Treatment Of Radiation-induced Lung Injury Research Articles

Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury.

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/- mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/- mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.

Exploration of molecular mechanism underlying protective effect of astragaloside IV against radiation-induced lung injury by suppressing ferroptosis

In this study, we aimed to investigate the pharmacological effects and underlying mechanisms of astragaloside IV (AS IV) against radiation-induced lung injury. We established experimental models of radiation-induced lung injury and observed the effect of AS IV on cell viability, cell death, inflammatory responses and ferroptosis. Accordingly, we found that AS IV restored the suppressed cell viability and promoted cell death induced by X-ray irradiation. Moreover, radiation-induced up-regulation of lactate dehydrogenase (LDH) release, ferroptosis, reactive oxygen species (ROS) and inflammatory responses were also restored by AS IV in a dose-dependent manner. Besides, in radiation-induced lung injury C57BL/6 mice, AS IV evidently alleviated lung injury and promoted the survival rate of lung-injured mice. And the ferroptosis level in mice lung tissues were also alleviated by the administration of AS IV in a dose-dependent manner. As a conclusion, by comparing the changes of ferroptosis, ROS and inflammatory responses in the experimental models, we validated that AS IV could inhibit inflammatory responses and cell injury in the treatment of radiation-induced lung injury by suppressing ferroptosis. This finding not only find potentially effective treatments to mitigate radiation-induced lung injury, but also provides supporting evidence for clinical application of AS IV to improve the management of radiation-treated patients and minimize the associated lung complications or other adverse effects. Moreover, as inflammation and ROS are key contributors to tissue damage in various diseases, our study suggested the potential application of AS IV in the treatments for other diseases.

Mesenchymal stem cells in radiation-induced lung injury: From mechanisms to therapeutic potential.

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.

Efficacy of astragalus in the treatment of radiation-induced lung injury based on traditional Chinese medicine: A systematic review and meta-analysis of 25 RCTs.

Astragalus (Hedysarum Multijugum Maxim., Huangqi) is a Chinese herbal medicine, and according to the theory of traditional Chinese medicine (TCM), Chinese medicinal preparations containing astragalus can be used clinically to treat radiation-induced lung injury (RILI). To systematically review the efficacy and safety of Chinese medicinal preparations containing astragalus in the prevention and treatment of RILI by means of meta-analysis. A systematic literature on randomized controlled trials (RCTs) of prescriptions containing astragalus in the treatment of RILI by Pubmed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, WANFANG Database. The retrieval time is from the establishment of the database to January 18, 2022. Meta-analysis, heterogeneity test and sensitivity analysis were performed on eligible RCTs using Revman 5.4 software and STATA 17.0 software, and a "funnel plot" was used to analyze potential publication bias. A total of 25 RCTs were included, including 1762 patients, and the most widely used drugs were heat-clearing and detoxifying, yin-nourishing and qi-nourishing. The prescriptions containing astragalus can significantly reduce the total incidence of RILI (P < .01), improve the total effective rate and cure rate of RILI (P < .01), improve the quality of life of patients, alleviate breathing difficulties and reduce the expression of inflammatory factors (P < .01), and no adverse reactions related to TCM treatment were reported. The traditional Chinese medicinal preparation containing astragalus can effectively alleviate the clinical symptoms of RILI, reduce the toxic side effects, and is safe to use in clinic.

NVP-AUY922 alleviates radiation-induced lung injury via inhibition of autophagy-dependent ferroptosis

Radiation-induced lung injury (RILI) is a common complication of radiotherapy for which no effective interventions are available. NVP-AUY922, a resorcinylic isoxazole amide drug, exhibits anti-inflammatory, immunomodulatory, and therapeutic effects against various types of cancers. In this study, we explore the role and underlying mechanisms of NVP-AUY922 in the treatment of RILI. We established a model of BEAS-2B cell injury and a mouse model of RILI. Cell proliferation, death, gross weight, and survival rates of mice, and histological parameters were assessed. Additionally, inflammation-related indices and indicators related to ferroptosis were evaluated. Furthermore, immunofluorescence and co-immunoprecipitation were used to determine the interaction between GPX4, LAMP-2A, and HSC70. NVP-AUY922 significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, proinflammatory cytokine release, and lung epithelial BEAS-2B cell damage. NVP-AUY922 markedly limited the activation of ferroptosis, which is involved in RILI. Mechanistically, NVP-AUY922 prevented chaperone-mediated autophagy of the GPX4 pathway in vitro and in vivo, and the autophagy inhibitor Baf-A1 significantly increased the level of GPX4 and alleviated lung inflammation. NVP-AUY922 can alleviate RILI by inhibiting chaperone-mediated lysosomal degradation of GPX4, demonstrating its potential as a novel protective agent against RILI.

Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the miR-21/TGF-β1/Smad3 pathway

Radiation-induced lung injury (RILI) is a complication commonly found in victims suffering from nuclear accidents and patients treated with chest tumor radiotherapy, and drugs are limited for effective prevention and treatment. Melatonin (MET) has an anti-radiation effect, but its metabolic period in the body is short. In order to prolong the metabolism period of MET, we prepared MET entrapped poly (lactic-co-glycolic acid) nanoparticles (MET/PLGANPS) for the treatment of RILI. As a result, the release rate of MET/PLGANPS in vitro was lower than MET, with stable physical properties, and it caused no changes in histopathology and biochemical indicators. After 2 weeks and 16 weeks of irradiation with the dose of 15 Gy, MET and MET/PLGANPS could reduce the expression of caspase-3 proteins, inflammatory factors, TGF-β1 and Smad3 to alleviate radiation-induced lung injury. MET/PLGANPS showed better therapeutic effect on RILI than MET. In addition, we also found that high expression of miR-21 could increase the expression levels of TGF-β1, and inhibit the protective effect of MET/PLGANPS. In conclusion, MET/PLGANPS may alleviate RILI by inhibiting the miR-21/TGF-β1/Smad3 pathway, which would provide a new target for the treatment of radiation-induced lung injury.

Prevention and treatment of radiation-induced lung injury.

Radiation-induced lung injury (RILI) is a common complication in cancer patients receiving local thoracic radiation and bone marrow transplantation conditioning. It is divided into early-stage radiation pneumonitis and advanced radiation fibrosis of thelung. This severely hampers the quality of life and survival of cancer patients. Meanwhile, RILI is a major factor limiting radiation doses in clinical practice, which affects the local control of cancer. Unfortunately, the mechanism of RILI is still not well defined, and there are no treatment options available for these patients. In this reviewwe summarizethe methods and agents used for the treatment and prevention of RILI, with theaim of increasingunderstanding ofRILI.

MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation

Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. Following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time post-exposure. Understanding the functional roles N-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury.

Progression of Anti-oxygen Therapy in Radiation-Induced Lung Injury

放射性肺损伤（radiation induced lung injury, RILI）是临床上胸部肿瘤患者放疗后发生的严重并发症，主要表现为气短、低热、咳嗽等，严重影响患者生存，如何更好地防治RILI是亟待探索的问题。RILI的发生机制主要包括靶细胞学说、细胞因子学说、自由基学说、血管内皮细胞损伤学说。其中放疗产生的活性氧（reactive oxygen species, ROS）对组织的损伤贯穿整个RILI病程，对放射性肺炎和放射性肺纤维化均具有直接促进作用。包括巯基化合物、抗氧化酶、植物抗氧化剂等在内的治疗手段已被用于防治RILI，本文即就抗氧化治疗在RILI中的研究与应用作一综述。

Research progress in radiation-induced lung injury

Radiation-induced lung injury (RILI) is a severe complication which commonly occurs after radiotherapy in patients diagnosed with thoracic cancer patients. RILI includes acute radiation-induced pneumonitis and fibrosis. RILI not only limits the radiotherapy dose, but also affects subsequent clinical efficacy and quality of life of patients. The mechanism underlying RILI has been mainly investigated in animal models. Multiple cells, cytokines and molecules participate in the regulation of immune response, eventually leading to the incidence of RILI. No guidelines or standards have been established for the treatment of RILI, which primarily depend upon clinical experience and professional recommendations. In this article, recent RILI-related studies have been summarized to unravel the pathophysiological changes, clinical symptoms, imaging findings, clinical diagnosis and treatment of RILI. Key words: Radiation-induced lung injury; Mechanism; Thoracic neoplasm/radiotherapy

Mesenchymal stem cells in radiation-induced lung injury treatment

Radiotherapy plays a significant role in the treatment of lung malignant tumor.However,as the most main complication of radiotherapy used to treat lung malignant tumor,radiation-induced lung injury is an important influencing factor in impeding further and higher dose radiotherapy.Previous studies show that mesenchymal stem cells (MSCs) have the characteristics of self-replication,multiple differentiation,immunoregulation and directional migration. MSCs can help to repair many kinds of acute and chronic lung injury,meanwhile stem cell transplantation stimulates production of many cytokines to attenuate acute lung injury.So stem cell therapy provides a new kind of thinking in the prevention and treatment of radiation-induced lung injury. Key words: Mesenchymal stem cells; Radiation pneumonitis; Cytokines

Modulation of radiation-induced tumour necrosis factor-α and transforming growth factor β1 expression in the lung tissue by Shengqi Fuzheng injection

Radiation-induced lung injury (RILI) is one of the most common and severe side effects of thoracic radiotherapy. Therefore, novel therapeutic approaches to improve the effectiveness of RILI treatment are required. The present study was designed to determine the effectiveness of a traditional Chinese medicine regimen, Shenqi Fuzheng injection (SFI), in the treatment of RILI. SFI is composed of extracts from codonopsis pilosula and radix astragali. Here, we determined the protective effects of SFI on RILI with a single-dose irradiation (RT) of 12 Gy in C57BL/6 8-week-old mice. The mice were divided into four groups treated with i) phosphate-buffered saline (PBS; pH 7.4, 20 ml/kg/day) alone as normal a control; ii) SFI only (20 ml/kg/day); iii) RT + PBS (20 ml/kg/day); and iv) RT + SFI (20 ml/kg/day). SFI and PBS were administered via intraperitoneal injection 1 week before and 2 weeks after RT. The pathology of RILI and any clinical signs of toxicity were monitored. The expression of tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 in the lungs was analyzed by RT-PCR and immunohistochemistry. TNF-α and TGF-β1 expression was increased by RT, but was reversed by SFI treatment during the radiation pneumonic and fibrotic phases (P<0.05). Lung histology at 24 weeks revealed a significant decrease in structural damage and collagen deposition in the RT + SFI group compared to the RT + PBS group. In conclusion, TNF-α and TGF-β1 are key mediators for the pathogenesis of RILI, and SFI reduces TNF-α and TGF-β1 expression after RT. This may be a key mechanism behind the preventive effects of SFI on lung injury after radiation.