Pathogenic mechanisms and latest therapeutic approaches for radiation-induced lung injury: a narrative review.

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.

TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation.

BACKGROUND: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. RESULTS: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. CONCLUSIONS: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

Evaluation of chest CT-scans following lung stereotactic ablative radiotherapy: Challenges and new insights.

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.

Liposomal sodium clodronate mitigates radiation-induced lung injury through macrophage depletion.

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-1ß, 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.

Integrating local and distant radiation-induced lung injury: Development and validation of a predictive model for ventilation loss.

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.

Optimal management of radiation pneumonitis: Findings of an international Delphi consensus study.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study. METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3. RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease. CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.

Transcriptional Changes in Radiation-Induced Lung Injury: A Comparative Analysis of Two Radiation Doses for Preclinical Research.

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.

Radiomics approach for identifying radiation-induced normal tissue toxicity in the lung.

Radiomic features were used in efforts to characterize radiation-induced normal tissue injury as well as identify if human embryonic stem cell (hESC) derived Extracellular Vesicle (EV) treatment could resolve certain adverse complications. A cohort of mice (n=12/group) were given whole lung irradiation (3×8Gy), local irradiation to the right lung apex (3×12Gy), or no irradiation. The hESC-derived EVs were systemically administered three times via retro-orbital injection immediately after each irradiation. Cone-Beam Computed Tomography (CBCT) images were acquired at baseline and 2 weeks after the final radiation/EV treatment. Whole lung image segmentation was performed and radiomic features were extracted with wavelet filtering applied. A total of 851 features were extracted per image and recursive feature elimination was used to refine, train and validate a series of random forest classification models. Classification models trained to identify irradiated from unirradiated animals or EV treated from vehicle-injected animals achieved high prediction accuracies (94% and 85%). In addition, radiomic features from the locally irradiated dataset showed significant radiation impact and EV sparing effects that were absent in the unirradiated left lung. Our data demonstrates that radiomics has the potential to characterize radiation-induced lung injury and identify therapeutic efficacy at early timepoints.

Therapeutic potential of dihydroartemisinin in mitigating radiation-induced lung injury: Inhibition of ferroptosis through Nrf2/HO-1 pathways in mice.

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-ß (TGF-ß), 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-ß 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.

Application of dose-gradient function in reducing radiation induced lung injury in breast cancer radiotherapy.

OBJECTIVE: Try to create a dose gradient function (DGF) and test its effectiveness in reducing radiation induced lung injury in breast cancer radiotherapy. MATERIALS AND METHODS: Radiotherapy plans of 30 patients after breast-conserving surgery were included in the study. The dose gradient function was defined as DGH=VDVp3, then the area under the DGF curve of each plan was calculated in rectangular coordinate system, and the minimum area was used as the trigger factor, and other plans were triggered to optimize for area reduction. The dosimetric parameters of target area and organs at risk in 30 cases before and after re-optimization were compared. RESULTS: On the premise of ensuring that the target dose met the clinical requirements, the trigger factor obtained based on DGF could further reduce the V5, V10, V20, V30 and mean lung dose (MLD) of the ipsilateral lung in breast cancer radiotherapy, P < 0.01. And the D2cc and mean heart dose (MHD) of the heart were also reduced, P < 0.01. Besides, the NTCPs of the ipsilateral lung and the heart were also reduced, P < 0.01. CONCLUSION: The trigger factor obtained based on DGF is efficient in reducing radiation induced lung injury in breast cancer radiotherapy.

Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management.

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

Early, non-invasive detection of radiation-induced lung injury using PET/CT by targeting CXCR4.

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.

Regulatory Mechanism of Radiation Therapy for Lung Cancer with Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Lung cancer is the fastest-growing cancer type in terms of incidence and mortality worldwide， posing a huge threat to the health and life of the population. Radiation therapy is one of the main methods for treating lung cancer， and there is a clear dose-effect relationship between the radiation dose and local control rate of lung cancer. However， the lung is a radiation dose-limiting organ， and the radiation resistance of lung cancer tissues and the radiation damage to normal tissues limit the radiation efficacy for lung cancer. The pathogenesis of lung cancer in traditional Chinese medicine （TCM） is characterized by an initial deficiency in vital Qi， followed by the internal invasion and gradual accumulation of pathogenic Qi. After radiation therapy for lung cancer， the body's vital Qi becomes weaker， and syndromes of phlegm coagulation， Qi stagnation， and static blood blocking collaterals become more severe， leading to radiation resistance of lung cancer tissues. Therefore， the key issue to better clinical efficacy of radiation therapy for lung cancer patients is to use drugs to enhance the radiation sensitivity of lung cancer cells and improve the radiation tolerance of normal lung tissues. TCM can be used as a radiation sensitizer by regulating the cell cycle to increase the proportion of cells in the radiation-sensitive phase， promoting upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes to induce cell apoptosis， enhancing DNA damage caused by radiation and inhibiting damage repair， improving blood circulation and tissue oxygen supply， and so on， to enhance the sensitivity of tumor cells to radiation and amplify the toxicity of radiation to tumor tissues. TCM can also be used as a radiation protector by inhibiting cell damage， regulating cytokines and immune balance， reducing the release of inflammatory and fibrotic factors， and inhibiting the activation of related signaling pathways to prevent and treat radiation-induced lung injury. This article systematically reviewed the research results of TCM on radiation sensitization and radiation protection in lung cancer in recent years， aiming to elucidate the mechanism of TCM in regulating the effect of radiation therapy for lung cancer and provide more theoretical and practical basis for TCM to participate in improving the prognosis of lung cancer patients undergoing radiation therapy.

BMSCs promote M2 macrophage polarization to attenuate acute radiation-induced lung injury / 中国辐射卫生

Objective To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) for radiation-induced lung injury (RILI) and the underlying mechanism. Methods Forty-five healthy adult male C57BL/6 mice were randomly divided into control, model, and BMSCs groups. The model and BMSCs groups received a single irradiation dose of 20 Gy to the chest, while the control group did not receive X-ray irradiation. For the BMSCs group, an injection of 1 × 106 BMSCs cells was administered via the tail vein within 6 h after irradiation. In the 5th week, the lung tissue was taken to observe pathological changes with HE staining; examine the expression of the inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) with immunohistochemical staining; observe the polarization of macrophages with immunofluorescence staining; and measure the expression of the epithelial-mesenchymal transition markers E-cadherin, N-cadherin, and vimentin proteins by Western blot. Results After radiation, the model group developed pulmonary vasodilation and congestion with septal thickening and inflammatory cell infiltration, and these changes were markedly reduced in the BMSCs group. The model group showed significantly down-regulated expression of IL-6 and TNF-α compared with significantly increased levels in the model group (P < 0.01, P < 0.05). Treatment with BMSCs significantly increased the polarization of lung macrophages towards the M2 type, while significantly decreasing the abnormally increased N-cadherin and vimentin levels in RILI mice (P < 0.05, P < 0.01). Conclusion BMSCs have therapeutic effects for RILI mice, which may be through promoting macrophage polarization from M1 to M2.

Hydrogen therapy promotes macrophage polarization to the M2 subtype by inhibiting the NF-κB signaling pathway / 中国辐射卫生

Objective To investigate the role of hydrogen therapy in reducing radiation-induced lung injury and the specific mechanism. Methods Forty C57BL/6 mice were randomly divided into four groups: normal control group, model group, hydrogen therapy group I, and hydrogen therapy group II. A mouse model of radiation-induced lung injury was established. The pathological changes in the lung tissue of the mice were examined with HE staining. Immunofluorescence staining was used to detect the expression of surface markers of M1 and M2 macrophages to observe macrophage polarization. The expression of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-10 in the lung tissue was measured by immunohistochemistry. The expression of nuclear factor-kappa B (NF-κB) p65 and phosphorylated NF-κB (P-NF-κB) p65 was measured by Western blot. Results HE staining showed that compared with the control group, the model group exhibited alveolar septal swelling and thickening, vascular dilatation and congestion, and inflammatory cell infiltration in the lung tissue; the hydrogen groups had significantly reduced pathological damage and inflammatory response than the model group, with more improvements in hydrogen group II than in hydrogen group I. Immunohistochemical results showed that compared with those in the control group, the levels of the inflammatory cytokines IL-6 and TNF-α were significantly increased in the model group; the hydrogen groups showed significantly decreased IL-6 and TNF-α levels and a significantly increased level of the anti-inflammatory factor IL-10 than the model group, which were more marked in hydrogen group II than in hydrogen group I. Immunofluorescence results showed that compared with the control group, the expression of the surface marker of M1 macrophages in the model group was significantly upregulated; the hydrogen groups showed significantly downregulated M1 marker and significantly upregulated M2 marker, and hydrogen group II showed significantly increased M2 marker compared with hydrogen group I. Western blot results showed that compared with that in the control group, the ratio of P-NF-κB p65/NF-κB p65 in the model group was significantly increased; the P-NF-κB p65/NF-κB p65 ratio was significantly reduced in the hydrogen groups than in the model group, and was significantly lower in hydrogen group II than in hydrogen group I. Conclusion Hydrogen inhalation therapy may reduce the inflammatory response of radiation-induced lung injury by inhibiting the NF-κB signaling pathway to promote the polarization of the macrophage M1 subtype to the M2 subtype.

Professor LIN Shengyou's Treatment of Radiation-Induced Lung Injury Based on the Theory of Pathogenesis Evolution / 浙江中医药大学学报

[Objective]To summarize Professor LIN Shengyou's experience in the treatment of radiation-induced lung injury based on the theory of pathogenesis evolution.[Methods]Through clinical visits,organizing medical records,studying ancient and modern literature,starting from the evolution of the disease mechanism,this paper summarizes Professor LIN's clinical experience in application of the theory of pathogenesis evolution in the treatment of radiation-induced lung injury,and provides evidence with a clinical trial.[Results]Because of the special effect of radiation on the human body,Professor LIN believes that the basic pathogenesis of radiation-induced lung injury runs through the whole time,that is,heat evil harms the lung.With the development of the disease,the pathogenesis can be divided into three stages:at the beginning,the evil is flourishing,and the heat is damaging the lung;in the middle stage,the evil causes vital Qi decline,and the heat causes Yin injury first,then the lung and kidney deficiency;over time Yin damage affects Yang,leading to Yin and Yang deficiency.In clinic doctors should grasp the basic pathogenesis,identify the present pathogenesis and deduce the potential pathogenesis.Classic formula Maxing Shigan Decoction can be selected as the basic formula of the disease,added or subtracted according to the pathogenesis of each stage.In the case,according to the law of pathogenesis evolution,Maxing Shigan Decoction was added or subtracted as the main formula,and satisfactory curative effect was obtained.[Conclusion]By differentiating the syndrome of radiation-induced lung injury through the theory of pathogenesis evolution,Professor LIN has unique insights and significant curative effect,which is worthy of further clinical promotion and research.

Prevention and Treatment of Radiation-Induced Pulmonary Fibrosis by the Method of Dispelling Stasis to Promote Regeneration / 中医杂志

Blood stasis is an important pathological factor throughout the whole course of radiation-induced pulmonary fibrosis， which could evolve from new into long stagnation， and the methods of dispelling stasis to promote regeneration should throughout the whole disease progress. It is believed that the basis of the radiation-induced pulmonary fibrosis is heat toxin dispersing qi and yin， and deficiency of healthy qi promoting blood stasis. The process of the disease showed latent fire burning pulmonary collaterals， and the binding of phlegm and stasis. The key factors of the disease were the damage of ying-wei （营卫） qi in channels and collaterals， as well as the blood stasis evolving into dried blood. It is suggested that during radiotherapy， we should pay more attention to relieve heat， moisten dryness， supplement qi and yin， nourish and harmonize blood， and remove blood stasis， so as to prevent disease before it arises. If there is radiation pneumonia， we could focus on dissolving phlegm， removing blood stasis， clearing latent fire， and unblocking the collaterals and veins， in order to "control the development of existing disease". If it develops into radiation-induced pulmonary fibrosis， we could relive the center and supplement deficiency， tonify original qi， dispel stasis to promote regeneration， and clear dried blood， for the purpose of slowing the progression of disease. These ideas might provide reference for clinical treatment.

Effects of Radioactive 56MnO2 Particle Inhalation on Mouse Lungs: A Comparison between C57BL and BALB/c.

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.

Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-ß1/Smad 3 signaling pathway.

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-ß1 (TGF-ß1), 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-ß1 (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-ß1/Smad 3 signaling pathway.

Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe.

Rationale: Radiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Objective: To noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. Methods: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen, 68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally, 68Ga-CBP8 PET was used to assess RILI in vivo in six human subjects. Results: Murine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. Conclusions: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.Clinical trial registered with www.clinicaltrials.gov (NCT04485286, NCT03535545).