critical need for predictive dose‐response models that effectively incorporate both local and distant RILI effects. Purpose: We develop and validate a predictive model for ventilation loss after lung RT. This model, referred to as P+A, integrates local (parenchyma [P]) and distant (central and peripheral airways [A]) radiation‐induced damage, modeling partial (narrowing) and complete (collapse) obstruction of airways. Methods: In an IRB‐approved prospective study, pre‐RT breath‐hold CTs (BHCTs) and pre‐ and one‐year post‐RT 4DCTs were acquired from lung cancer patients treated with definitive RT. Up to 13 generations of airways were automatically segmented on the BHCTs using a research virtual bronchoscopy software. Ventilation maps derived from the 4DCT scans were utilized to quantify pre‐ and post‐RT ventilation, serving, respectively, as input data and reference standard (RS) in model validation. To predict ventilation loss solely due to parenchymal damage (referred to as P model), we used a normal tissue complication probability (NTCP) model. Our model used this NTCP‐based estimate and predicted additional loss due radiation‐induced partial or complete occlusion of individual airways, applying fluid dynamics principles and a refined version of our previously developed airway radiosensitivity model. Predictions of post‐RT ventilation were estimated in the sublobar volumes (SLVs) connected to the terminal airways. To validate the model, we conducted a k‐fold cross‐validation. Model parameters were optimized as the values that provided the lowest root mean square error (RMSE) between predicted post‐RT ventilation and the RS for all SLVs in the training data. The performance of the P+A and the P models was evaluated by comparing their respective post‐RT ventilation values with the RS predictions. Additional evaluation using various receiver operating characteristic (ROC) metrics was also performed. Results: We extracted a dataset of 560 SLVs from four enrolled patients. Our results demonstrated that the P+A model consistently outperformed the P model, exhibiting RMSEs that were nearly half as low across all patients (13 ± 3 percentile for the P+A model vs. 24 ± 3 percentile for the P model on average). Notably, the P+A model aligned closely with the RS in ventilation loss distributions per lobe, particularly in regions exposed to doses ≥13.5 Gy. The ROC analysis further supported the superior performance of the P+A model compared to the P model in sensitivity (0.98 vs. 0.07), accuracy (0.87 vs. 0.25), and balanced predictions. Conclusions: These early findings indicate that airway damage is a crucial factor in RILI that should be included in dose‐response modeling to enhance predictions of post‐RT lung function. [ABSTRACT FROM AUTHOR]

Radiation-induced lung injury (RILI) is a severe complication arising from thoracic tumor radiotherapy, which constrains the possibility of increasing radiation dosage. Current RILI therapies provide only limited relief and may result in undesirable side effects. Therefore, there is an urgent demand for effective and low-toxicity treatments for RILI. Macrophages play a pivotal role in RILI, promoting inflammation in the initial stages and facilitating fibrosis in the later stages. Sodium clodronate, a bisphosphonate, can induce macrophage apoptosis when encapsulated in liposomes. In this study, we explored the potential of liposomal sodium clodronate (LC) as a specific agent for depleting macrophages to alleviate acute RILI. We assessed the impact of LC on macrophage consumption both in vitro and in vivo. In a mouse model of acute RILI, LC treatment group led to a reduction in alveolar macrophage counts, mitigated lung injury severity, and lowered levels of pro-inflammatory cytokines in both plasma and bronchoalveolar lavage fluid. Additionally, we further elucidated the specific effects and mechanism of LC on macrophages in vitro. Alveolar macrophages MHS cells were subjected to varying concentrations of LC (0, 50, 100, 200 μg/ml), and the results demonstrated its dose-dependent inhibition of cell proliferation and induction of apoptosis. Moreover, LC decreased the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Conditioned media from LC-treated macrophages protected alveolar epithelial cells MLE-12 from radiation-induced damage, as demonstrated by reduced apoptosis and DNA damage. These findings imply that LC-mediated macrophage depletion may present a promising therapeutic strategy for alleviating radiation-induced lung injury.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury. [ABSTRACT FROM AUTHOR]

Purpose: Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy (RT) for thoracic malignancies and we currently lack established methods for the early detection of RILI. In this study, we synthesized a new tracer, [18F]AlF-NOTA-QHY-04, targeting C-X-C-chemokine-receptor-type-4 (CXCR4) and investigated its feasibility to detect RILI. Methods: An RILI rat model was constructed and scanned with [18F]AlF-NOTA-QHY-04 PET/CT and [18F]FDG PET/CT periodically after RT. Dynamic, blocking, autoradiography, and histopathological studies were performed on the day of peak uptake. Fourteen patients with radiation pneumonia, developed during or after thoracic RT, were subjected to PET scan using [18F]AlF-NOTA-QHY-04. Results: The yield of [18F]AlF-NOTA-QHY-04 was 28.5–43.2%, and the specific activity was 27–33 GBq/μmol. [18F]AlF-NOTA-QHY-04 was mainly excreted through the kidney. Significant increased [18F]AlF-NOTA-QHY-04 uptake in the irradiated lung compared with that in the normal lung in the RILI model was observed on day 6 post-RT and peaked on day 14 post-RT, whereas no apparent uptake of [18F]FDG was shown on days 7 and 15 post-RT. MicroCT imaging did not show pneumonia until 42 days post-RT. Significant intense [18F]AlF-NOTA-QHY-04 uptake was confirmed by autoradiography. Immunofluorescence staining demonstrated expression of CXCR4 was significantly increased in the irradiated lung tissue, which correlated with results obtained from hematoxylin–eosin and Masson's trichrome staining. In 14 patients with radiation pneumonia, maximum standardized uptake values (SUVmax) were significantly higher in the irradiated lung compared with those in the normal lung. SUVmax of patients with grade 2 RILI was significantly higher than that of patients with grade 1 RILI. Conclusion: This study indicated that [18F]AlF-NOTA-QHY-04 PET/CT imaging can detect RILI non-invasively and earlier than [18F]FDG PET/CT in a rat model. Clinical studies verified its feasibility, suggesting the clinical potential of [18F]AlF-NOTA-QHY-04 as a PET/CT tracer for early monitoring of RILI. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI. Methods: Twenty-four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF-α), transforming growth factor-β (TGF-β), glutathione peroxidase (GPX4), Nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed. Results: DHA attenuated radiation-induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF-α and TGF-β after irradiation. DHA may additionally stimulate the Nrf2/HO-1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI. Conclusion: DHA modulated the Nrf2/HO-1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI. [ABSTRACT FROM AUTHOR]

The effects of residual radiation from atomic bombs have been considered to be minimal because of its low levels of external radioactivity. However, studies involving atomic bomb survivors exposed to only residual radiation in Hiroshima and Nagasaki have indicated possible adverse health effects. Thus, we investigated the biological effects of radioactive dust of manganese dioxide 56 (56MnO2), a major radioisotope formed in soil by neutron beams from a bomb. Previously, we investigated C57BL mice exposed to 56MnO2 and found pulmonary gene expression changes despite low radiation doses. In this study, we examined the effects in a radiation-sensitive strain of mice, BALB/c, and compared them with those in C57BL mice. The animals were exposed to 56MnO2 particles at two radioactivity levels and examined 3 and 65 days after exposure. The mRNA expression of pulmonary pathophysiology markers, including Aqp1, Aqp5, and Smad7, and radiation-sensitive genes, including Bax, Phlda3, and Faim3, was determined in the lungs. The radiation doses absorbed in the lungs ranged from 110 to 380 mGy; no significant difference was observed between the two strains. No exposure-related pathological changes were observed in the lungs of any group. However, the mRNA expression of Aqp1 was significantly elevated in C57BL mice but not in BALB/c mice 65 days after exposure, whereas no changes were observed in external γ-rays (2 Gy) in either strain. In contrast, Faim3, a radiation-dependently downregulated gene, was reduced by 56MnO2 exposure in BALB/c mice but not in C57BL mice. These data demonstrate that inhalation exposure to 56MnO2 affected the expression of pulmonary genes at doses <380 mGy, which is comparable to 2 Gy of external γ-irradiation, whereas the responses differed between the two mouse strains. [ABSTRACT FROM AUTHOR]

Radiation‐induced lung injury (RILI) is a common side effect in thoracic tumor patients undergoing radiotherapy. At present, there is no ideal radio‐protective agent which is widely used in RILI treatment. Astilbin (AST), a bioactive flavonoid, exhibits various biological effects, including anti‐inflammatory, antioxidant, and anti‐fibrotic activities, which partly result from reducing oxidative stress and inflammation in various pathogenic conditions. However, the protective efficacy of AST to ameliorate RILI has not been reported. In this study, we employed network pharmacology, RNA sequencing, and experimental evaluation to reveal the effects and pharmacological mechanism of AST to treat RILI in vivo and in vitro. We observed that AST reduced radiation‐induced apoptosis, DNA damage, inflammatory reactions, and the reactive oxygen species (ROS) level in human normal lung epithelial cells BEAS‐2B. Further study showed that AST treatment significantly ameliorated RILI by reducing the radiation‐induced pathology changes and inflammatory reaction of lung tissue in C57BL/6J mice. Mechanistically, the expression of epithelial‐mesenchymal transition (EMT) markers and radiation‐triggered acetylation of the p53 protein were alleviated by AST treatment. Furthermore, AST alleviated the acetylation of p53 after intervention of Trichostatin A (TSA). Our data indicate that AST can alleviate RILI by inhibiting inflammatory reactions and the EMT process through decreasing the expression of p53 acetylation. In conclusion, our study suggests that AST has great potential to be a new protective and therapeutic compound for RILI. [ABSTRACT FROM AUTHOR]

To investigate the effect of adipose-derived stem cells (ASCs) transplantation on radiation-induced lung injury (RILI), Sprague-Dawley rats were divided into phosphate-buffered saline (PBS) group, ASCs group, Radiation + PBS group, and Radiation + ASCs group. Radiation + PBS and Radiation + ASCs groups received single dose of 30 Gy X-ray radiation to the right chest. The Radiation + PBS group received 1 mL PBS suspension and Radiation + ASCs group received 1 mL PBS suspension containing 1 × 107 CM-Dil-labeled ASCs. The right lung tissue was collected on Days 30, 90, and 180 after radiation. Hematoxylin–eosin and Masson staining were performed to observe the pathological changes and collagen fiber content in the lung tissue. Immunohistochemistry (IHC) and western blot (WB) were used to detect levels of fibrotic markers collagen I (Collal), fibronectin (FN), as well as transforming growth factor-β1 (TGF-β1), p-Smad 3, and Smad 3. Compared with the non-radiation groups, the radiation groups showed lymphocyte infiltration on Day 30 after irradiation and thickened incomplete alveolar walls, collagen deposition, and fibroplasia on Days 90 and 180. ASCs relieved these changes on Day 180 (Masson staining, P = 0.0022). Compared with Radiation + PBS group, on Day 180 after irradiation, the Radiation + ASCs group showed that ASCs could significantly decrease the expressions of fibrosis markers Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) and inhibit the expressions of TGF-β1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) in radiation-induced injured lung tissue. These indicated that ASCs could relieve RILI by inhibiting TGF-β1/Smad 3 signaling pathway.

Abstract Background Radiation-induced lung injury (RILI) is a prevalent complication of thoracic radiotherapy in cancer patients. A comprehensive understanding of the underlying mechanisms of RILI is essential for the development of effective prevention and treatment strategies. Methods To investigate RILI, we utilized a mouse model that received 12.5 Gy whole-thoracic irradiation. The evaluation of RILI was performed using a combination of quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), histology, western blot, immunohistochemistry, RNA sequencing, and flow cytometry. Additionally, we established a co-culture system consisting of macrophages, lung epithelial cells, and fibroblasts for in vitro studies. In this system, lung epithelial cells were irradiated with a dose of 4 Gy, and we employed STING knockout macrophages. Translational examinations were conducted to explore the relationship between STING expression in pre-radiotherapy lung tissues, dynamic changes in circulating CCL2, and the development of RILI. Results Our findings revealed significant activation of the cGAS-STING pathway and M1 polarization of macrophages in the lungs of irradiated mice. In vitro studies demonstrated that the deficiency of cGAS-STING signaling led to impaired macrophage polarization and RILI. Through RNA sequencing, cytokine profiling, and rescue experiments using a CCL2 inhibitor called Bindarit, we identified the involvement of CCL2 in the regulation of macrophage polarization and the development of RILI. Moreover, translational investigations using patient samples collected before and after thoracic radiotherapy provided additional evidence supporting the association between cGAS-STING signaling activity, CCL2 upregulation, and the development of radiation pneumonitis. Conclusions The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI.

Abstract Background To compare the severity of radiation-induced lung injury (RILI) after the right lung of SD rats received interstitial brachytherapy and stereotactic radiotherapy (SBRT). Methods RILI rat model was established using interstitial brachytherapy and SBRT methods, respectively. CT scan was performed to analyze the lung volume and the CT value difference between the left and right lungs in rats. Then the lung tissues were analyzed through H&E staining, peripheral blood was extracted to detect the expression levels of serum inflammatory cytokines, pro-fibrotic cytokines, and fibrotic-inhibiting cytokines by ELISA. Results The difference between right and left lung CT values was significantly elevated in the SBRT group when compared with the control group and the interstitial brachytherapy group (P

Radiation therapy is one of the main treatment methods for patients with thoracic malignant tumors, which can effectively improve the survival rate of the patients. However, radiation therapy can also cause damage to normal tissues while treating tumors, leading to radiation-induced lung injury such as radiation pneumonia and pulmonary fibrosis. Radiation-induced lung injury is a complex pathophysiological process involving many factors, and its prevention and treatment is one of the difficult problems in the field of radiation medicine. Therefore, the search for sensitive predictors of radiation-induced lung injury can guide clinical radiotherapy and reduce the incidence of radiation-induced lung injury. With the in-depth study of intestinal flora, it can drive immune cells or metabolites to reach lung tissue through the circulatory system to play a role, and participate in the occurrence, development and treatment of lung diseases. At present, there are few studies on intestinal flora and radiation-induced lung injury. Therefore, this paper will comprehensively elaborate the interaction between intestinal flora and radiation-induced lung injury, so as to provide a new direction and strategy for studying the protective effect of intestinal flora on radiation-induced lung injury.

Nan Zhang,1,&ast; Gui-yuan Song,2,3,&ast; Yong-jian Hu,4 Xia Wang,4 Tian-zhu Chao,1 Yao-yao Wu,1 Ping Xu1 1School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, 277160, People’s Republic of China; 2School of Public Health, Weifang Medical University, Weifang, Shandong, 261000, People’s Republic of China; 3Radiology Laboratory, Central Laboratory, Rizhao People’s Hospital, Rizhao, Shandong, 276800, People’s Republic of China; 4Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Xu, Tel +86 19863349848, Email 13273730271@163.comBackground: Radiation-induced lung injury (RILI) is a critical factor that leads to pulmonary fibrosis and other diseases. LncRNAs and miRNAs contribute to normal tissue damage caused by ionizing radiation. Troxerutin offers protection against radiation; however, its underlying mechanism remains largely undetermined.Methods: We established a model of RILI in mice pretreated with troxerutin. The lung tissue was extracted for RNA sequencing, and an RNA library was constructed. Next, we estimated the target miRNAs of differentially expressed (DE) lncRNAs, and the target mRNAs of DE miRNAs. Then, functional annotations of these target mRNAs were performed using GO and KEGG.Results: Compared to the control group, 150 lncRNA, 43 miRNA, and 184 mRNA were significantly up-regulated, whereas, 189 lncRNA, 15 miRNA, and 146 mRNA were markedly down-regulated following troxerutin pretreatment. Our results revealed that the Wnt, cAMP, and tumor-related signaling pathways played an essential role in RILI prevention via troxerutin using lncRNA-miRNA-mRNA network.Conclusion: These evidences revealed that the abnormal regulation of RNA potentially leads to pulmonary fibrosis. Therefore, targeting lncRNA and miRNA, along with a closer examination of competitive endogenous RNA (ceRNA) networks are of great significance to the identification of troxerutin targets that can protect against RILI.Keywords: troxerutin, radiation-induced lung injury, ceRNA, lncRNA-miRNA-mRNA network, AKT, wnt signal pathway

Radiation therapy using conventional or newer high-precision dose techniques, including three-dimensional conformal radiotherapy, intensity-modulated radiation therapy, stereotactic body radiation therapy, four-dimensional conformational radiotherapy, and proton therapy, is an important component of treating patients with lung cancer. Knowledge of the radiation technique used and the expected temporal evolution of radiation-induced lung injury, as well as patient-specific parameters such as previous radiotherapy, concurrent chemoradiotherapy, or immunotherapy, is important in image interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations, as well as the differences between conventional and high-precision dose radiotherapy techniques. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) is a prevalent complication of thoracic radiotherapy in cancer patients. A comprehensive understanding of the underlying mechanisms of RILI is essential for the development of effective prevention and treatment strategies. Methods: To investigate RILI, we utilized a mouse model that received 12.5 Gy whole-thoracic irradiation. The evaluation of RILI was performed using a combination of quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), histology, western blot, immunohistochemistry, RNA sequencing, and flow cytometry. Additionally, we established a co-culture system consisting of macrophages, lung epithelial cells, and fibroblasts for in vitro studies. In this system, lung epithelial cells were irradiated with a dose of 4 Gy, and we employed STING knockout macrophages. Translational examinations were conducted to explore the relationship between STING expression in pre-radiotherapy lung tissues, dynamic changes in circulating CCL2, and the development of RILI. Results: Our findings revealed significant activation of the cGAS-STING pathway and M1 polarization of macrophages in the lungs of irradiated mice. In vitro studies demonstrated that the deficiency of cGAS-STING signaling led to impaired macrophage polarization and RILI. Through RNA sequencing, cytokine profiling, and rescue experiments using a CCL2 inhibitor called Bindarit, we identified the involvement of CCL2 in the regulation of macrophage polarization and the development of RILI. Moreover, translational investigations using patient samples collected before and after thoracic radiotherapy provided additional evidence supporting the association between cGAS-STING signaling activity, CCL2 upregulation, and the development of radiation pneumonitis. Conclusions: The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI. [ABSTRACT FROM AUTHOR]

Abstract Background Interstitial lung diseases (ILDs) can be induced and even exacerbated by radiotherapy in thoracic cancer patients. The roles of immune responses underlying the development of these severe lung injuries are still obscure and need to be investigated. Methods A severe lung damage murine model was established by delivering 16 Gy X-rays to the chest of mice that had been pre-treated with bleomycin (BLM) and thus hold ILDs. Bioinformatic analyses were performed on the GEO datasets of radiation-induced lung injury (RILI) and BLM-induced pulmonary fibrosis (BIPF), and RNA-sequencing data of the severely damaged lung tissues. The screened differentially expressed genes (DEGs) were verified in lung epithelial cell lines by qRT-PCR assay. The injured lung tissue pathology was analyzed with H&E and Masson’s staining, and immunohistochemistry staining. The macrophage chemotaxis and activity promoted by the stressed epithelial cells were determined by using a cell co-culture system. The expressions of p21 in MLE-12 and Beas-2B cells were detected by qRT-PCR, western blot, and immunofluorescence. The concentration of CCL7 in cell supernatant was measured by ELISA assay. In some experiments, Beas-2B cells were transfected with p21-siRNA or CCL7-siRNA before irradiation and/or BLM treatment. Results After the treatment of irradiation and/or BLM, the inflammatory and immune responses, chemokine-mediated signaling pathways were steadily activated in the severely injured lung, and p21 was screened out by the bioinformatic analysis and further verified to be upregulated in both mouse and human lung epithelial cell lines. The expression of P21 was positively correlated with macrophage infiltration in the injured lung tissues. Co-culturing with stressed Beas-2B cells or its conditioned medium containing CCL7 protein, U937 macrophages were actively polarized to M1-phase and their migration ability was obviously increased along with the damage degree of Beas-2B cells. Furthermore, knockdown p21 reduced CCL7 expression in Beas-2B cells and then decreased the chemotaxis of co-cultured macrophages. Conclusions P21 promoted CCL7 release from the severely injured lung epithelial cell lines and contributed to the macrophage chemotaxis in vitro, which provides new insights for better understanding the inflammatory responses in lung injury.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.

Background: To compare the severity of radiation-induced lung injury (RILI) after the right lung of SD rats received interstitial brachytherapy and stereotactic radiotherapy (SBRT). Methods: RILI rat model was established using interstitial brachytherapy and SBRT methods, respectively. CT scan was performed to analyze the lung volume and the CT value difference between the left and right lungs in rats. Then the lung tissues were analyzed through H&E staining, peripheral blood was extracted to detect the expression levels of serum inflammatory cytokines, pro-fibrotic cytokines, and fibrotic-inhibiting cytokines by ELISA. Results: The difference between right and left lung CT values was significantly elevated in the SBRT group when compared with the control group and the interstitial brachytherapy group (P < 0.05). The IFN-γ expression in the interstitial brachytherapy group was significantly different from that in the SBRT group at week 1, 4, 8 and 16. Besides, the expressions of IL-2, IL-6 and IL-10 in SBRT group were significantly higher than that of interstitial brachytherapy group (P < 0.05). The TGF-β expression in interstitial brachytherapy group reached its peak with the increase of time from week 1 to week 16, and it was significantly lower than SBRT group (P < 0.05). The mortality rate in the SBRT group was 16.7%, which was significantly higher than that in the interstitial brachytherapy group. Conclusion: The treatment method of interstitial brachytherapy is considered as an effective and safe tool by reducing the side effects of radiotherapy and increasing the radiation dose of radiotherapy. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effect of Phragmitis rhizoma aqueous extract （PRE） on radiation-induced lung injury （RILI） in mice, and to explore the underlying mechanism. METHODS: A RILI model was established in C57BL/6 mice using a single dose of 15 Gy X-ray thoracic radiation, and PRE was then administered by gavage for 4 weeks. The protective effect of PRE on RILI was assessed based on the general survival status of mice and the results of pulmonary tests and HE staining. Pulmonary fibrosis was evaluated by Masson staining and hydroxyproline content detection. The mRNA expression of fibrosis-related factors collagen type I （Col-I）, collagen type III （Col-III）, α-smooth muscle actin（ α-SMA） and fibronectin was detected by RT-qPCR. Cell apoptosis was detected by TUNEL staining and cleaved caspase-3 immunohistochemistry. The serum levels of inflammatory cytokines tumor necrosis factor-α （TNF-α）, interleukin-6（ IL-6） and IL-1β were analyzed by ELISA. The levels of proteins related to NF-κB signaling pathway in lung tissues of the mice were examined by Western blot. RESULTS: Treatment with PRE attenuated RILI in mice. It also down-regulated the expression of Col-I, Col-III, α-SMA and fibronectin in lung tissues, decreased the serum levels of inflammatory cytokines（ TNF-α, IL-6 and IL-1β）, inhibited the apoptosis in lung tissues, and reduced the protein levels of p-IκBα and p-P65 in lung tissues （P<0. 05 or P<0. 01）. CONCLUSION: Treatment with PRE alleviated radiation-induced lung inflammation and fibrosis in mice, and the mechanism may be related to the suppression of NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. Methods RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1β on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. Results NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1β secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. Conclusions Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.

Abstract Background Radiation-induced lung injury (RILI) often occurs during clinical chest radiotherapy and acute irradiation from accidental nuclear leakage. This study explored the role of monophosphoryl lipid A (MPLA) in RILI. Materials and Methods The entire thoracic cavity of C57BL/6N mice was irradiated at 20 Gy with or without pre-intragastric administration of MPLA. HE staining, Masson trichrome staining, and TUNEL assay were used to assess lung tissue injury after treatment. The effect of irradiation on the proliferation of MLE-12 cells was analyzed using the Clonogenic assay. The effect of MPLA on the apoptosis of MLE-12 cells was analyzed using flow cytometry. Expression of γ-H2AX and epithelial-mesenchymal transition (EMT) markers in MLE-12 cells was detected by immunofluorescence and Western blot, respectively. Results MPLA attenuated early pneumonitis and late pulmonary fibrosis after thoracic irradiation and reversed radiation-induced EMT in C57 mice. MPLA further promoted proliferation and inhibited apoptosis of irradiated MLE-12 cells in vitro. Mechanistically, the radioprotective effect of MPLA was mediated by exosomes secreted by stimulated macrophages. Macrophage-derived exosomes modulated DNA damage in MLE-12 cells after irradiation. MPLA promoted the polarization of RAW 264.7 cells to the M1 phenotype. The exosomes secreted by M1 macrophages suppressed EMT in MLE-12 cells after irradiation. Conclusion MPLA is a novel treatment strategy for RILI. Exosomes derived from macrophages are key to the radioprotective role of MPLA in RILI.

Background: Interstitial lung diseases (ILDs) can be induced and even exacerbated by radiotherapy in thoracic cancer patients. The roles of immune responses underlying the development of these severe lung injuries are still obscure and need to be investigated. Methods: A severe lung damage murine model was established by delivering 16 Gy X-rays to the chest of mice that had been pre-treated with bleomycin (BLM) and thus hold ILDs. Bioinformatic analyses were performed on the GEO datasets of radiation-induced lung injury (RILI) and BLM-induced pulmonary fibrosis (BIPF), and RNA-sequencing data of the severely damaged lung tissues. The screened differentially expressed genes (DEGs) were verified in lung epithelial cell lines by qRT-PCR assay. The injured lung tissue pathology was analyzed with H&E and Masson's staining, and immunohistochemistry staining. The macrophage chemotaxis and activity promoted by the stressed epithelial cells were determined by using a cell co-culture system. The expressions of p21 in MLE-12 and Beas-2B cells were detected by qRT-PCR, western blot, and immunofluorescence. The concentration of CCL7 in cell supernatant was measured by ELISA assay. In some experiments, Beas-2B cells were transfected with p21-siRNA or CCL7-siRNA before irradiation and/or BLM treatment. Results: After the treatment of irradiation and/or BLM, the inflammatory and immune responses, chemokine-mediated signaling pathways were steadily activated in the severely injured lung, and p21 was screened out by the bioinformatic analysis and further verified to be upregulated in both mouse and human lung epithelial cell lines. The expression of P21 was positively correlated with macrophage infiltration in the injured lung tissues. Co-culturing with stressed Beas-2B cells or its conditioned medium containing CCL7 protein, U937 macrophages were actively polarized to M1-phase and their migration ability was obviously increased along with the damage degree of Beas-2B cells. Furthermore, knockdown p21 reduced CCL7 expression in Beas-2B cells and then decreased the chemotaxis of co-cultured macrophages. Conclusions: P21 promoted CCL7 release from the severely injured lung epithelial cell lines and contributed to the macrophage chemotaxis in vitro, which provides new insights for better understanding the inflammatory responses in lung injury. [ABSTRACT FROM AUTHOR]

Objective: To investigate the X-ray-specific sensitive genes and potential signaling pathways involved in the latent period of radiation-induced lung injury (RILI) in mouse models. Method: Mice were randomized into groups for whole thoracic irradiation with a single fraction of 20 Gy X-ray or 12.5 Gy carbon heavy ion. Lungs were harvested 3 weeks after the irradiation, whole RNA was extracted and detected with the genome-wide transcriptional microarrays. Differentially expressed genes (DEGs) were calculated for each group and the X-ray-specific sensitive genes were determined, followed by the gene enrichment analysis of those DEGs exploring the potentially relevant signaling pathways and biological processes in latent RILI. Results: Three weeks after irradiation, gene expression levels varied between groups. 76 up-regulated DEGs were determined with mice in the X-ray group and gene ontology enrichment analysis for biological process (GO-BP) obtained several processes which were associated with radiation reaction, mitotic, immune cell chemotaxis or metastasis, immune factors, p53 apoptosis, and tissue remodeling. KEGG signaling pathway enrichment analysis showed that those 76 up-regulated DEGs were enriched in p53, IL-17, FoXO, melanoma, and non-small-cell lung cancer signaling pathways. By comparing the DEGs in X-ray and heavy ion groups, X-ray-specific sensitive genes were determined, the top 10 genes were Adamts9, Aacs, Col6a2, Fdps, Mdk, Mcam, Stbd1, Lbh, Ak3, and Emid1. The expression level of the top 10 genes was found to be significantly higher in the X-ray group than in the control and heavy ion groups. Conclusion: Our research determined the X-ray-specific sensitive gene set in mice lungs after exposure to radiation. The gene set could be used as a genetic marker to suggest the latency of RILI. The enrichment analysis results suggested that the relevant signaling pathways were potentially involved in the development of RILI. Further validation of those genes and signaling pathways is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Radiation-induced lung injury (RILI) including radiation-induced pneumonitis and radiation-induced pulmonary fibrosis is a side effect of radiotherapy for thoracic tumors. Azithromycin is a macrolide with immunomodulatory properties and anti-inflammatory effects. The immunopathology of RILI that results from irradiation is robust pro-inflammatory responses with high levels of chemokine and cytokine expression. In some patients, pulmonary interstitial fibrosis results usually due to an overactive immune response. Growing clinical studies recently proposed that the anti-inflammatory and immunomodulatory effects of azithromycin may benefit patients with acute lung injury. It has been shown potential benefits for patients with RILI in preclinical studies. Azithromycin has a variety of immunomodulatory effect to improve the process of disease, including inhibition of pro-inflammatory cytokines production participating in the regulatory function of macrophages, changes in autophagy, and inhibition of neutrophil influx. We review the published evidence of mechanisms of azithromycin, and focus on the potential effect of azithromycin on the immune response to RILI. [ABSTRACT FROM AUTHOR]

Radiation induced lung injury (RILI) is a common complication after radiation therapy of breast tumors and bone marrow transplantation pretreatment, and it is a critical limiting factor of radiotherapy doses in patients. Once RILI progresses to the radiation-induced pulmonary fibrosis stage, it seriously reduces the patient’s quality of life, while causing the patient’s respiratory failure and eventually leading to death. Ionizing radiation (IR) can induce cell injuries, including apoptosis, epithelial-mesenchymal transition, senescence, pyroptosis and ferroptosis, and these injuries can play an important role in the occurrence and development of radioactive lung injury. Starting from discussion of the occurrence of different forms of injury in different cells after IR stimulation, this review summarizes the pathogenesis of RILI and its clinical prevention and treatment. [ABSTRACT FROM AUTHOR]

Radiotherapy is a prevalent treatment modality for thoracic tumors; however, it can lead to radiation-induced lung injury (RILI), which currently lacks effective interventions. ACT001, a prodrug of micheliolide, has demonstrated promising clinical application potential, yet its impact on RILI requires further validation. This study aims to investigate the radioprotective effects of ACT001 on RILI and elucidate its underlying mechanism. Sprague-Dawley rats were utilized to induce RILI following 20 Gy X-ray chest irradiation, and lung tissue inflammation and fibrosis were assessed using hematoxylin and eosin (H&E) and Masson staining. Lung injury, inflammation, and oxidative stress markers were evaluated employing commercial kits. Pyroptosis-related differentially expressed genes (DEGs) were analyzed using a microarray dataset from the Gene Expression Omnibus (GEO) database, and their functions and hub genes were identified through protein-protein interaction networks. Pyroptosis-related genes were detected via RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. The results demonstrated that ACT001 ameliorated RILI, diminished pro-inflammatory cytokine release and fibrosis, and mitigated the activation of the NLRP3 inflammasome while inhibiting pyroptosis in lung tissue. In conclusion, our study reveals that ACT001 can suppress NLRP3 inflammasome-mediated pyroptosis and improve RILI, suggesting its potential as a novel protective agent for RILI.

The effects of residual radiation from atomic bombs have been considered to be minimal because of its low levels of external radioactivity. However, studies involving atomic bomb survivors exposed to only residual radiation in Hiroshima and Nagasaki have indicated possible adverse health effects. Thus, we investigated the biological effects of radioactive dust of manganese dioxide 56 (56MnO2), a major radioisotope formed in soil by neutron beams from a bomb. Previously, we investigated C57BL mice exposed to 56MnO2 and found pulmonary gene expression changes despite low radiation doses. In this study, we examined the effects in a radiation-sensitive strain of mice, BALB/c, and compared them with those in C57BL mice. The animals were exposed to 56MnO2 particles at two radioactivity levels and examined 3 and 65 days after exposure. The mRNA expression of pulmonary pathophysiology markers, including Aqp1, Aqp5, and Smad7, and radiation-sensitive genes, including Bax, Phlda3, and Faim3, was determined in the lungs. The radiation doses absorbed in the lungs ranged from 110 to 380 mGy; no significant difference was observed between the two strains. No exposure-related pathological changes were observed in the lungs of any group. However, the mRNA expression of Aqp1 was significantly elevated in C57BL mice but not in BALB/c mice 65 days after exposure, whereas no changes were observed in external γ-rays (2 Gy) in either strain. In contrast, Faim3, a radiation-dependently downregulated gene, was reduced by 56MnO2 exposure in BALB/c mice but not in C57BL mice. These data demonstrate that inhalation exposure to 56MnO2 affected the expression of pulmonary genes at doses

The risk of overlapping pulmonary toxicity induced by thoracic radio(chemo)therapy and immune checkpoint inhibitor therapy in the treatment of patients suffering from non-small cell lung cancer (NSCLC) is one important challenge in successful radioimmunotherapy. In the present opinion we highlight factors that we find important to be considered before treatment initiation, during the treatment sequence, and after treatment completion combined or sequential application of radio(chemo)therapy and immune checkpoint inhibitor therapy. A major aim is to optimize the therapeutic index and to avoid immune related adverse effects. The goals in the future will be focused not only on identifying patients already in the pretreatment phase who could benefit from this complex treatment, but also in identifying patients, who are most likely to have higher grade toxicity. In this respect, proper assessment of clinical performance status, monitoring for the presence of certain comorbidities, evaluation of laboratory parameters such as TGF-α and IL-6 levels, human leukocyte antigens (HLA), and consideration of other potential biomarkers which will evolve in near future are essential. Likewise, the critical parameters must be monitored during the treatment phase and follow-up care to detect potential side effects in time. With the help of high-end imaging which is already used on a daily basis in image guided radiotherapy (IGRT) for intensity modulated radiotherapy (IMRT), its advanced form volumetric modulated arc therapy (VMAT), and adaptive radiation therapy (ART), clinically relevant changes in lung tissue can be detected at an early stage of disease. Concurrent radiotherapy and immunotherapy requires a special focus on adverse events, particularly of the lung, but, when properly approached and applied, it may offer new perspectives for patients with locally advanced NSCLC to be seriously considered as a curative option.

Lung stereotactic body radiotherapy (SBRT) is increasingly proposed, especially for patients with poor lung function who are not eligible for surgery. However, radiation-induced lung injury remains a significant treatment-related adverse event in these patients. Moreover, for patients with very severe COPD, we have very few data about the safety of SBRT for lung cancer. We present the case of a female with very severe chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in one second (FEV1) of 0.23 L (11%), for whom a localized lung tumor was found. Lung SBRT was the only possible treatment. It was allowed and safely performed, based on a pre-therapeutic evaluation of regional lung function with Gallium-68 perfusion lung positron emission tomography combined with computed tomography (PET/CT). This is the first case report to highlight the potential use of a Gallium-68 perfusion PET/CT in order to safely select patients with very severe COPD who can benefit from SBRT. [ABSTRACT FROM AUTHOR]

Radiation-induced lung injury (RILI), a potentially fatal and dose-limiting complication of radiotherapy for thoracic tumors, is divided into early reversible pneumonitis and irreversible advanced-stage fibrosis. Early detection and intervention contribute to improving clinical outcomes of patients. However, there is still a lack of reliable biomarkers for early prediction and clinical diagnosis of RILI. Given the central role of inflammation in the initiation and progression of RILI, we explored specific inflammation-related biomarkers during the development of RILI in this study. Two expression profiles from the Gene Expression Omnibus (GEO) database were downloaded, in which 75 differentially expressed genes (DEGs) were screened out. Combining Gene Oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein–protein interaction (PPI) network analysis, we identified four inflammation-related hub genes in the progression of RILI—MMP9, IL-1β, CCR1 and S100A9. The expression levels of the hub genes were verified in RILI mouse models, with S100A9 showing the highest level of overexpression. The level of S100A9 in bronchoalveolar lavage fluid (BALF) and the expression of S100A9 in lung tissues were positively correlated with the degree of inflammation in RILI. The results above indicate that S100A9 is a potential biomarker for the early prediction and diagnosis of the development of RILI. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. Methods: RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1β on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. Results: NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1β secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. Conclusions: Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings. [ABSTRACT FROM AUTHOR]

To investigate the effect of adipose-derived stem cells (ASCs) transplantation on radiation-induced lung injury (RILI), Sprague-Dawley rats were divided into phosphate-buffered saline (PBS) group, ASCs group, Radiation + PBS group, and Radiation + ASCs group. Radiation + PBS and Radiation + ASCs groups received single dose of 30 Gy X-ray radiation to the right chest. The Radiation + PBS group received 1 mL PBS suspension and Radiation + ASCs group received 1 mL PBS suspension containing 1 × 107 CM-Dil-labeled ASCs. The right lung tissue was collected on Days 30, 90, and 180 after radiation. Hematoxylin–eosin and Masson staining were performed to observe the pathological changes and collagen fiber content in the lung tissue. Immunohistochemistry (IHC) and western blot (WB) were used to detect levels of fibrotic markers collagen I (Collal), fibronectin (FN), as well as transforming growth factor-β1 (TGF-β1), p-Smad 3, and Smad 3. Compared with the non-radiation groups, the radiation groups showed lymphocyte infiltration on Day 30 after irradiation and thickened incomplete alveolar walls, collagen deposition, and fibroplasia on Days 90 and 180. ASCs relieved these changes on Day 180 (Masson staining, P = 0.0022). Compared with Radiation + PBS group, on Day 180 after irradiation, the Radiation + ASCs group showed that ASCs could significantly decrease the expressions of fibrosis markers Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) and inhibit the expressions of TGF-β1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) in radiation-induced injured lung tissue. These indicated that ASCs could relieve RILI by inhibiting TGF-β1/Smad 3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) often occurs during clinical chest radiotherapy and acute irradiation from accidental nuclear leakage. This study explored the role of monophosphoryl lipid A (MPLA) in RILI. Materials and Methods: The entire thoracic cavity of C57BL/6N mice was irradiated at 20 Gy with or without pre-intragastric administration of MPLA. HE staining, Masson trichrome staining, and TUNEL assay were used to assess lung tissue injury after treatment. The effect of irradiation on the proliferation of MLE-12 cells was analyzed using the Clonogenic assay. The effect of MPLA on the apoptosis of MLE-12 cells was analyzed using flow cytometry. Expression of γ-H2AX and epithelial-mesenchymal transition (EMT) markers in MLE-12 cells was detected by immunofluorescence and Western blot, respectively. Results: MPLA attenuated early pneumonitis and late pulmonary fibrosis after thoracic irradiation and reversed radiation-induced EMT in C57 mice. MPLA further promoted proliferation and inhibited apoptosis of irradiated MLE-12 cells in vitro. Mechanistically, the radioprotective effect of MPLA was mediated by exosomes secreted by stimulated macrophages. Macrophage-derived exosomes modulated DNA damage in MLE-12 cells after irradiation. MPLA promoted the polarization of RAW 264.7 cells to the M1 phenotype. The exosomes secreted by M1 macrophages suppressed EMT in MLE-12 cells after irradiation. Conclusion: MPLA is a novel treatment strategy for RILI. Exosomes derived from macrophages are key to the radioprotective role of MPLA in RILI. [ABSTRACT FROM AUTHOR]

The treatment of thoracic tumors with ionizing radiation can cause radiation-induced lung injury (RILI), which includes radiation pneumonitis and radiation-induced pulmonary fibrosis. Preventing RILI is crucial for controlling tumor growth and improving quality of life. However, the serious adverse effects of traditional RILI treatment methods remain a major obstacle, necessitating the development of novel treatment options that are both safe and effective. This review summarizes the molecular mechanisms of RILI and explores novel treatment options, including natural compounds, gene therapy, nanomaterials, and mesenchymal stem cells. These recent experimental approaches show potential as effective prevention and treatment options for RILI in clinical practice. • For patients who have used RILI drugs for a long time, the toxic side effects of the drugs can lead to poor tolerance and limited application. Natural compounds with low toxic side effects such as PM014, glucosamine and ulinastatin have been shown to have potential as radiation protectants, sustained-release agents or therapeutic agents. • Most previous treatment strategies targeted only the early stages of RILI, with few effective treatments for the nearly irreversible stage of RPF. Fortunately, ABT-263, FG-3019 and MSCs have been shown to have the potential to reverse lung remodeling. • Other new therapeutic approaches, including gene therapy and nanomaterials, have also provided new insights into the treatment of RILI. [ABSTRACT FROM AUTHOR]

Radiation therapy using conventional or newer high-precision dose techniques, including three-dimensional conformal radiotherapy, intensity-modulated radiation therapy, stereotactic body radiation therapy, four-dimensional conformational radiotherapy, and proton therapy, is an important component of treating patients with lung cancer. Knowledge of the radiation technique used and the expected temporal evolution of radiation-induced lung injury, as well as patient-specific parameters such as previous radiotherapy, concurrent chemoradiotherapy, or immunotherapy, is important in image interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations, as well as the differences between conventional and high-precision dose radiotherapy techniques.

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Radiation-induced lung injury (RILI) is a serious complication of radiotherapy, and the role of IL-17A in this process is not well understood. While IL-17A has been shown to modulate autophagy, conflicting reports exist regarding its activation or inhibition of autophagy. This study investigates the role of IL-17A in RILI and its effects on autophagy via the PP2A-mTOR pathway, with a focus on the PP2A B56α subunit., Methods: C57BL/6J mice and human lung epithelial cells (BEAS-2B) were exposed to radiation with or without recombinant IL-17A. Autophagy markers were analyzed using Western blotting, immunofluorescence, and autophagy flux assays. PP2A activity, specifically the B56α subunit, was measured. A PP2A agonist (DT-061) was used to verify its role in reversing IL-17A-mediated autophagy inhibition., Results: IL-17A inhibited autophagy in lung epithelial cells exposed to radiation by suppressing PP2A activity, particularly through downregulation of the B56α subunit, leading to mTOR activation and reduced autophagosome formation. Treatment with DT-061 restored autophagic activity and improved cell viability. These findings align with reports suggesting that IL-17A inhibits autophagy in certain contexts, while other studies have shown opposing effects., Conclusion: IL-17A inhibits autophagy in RILI through the PP2A B56α-mTOR pathway, exacerbating lung damage. Further research is needed to clarify the role of IL-17A in different cell types and conditions. Targeting the IL-17A-PP2A B56α-mTOR axis may offer new therapeutic strategies for RILI management., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

Radiation-induced lung injury (RILI) is a severe complication arising from thoracic tumor radiotherapy, which constrains the possibility of increasing radiation dosage. Current RILI therapies provide only limited relief and may result in undesirable side effects. Therefore, there is an urgent demand for effective and low-toxicity treatments for RILI. Macrophages play a pivotal role in RILI, promoting inflammation in the initial stages and facilitating fibrosis in the later stages. Sodium clodronate, a bisphosphonate, can induce macrophage apoptosis when encapsulated in liposomes. In this study, we explored the potential of liposomal sodium clodronate (LC) as a specific agent for depleting macrophages to alleviate acute RILI. We assessed the impact of LC on macrophage consumption both in vitro and in vivo. In a mouse model of acute RILI, LC treatment group led to a reduction in alveolar macrophage counts, mitigated lung injury severity, and lowered levels of pro-inflammatory cytokines in both plasma and bronchoalveolar lavage fluid. Additionally, we further elucidated the specific effects and mechanism of LC on macrophages in vitro. Alveolar macrophages MHS cells were subjected to varying concentrations of LC (0, 50, 100, 200 μg/ml), and the results demonstrated its dose-dependent inhibition of cell proliferation and induction of apoptosis. Moreover, LC decreased the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Conditioned media from LC-treated macrophages protected alveolar epithelial cells MLE-12 from radiation-induced damage, as demonstrated by reduced apoptosis and DNA damage. These findings imply that LC-mediated macrophage depletion may present a promising therapeutic strategy for alleviating radiation-induced lung injury., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests or financial conflicts to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Yida Li,1,2,&ast; Liqing Zou,1,2,&ast; Li Chu,1,2 Luxi Ye,1,2 Jianjiao Ni,1,2 Xiao Chu,1,2 Tiantian Guo,1,2 Xi Yang,1,2 Zhengfei Zhu1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengfei Zhu; Xi YangDepartment of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People’s Republic of ChinaTel +86-18017312901; +8617321296901Fax +86-2164175242Email fuscczzf@163.com; ntgeorge@qq.comBackground: Radiation-induced lung injury (RILI) is a main threat to patients who received thoracic radiotherapy. Thus, understanding the molecular mechanism of RILI is of great importance. Circular RNAs (circRNAs) have been found to act as a regulator of multiple biological processes, and the circRNA-microRNA (miRNA)-mRNA axis could play an important role in the signaling pathway of many human diseases including radiation injury.Methods: First, the circRNA and miRNA of RILI in a mouse model were investigated. The mice received 12 Gy of thoracic irradiation, and the irradiated lung tissues at 48 hours after irradiation were analyzed by RNA sequencing (RNA-seq) compared with normal lung tissues. Then, Gene Ontology analysis of the target mRNAs of the significantly differently expressed circRNAs was performed.Results: In the irradiated group, inflammatory changes in lungs were observed; 21 significantly up-regulated and 33 down-regulated significantly miRNAs were identified (p < 0.05). Among 27 differentially expressed circRNAs, 10 were down-regulated and 17 were up-regulated in the irradiated group [log2 (fold change) > 1 or < − 1, p< 0.05]. These differentially expressed miRNAs took part in a series of cellular processes, such as positive regulation of alpha-beta T-cell proliferation, interstitial matrix, collagen fibril organization, chemokine receptor activity, cellular defense response, and B-cell receptor signaling pathway. The differentially expressed circRNAs were related to Th1 and Th2 differentiation pathways, and the predicted mRNAs were verified.Conclusion: This study revealed immune-related molecular pathways play an important role in the early response after radiotherapy. In the future, research on the target mechanism and early intervention of circRNAs with associated miRNAs such as circRNA5229, circRNA544, and circRNA3340, could benefit the treatment of RILI.Keywords: circRNA, miRNA, radiation-induced lung injury, T cell proliferation

Background and Aims: Radiation-induced lung injury (RILI) is the most common complication associated with chest tumors, such as lung and breast cancers, after radiotherapy; however, the pathogenic mechanisms are unclear. Single-cell RNA sequencing has laid the foundation for studying RILI at the cellular microenvironmental level. This study focused on changes during the acute pneumonitis stage of RILI at the cellular microenvironmental level and investigated the interactions between different cell types. Methods: An acute RILI model in mice and a single-cell transcriptional library were established. Intercellular communication networks were constructed to study the heterogeneity and intercellular interactions among different cell types. Results: A single-cell transcriptome map was established in a mouse model of acute lung injury. In total, 18,500 single-cell transcripts were generated, and 10 major cell types were identified. The heterogeneity and radiosensitivity of each cell type or subtype in the lung tissues during the acute stage were revealed. It was found that immune cells had higher radiosensitivity than stromal cells. Immune cells were highly heterogeneous in terms of radiosensitivity, while some immune cells had the characteristics of radiation resistance. Two groups of radiation-induced Cd8+Mki67+ T cells and Cd4+Cxcr6+ helper T cells were identified. The presence of these cells was verified using immunofluorescence. The ligandreceptor interactions were analyzed by constructing intercellular communication networks. These explained the origins of the cells and revealed that they had been recruited from endothelial cells to the inflammatory site. Conclusions: This study revealed the heterogeneity of in vivo radiosensitivity of different cell types in the lung at the initial stage post irradiation. [ABSTRACT FROM AUTHOR]

Objective: Transfer RNA-derived small RNAs (tsRNAs) are a novel type of non-coding RNA with various regulatory functions. They are associated with oxidative stress in various diseases, but their potential functions in radiation-induced lung injury (RILI) remain uncertain. Methods: To explore the role of tsRNAs in RILI, we used X-rays to irradiate human bronchial epithelial cells and examined the expression profile of altered tsRNAs by RNA sequencing and bioinformatics analysis. Sequencing results were verified by qRT-PCR. tsRNA functions were explored using several methods, including CCK-8, reactive oxygen species (ROS) assays, cell transfection, and western blotting. Results: Eighty-six differentially expressed tRNA-derived fragments (tRFs) were identified: 64 were upregulated, and 22 were downregulated. Among them, the regulation of tRF-Gly-GCC, associated with oxidative stress, may be mediated by the inhibition of cell proliferation, promotion of ROS production, and apoptosis in the occurrence and development of RILI. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the underlying molecular mechanism may involve the PI3K/AKT and the FOXO1 signaling pathways. Conclusion: Our findings provide new insights into the molecular mechanisms underpinning RILI, advancing the clinical prevention and treatment of this disease. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments. Methods: The predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB. Results: A total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway. Conclusions: NaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI. [ABSTRACT FROM AUTHOR]

Abstract Background Symptomatic radiation pneumonitis (RP) may be a serious complication after thoracic radiation therapy (RT) for non-small cell lung cancer (NSCLC). This prospective observational study sought to evaluate the utility of a novel radiation-induced lung injury (RILI) grading scale (RGS) for the prediction of RP. Materials and methods Data of 41 patients with NSCLC treated with thoracic RT of 60–66 Gy were analysed. CT scans were scheduled before RT, one month post-RT, and every three months thereafter for one year. Symptomatic RP was defined as Common Terminology Criteria for Adverse Events grade ≥ 2. RGS grading ranged from 0 to 3. The inter-observer variability of the RGS was assessed by four senior radiologists. CT scans performed 28 ± 10 days after RT were used to analyse the predictive value of the RGS. The change in the RGS severity was correlated to dosimetric parameters. Results The CT obtained one month post-RT showed RILI in 36 (88%) of patients (RGS grade 0 [5 patients], 1 [25 patients], 2 [6 patients], and 3 [5 patients]). The inter-observer agreement of the RGS grading was high (Kendall’s W coefficient of concordance = 0.80, p

Radiotherapy plays an important role in the treatment of localized primary malignancies involving the chest wall or intrathoracic malignancies. Secondary effects of radiotherapy on the lung result in radiation-induced lung disease. The phases of lung injury from radiation range from acute pneumonitis to chronic pulmonary fibrosis. Radiation pneumonitis is a clinical diagnosis based on the history of radiation, imaging findings, and the presence of classic symptoms after exclusion of infection, pulmonary embolism, heart failure, drug-induced pneumonitis, and progression of the primary tumor. Computed tomography (CT) is the preferred imaging modality as it provides a better picture of parenchymal changes. Lung biopsy is rarely required for the diagnosis. Treatment is necessary only for symptomatic patients. Mild symptoms can be treated with inhaled steroids while subacute to moderate symptoms with impaired lung function require oral corticosteroids. Patients who do not tolerate or are refractory to steroids can be considered for treatment with immunosuppressive agents such as azathioprine and cyclosporine. Improvements in radiation technique, as well as early diagnosis and appropriate treatment with high-dose steroids, will lead to lower rates of pneumonitis and an overall good prognosis.

Abstract Radiation pneumonitis is a serious side effect of thoracic radiotherapy with no established treatment currently. Anlotinib is a small‐molecule tyrosine kinase inhibitor (TKI) with anti‐angiogenic effects. The effect of TKIs in the treatment of radiation pneumonitis remains to be elucidated. We investigated whether anlotinib could alleviate radiation pneumonitis. We report a case of a patient with esophageal cancer who received anlotinib for radiation pneumonitis following radiotherapy. We also reviewed related studies to address this issue. The results in this patient suggest that anlotinib may be a valid treatment option for radiation pneumonitis.

BackgroundRadiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments.MethodsThe predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.ResultsA total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.ConclusionsNaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

Abstract Radiation-induced lung injury (RILI) is one of the most common complications associated with radiotherapy, characterized by early-stage radiation pneumonia and subsequent radiation pulmonary fibrosis. However, effective therapeutic strategies for RILI are currently lacking. Recently, an increasing number of studies reported that mesenchymal stem cells (MSCs) can enhance the regeneration of damaged tissue, modulate the inflammatory response, reduce the levels of fibrotic cytokines and reactive oxygen species, and inhibit epithelial-mesenchymal transformation. Interestingly, MSCs can also exert immunosuppressive effects, which highlights a new potential therapeutic activity of MSCs for managing RILI. Here, we reviewed the potential applications and therapeutic mechanisms of action of MSCs in RILI, which will represent a good compendium of information for researchers in this field.

• SABR is increasingly used for the treatment of ES-NSCLC and pulmonary metastases. • Post-lung SABR follow-up is challenging due to radiation-induced lung injury. • RECIST, HRF and SUV lack specificity for reliable post-lung SABR assessment. • This review highlights current challenges, new insights and unknowns in this field. • A post-SABR-specific standardized workflow is provided for guidance and clarity. Stereotactic ablative radiotherapy (SABR) is increasingly used for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) and for pulmonary metastases. In patients with ES-NSCLC, SABR is highly successful with reported 5-year local control rates of approximately 90%. However, the assessment of local control following lung SABR can be challenging as radiological changes arising from radiation-induced lung injury (RILI) can be observed in up to 90% of patients. These so-called 'benign' radiological changes evolve with time and are often asymptomatic. Several radiological and metabolic features have been explored to help distinguish RILI from local recurrences (LR). These include the Response Evaluation Criteria for Solid Tumors (RECIST), high-risk features (HRF's) and maximum standardized uptake value (SUVmax) on FDG-PET-CT. However, use of some of these approaches have poor predictive values and low specificity for recurrence. A proposed new workflow for the evaluation of post-lung SABR radiological changes will be reviewed which uses the presence of so-called 'actionable radiological features' to trigger changes to imaging schedules and identifies the need for a multidisciplinary board review. Furthermore, this critical review of post-lung SABR imaging will highlight current challenges, new insights, and unknowns in this field. [ABSTRACT FROM AUTHOR]