Radiation Lung Injury Research Articles

EP.08F.02 Pifenidone Prophylactic Therapy for Radiation Lung Injury in Patients Who Have Previously Received Immune Checkpoint Inhibitors

EP.08F.02 Pifenidone Prophylactic Therapy for Radiation Lung Injury in Patients Who Have Previously Received Immune Checkpoint Inhibitors

Oxidative Stress: An Intersection Between Radiation and Sulfur Mustard Lung Injury.

Nuclear and chemical weapons of mass destruction share both a tragic and beneficial legacy in mankind's history and health. The horrific health effects of ionizing radiation and mustard gas exposures unleashed during disasters, wars, and conflicts have been harnessed to treat human health maladies. Both agents of destruction have been transformed into therapies to treat a wide range of cancers. The discovery of therapeutic uses of radiation and sulfur mustard was largely due to observations by clinicians treating victims of radiation and sulfur mustard gas exposures. Clinicians identified vulnerability of leukocytes to these agents and repurposed their use in the treatment of leukemias and lymphomas. Given the overlap in therapeutic modalities, it goes to reason that there may be common mechanisms to target as protective strategies against their damaging effects. This commentary will highlight oxidative stress as a common mechanism shared by both radiation and sulfur mustard gas exposures and discuss potential therapies targeting oxidative stress as medical countermeasures against the devastating lung diseases wrought by these agents.

Hydrogen therapy promotes macrophage polarization to the M2 subtype in radiation lung injury by inhibiting the NF-κB signalling pathway

BackgroundRadiotherapy has become a standard treatment for chest tumors, but a common complication of radiotherapy is radiation lung injury. Currently, there is still a lack of effective treatment for radiation lung injury. MethodsA mouse model of radioactive lung injury (RILI) was constructed and then treated with different cycles of hydrogen inhalation. Lung function tests were performed to detect changes in lung function.HE staining was used to detect pathological changes in lung tissue. Immunofluorescence staining was used to detect the polarization of macrophages in lung tissue. Immunohistochemistry was used to detect changes in cytokine expression in lung tissues. Western Blot was used to detect the expression of proteins related to the NF-κB signalling pathway. ResultsLung function test results showed that lung function decreased in the model group and improved in the treatment group.HE staining showed that inflammatory response was evident in the model group and decreased in the treatment group. Immunohistochemistry results showed that the expression of pro-inflammatory factors was significantly higher in the model group, and the expression of pro-inflammatory factors was significantly higher in the treatment group. The expression of pro-inflammatory factors in the treatment group was significantly lower than that in the model group, and the expression of anti-inflammatory factors in the treatment group was higher than that in the model group. Immunofluorescence showed that the expression of M1 subtype macrophages was up-regulated in the model group and down-regulated in the treatment group. The expression of M2 subtype macrophages was up-regulated in the treatment group relative to the model group. Western Blot showed that P–NF-κB p65/NF-κB p65 was significantly increased in the model group, and P–NF-κB p65/NF-κB p65 was decreased in the treatment group. ConclusionHydrogen therapy promotes macrophage polarization from M1 to M2 subtypes by inhibiting the NF-κB signalling pathway, thereby attenuating the inflammatory response to radiation lung injury.

The Application Value of Spiral CT Lung Densitometry Software in the Diagnosis of Radiation-Induced Lung Injury.

In order to study the application value of spiral CT lung density measurement software in the diagnosis of radioactive lung injury, the average CT values of lung apex, hilum, and diaphragm were measured by Pulmo automatic evaluation software of 16-slice spiral CT in 96 patients with different types of radiation lung injury diagnosed by conventional CT and 80 healthy subjects. The radiation lung injury on CT slices was classified, and the lung density was measured. In 96 patients with different types of radiation lung injury, 56 patients had different degrees of increase in average lung density, which was most obvious in the type of air insufficiency and chronic fibrosis. CT values of lung density in the ground glass stage and patch stage of acute radiation pneumonia had little influence due to the range and time of exposure. The lung density of 35 patients with radiation injury was measured in the normal range. There was a significant difference between normal lung density and abnormal lung density in different types of radiation lung injury (X2 = 56.718, P < 0.001). The mean lung density of 68 cases was normal and that of 12 cases was abnormal. There was a significant difference in lung density between the lung injury group and the normal group (X2 = 18.027, P < 0.001). Spiral CT lung density measurement can accurately evaluate the lung density values of different types of radiation lung injury and judge the correlation between lung density and different types of radiation lung injury. It is of great value to diagnose, locate, and master the radiation dose of different types of radiation lung injury.

Bibliometric analysis of research relating to radiation-induced lung injury [2001-2020

Radiotherapy is one of the common means of cancer treatment, especially in the treatment of lung cancer. However, radiation therapy can cause lung tissue radiation lung injury. The study of this disease can reduce its incidence and avoid the occurrence of radiation pulmonary fibrosis. In the past 20 years, the study of radiation-induced lung injury (RILI) has attracted more attention. This paper extracts the main text information of RILI-related literature from WOSCC database from 2001 to 2020, uses Citespace and VOSviewer for visual analysis, and presents the results. We found that in the past 20 years, there have been 4,665 articles on RILI, and the number of articles published reached a peak in 2017. The United States is the main leader in this research field, among which UNIV Texas MD Anderson Cancer Center has published many research results in this field. The most active author is Liao Zhongxing, and the most influential journal is Int J Radiat Oncol, which provides a platform for scholars in related fields to publish their articles. Current research focuses mainly on randomized controlled trials related to RILI, the relationship between dose-volume histogram analysis and RILI formation, the protection of normal lung tissue, the effect of stereoscopic radiotherapy on RILI and the pathogenesis of RILI. In the study of the formation mechanism of RILI, the main research directions include the apoptosis mechanism of epithelial and endothelial cells, cytokine cascade theory, immune mechanism regulation process, oxidative stress mechanism, etc.

Preclinical Studies and Clinical Prospects of Wharton's Jelly-Derived MSC for Treatment of Acute Radiation Syndrome.

Purpose of ReviewWharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) have received widespread attention from researchers owing to the remarkable benefits offered by these cells over other stem cells. The primitive nature of WJ-MSCs, ease of isolation, differentiation ability, and immuno-modulatory nature make these cells superior to bone marrow MSCs and ideal to treat various human ailments. This review explores ability of WJ-MSCs to mitigate acute radiation syndrome caused by planned or unplanned radiation exposure.Recent FindingsRecent reports suggest that WJ-MSCs home to damaged tissues in irradiated host and mitigate radiation induced damage to radiosensitive tissues such as hematopoietic and gastrointestinal systems. WJ-MSCs and conditioned media were found to protect mice from radiation induced mortality and also prevent radiation dermatitis. Local irradiation-induced lung toxicity in mice was significantly reduced by CXCR4 over-expressing WJ-MSCs.SummaryEmerging evidences support safety and effectiveness of WJ-MSCs for treatment of acute radiation syndrome and lung injury after planned or accidental exposure. Additionally, conditioned media collected after culturing WJ-MSCs can also be used for mitigation of radiation dermatitis. Clinical translation of these findings would be possible after careful evaluation of resilience, effectiveness, and molecular mechanism of action of xenogeneic WJ-MSCs in non-human primates.

Captopril reduces lung inflammation and accelerated senescence in response to thoracic radiation in mice.

ABSTRACTThe lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to mitigate radiation lung injury and to improve survival in animal models of thoracic irradiation, but the mechanism remains poorly understood. Here we investigated the effect of captopril on early inflammatory events in the lung in female CBA/J mice exposed to thoracic X-ray irradiation of 17–17.9 Gy (0.5–0.745 Gy min–1). For whole-body + thoracic irradiation, mice were exposed to 7.5 Gy (0.6 Gy min–1) total-body 60Co irradiation and 9.5 Gy thoracic irradiation. Captopril was administered orally (110 mg kg–1 day–1) in the drinking water, initiated 4 h through to150 days post-irradiation. Captopril treatment increased survival from thoracic irradiation to 75% at 150 days compared with 0% survival in vehicle-treated animals. Survival was characterized by a significant decrease in radiation-induced pneumonitis and fibrosis. Investigation of early inflammatory events showed that captopril significantly attenuated macrophage accumulation and decreased the synthesis of radiation-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines in the lungs of irradiated mice. Suppression of IL-1β and TNF-α correlated with an increase of the anti-inflammatory cytokine IL-10 in the spleen with captopril treatment. We also found that captopril decreased markers for radiation-induced accelerated senescence in the lung tissue. Our data suggest that suppression of inflammation and senescence markers, combined with an increase of anti-inflammatory factors, are a part of the mechanism for captopril-induced survival in thoracic irradiated mice.

Analysis of the efficacy and safety of iodine-125 seeds implantation in the treatment of patients with inoperable early-stage non-small cell lung cancer.

PurposeTo evaluate the efficacy and safety of iodine-125 (125I) seeds implantation for inoperable early-stage non-small cell lung cancer (NSCLC).Material and methodsPubMed, Cochrane Library, Embase, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched from inception until April 2020. Data were collected concerning overall survival, short-term efficacy, and complications. Meta-analysis was performed using R software (version 3.6.3).ResultsNine studies involving 308 patients were included. Meta-analysis showed that the 1-, 2-, and 3-year survival rates were 0.98% (95% CI: 0.95-0.99%), 0.83% (95% CI: 0.77-0.89%), and 0.65% (95% CI: 0.55-0.75%), respectively; short-term local control rate (LCR) and effective rates were 0.99% (95% CI: 0.98-1.00%) and 0.92% (95% CI: 0.83-0.98%), respectively; 1-, 2-, and 3-year LCRs were 0.96% (95% CI: 0.83-1.00%), 0.94% (95% CI: 0.85-0.99%), and 0.95% (95% CI: 0.76-1.00%), respectively. Sub-group analysis of the prescribed dose found that when the prescribed dose was > 120 Gy, short-term efficacy and 1-year LCR were increased significantly (p < 0.01). The incidence of bleeding, pneumothorax, and radiation lung injury was 0.14% (95% CI: 0.07-0.21%), 0.19% (95% CI: 0.11-0.28%), and 0.00% (95% CI: 0.00-0.03%), respectively. Two studies involving 106 patients compared 125I seeds combined with chemotherapy versus chemotherapy alone for NSCLC. Results showed that compared with chemotherapy alone, 125I seeds combined with chemotherapy could improve short-term LCR (RR = 1.34, 95% CI: 1.09-1.65%, p = 0.005) and short-term effective rate (RR = 1.49, 95% CI: 1.14-1.96%, p = 0.004).Conclusions125I seeds implantation is safe and effective approach for the treatment of inoperable early-stage NSCLC, but high-quality clinical research is still needed to further confirm the findings.

Evaluation of the Lung Dose in Three-dimensional Conformal Radiation Therapy of Left-Sided Breast Cancer: A Phantom Study.

Background:Three-dimensional 3D-CRT: conformal radiation therapy is a selective modality in many radiotherapy centers for the treatment of breast cancer. One of the most common side effects of this method is radiation lung injury. Considering such an injury, lung dose deserves to be studied in depth.Methods:Computed tomography scan of a node-positive left-sided breast cancer woman was used for generating a thorax phantom. Ten thermoluminescent dosimeters (TLDs) were distributed evenly in the left lung of the phantom, and the phantom was scanned. The optimal plan, including supraclavicular and tangential fields, was created by the treatment planning system (TPS). The results of TLD dose measurements at the selected points in the phantom were compared to TPS dose calculations.Results:Lung doses calculated by TPS are significantly different from those measured by the TLDs (P = 0.007). The minimum and maximum differences were −0.91% and 4.46%, respectively. TLDs that were on the inner margin of the lung and breast tissue showed higher dose differences than the TLDs in the lung.Conclusion:The results of this study showed that TPS generally overestimated doses compared to TLD measurements due to incorrect beam modeling caused by contaminated electrons in the lung.

Postmastectomy intensity modulation radiated therapy of chest wall and regional nodes: Retrospective analysis of the performance and complications up for 5 years.

To retrospectively evaluate the performance and complications of postmastectomy intensity modulation radiated therapy (IMRT) technique.From January 2010 to December 2014, IMRT technique was applied to 200 patients after modified radical mastectomy. The acute and late radiation toxicities have been followed up for 5 years. The treatment performance, toxicity incidence, and risk factors were investigated.All patients included had at least 1-year of follow-up; mean follow-up was 28.5 months. Three patients had grade 3 acute radiation dermatitis; 1 patient received grade 2 acute radiation induced lung injury, while 3 patients received acute radiation esophagitis. Seven patients had edema at the end of radiotherapy. Multivariate analyses revealed that neoadjuvant chemotherapy and hypertension were the most significant risk factors for acute skin dermatitis and acute radiation induced lung injury, respectively. Trastuzumab treatment was the independent risk factor for late radiation lung injury. Internal mammary nodes irradiation might relate to acute and late radiation induced lung injury. In the follow-ups there were 125 patients that were followed up with for >2 years. The 2-year local-regional recurrence (LRR), distant metastasis (DM), and disease free survival (DFS) were 1.6%, 6.4%, and 92.80%, respectively.Postmastectomy treatment with the IMRT technique can reduce the incidence rate of radiation toxicity by decreasing organs at risk (OARs) irradiation. Patients with risk factors for radiation toxicity should be strictly surveyed throughout radiotherapy.

Value of single-photon emission computed tomography perfusion lung scintigraphy in radiotherapy optimization for non-small cell lung cancer

Objective To explore the relationship between functional dosimetric parameters of radiotherapy plans and radiation-induced lung injury using single-photon emission computed tomography (SPECT) perfusion lung scintigraphy, and to investigate the advantages of SPECT in optimizing radiotherapy plans. Methods From 2014 to 2015, 23 patients with non-small cell lung cancer (NSCLC) who received SPECT perfusion lung scintigraphy before radiotherapy were enrolled as subjects. The functional dose-volume histogram (fDVH) was generated and the relationship between fVx (the volume proportion of the functional lung tissue exposed to ≥x Gy of radiation in the whole functional lung tissue) and radiation-induced pneumonitis (RP) was explored. The radiotherapy plans were optimized based on SPECT and the dosimetric parameters were then compared between the optimized and conventional radiotherapy plans. The SPSS 13 software was used for chi-square test and receiver operating characteristic curve analysis. Comparison of DVH and fDVH between conventional and optimized radiotherapy plans was made by paired t test. Results The fV13 value for both lungs was most correlated with the incidence of grade ≥2 RP. The fV10, fV13, fV20, fV25, and fV40 values were significantly reduced and the conformity index was significantly improved after optimization (P=0.006, 0.007, 0.010, 0.036, 0.035, 0.040). Conclusions SPECT can be used to optimize radiotherapy plans. The fV13 value may be correlated with the incidence and severity of RP. Key words: Tomography, X-ray computed, single-photon emission; Pulmonary perfusion imaging; Radiation lung injury; Dose volume histogram

IL-13 is a therapeutic target in radiation lung injury.

Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics.

Detection of the serum endothelin content in patients with acute lung injury and its value of severity evaluation

ObjectiveTo observe the correlation of serum endothelin content in patients with acute radiation lung injury and with the degree of inflammatory reaction and the lung functional level. Methods68 Patients with non-small cell lung cancer who received the radiotherapy in treatment from May 2013 to October 2015 in our hospital were selected as the object of study. 25 patients who had acute radiation induced lung injury within 24 months of the radiotherapy were rolled in the radiation induced lung injury group (RILI group), and the rest of 43 without acute lung injury were rolled in the negative control group (NC group). The contents of endothelin, tumor necrosis factor α, interleukin-1β, interleukin-6 in serum and the partial pressure of oxygen in artery, partial pressure of carbon dioxide in artery, vital capacity, forced expiratory volume in one second, maximal ventilatory volume, and diffusion capacity for carbon monoxide were tested. ResultsThe content of serum endothelin of the patients in the RILI group [(69.3 ± 7.5) pg/mL] were all obviously higher than that of the NC group [(24.1 ± 2.9) pg/mL]; the content of the serum tumor necrosis factor α [(49.6 ± 5.1) ng/mL vs. (22.7 ± 3.1) ng/mL], interleukin-1β [(29.4 ± 3.3) ng/mL vs. (15.7 ± 1.8) ng/mL], interleukin-6 [(163.4 ± 20.3) pg/mL vs. (89.4 ± 10.2) pg/mL] and the partial pressure of carbon dioxide in artery [(49.2 ± 5.2) mmHg vs. (40.3 ± 4.8) mmHg] were all obviously higher than that of the NC group, which were positively correlated with the serum endothelin content. But the partial pressure of oxygen in artery [(68.4 ± 7.8) mmHg vs. (87.3 ± 9.5) mmHg], vital capacity [(1203.4 ± 136.5) mL vs. (2034.8 ± 238.5) mL], forced expiratory volume in one second [(38.4 ± 4.1)% vs. (58.3 ± 6.2)%], maximum minute ventilation [(33.7 ± 3.8) L/min vs. (66.1 ± 7.9) L/min] and diffusing capacity of the lungs for carbon monoxide [(79.3 ± 8.9)% vs. (86.7 ± 9.4)%)] were obviously lower than that of the NC group, which were negatively correlated with the serum endothelin content. ConclusionThe elevated content of the endothelin in the serum of patients with acute radiation induced lung injury could assess the degree of inflammatory reaction and the lung functional level.

Multiple parametric approaches to assess acute radiation lung injury of rats radiation lung injury of rats.

The effect of whole body gamma irradiation (WBI) in single fraction was studied, as well as its influence on the secretion of various biochemical markers and cellular component that could be used as acute radiation lung injury marker. Sprague dawley rats were treated with WBI (60Co) of radiation dose from 1 Gy to 5 Gy (dose rate - 0.95 Gy/min). Bronchoalveolar lavage fluid was retrieved from all animals in control and radiation treated groups up to 72 h post radiation. Bronchoalveolar lavage fluid (BALF) was analyzed for lactate dehydrogenase (LDH ), acid phosphatase (AP ), alkaline phosphatase (ALP ), cell count and total protein. Intragroup and intergroup comparison of BALF parameters at different radiation doses showed significant difference. LDH was significantly increased as the dose increased from 1Gy to 5Gy (P = 0.00) after 2 h with effect size of difference (r > 0.3). ALP was significantly altered after 3Gy and 4Gy (P < 0.05). AP was significantly altered at 2Gy-5Gy (p < 0.05). Total protein level changed significantly from 1Gy to 5Gy (P < 0.00). Cellular content of BALF showed significant changes after radiation exposure. BALF parameters like LDH, AP, ALP, neutrophils, lymphocytes, total leukocyte count and total protein were sensitive to radiation exposure and their levels vary significantly up to 72 h after single whole body radiation exposure in Sprague dawley rats. It can be concluded that the biochemical indices in BALF have more wide application in evaluation of acute radiation induced lung injury.

Transforming growth factor alpha is a critical mediator of radiation lung injury.

Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson's trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-α on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-α(-/-) mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-α(-/-) mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 μg/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-α (-/-) mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1β, IL-4, TNF-α, TGF-β and EGF at multiple time points after irradiation were similar in C57-WT and TGF-α(-/-) mice. TGF-α in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-α(-/-) mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-α(-/-) mice. Treatment of NIH-3T3 fibroblasts with TGF-α resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-α as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-α as a mediator of collagen maturation through a TGF-β independent activation of lysyl oxidase.

FDG Pulmonary Uptake Changes During and Post-Radiation Therapy Compared to Pretreatment in Predicting Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer

We hypothesize that the 18F-fludeoxyglucose (18FDG) uptake changes during early radiation therapy reflect subclinical radiation lung injury that is predictive of post-treatment radiation induced lung toxicity (RILT). The primary aim of our study was to investigate the relationship between clinically significant RILT and pulmonary 18FDG uptake changes during and post-radiation therapy. We studied a prospectively recruited cohort of 84 NSCLC patients treated with chemoradiation therapy. All patients had 18FDG PET performed before and during RT and 49 patients also had post-RT PET images. Pulmonary 18FDG uptake were assessed using Hick's visual grading scale (0-3) by a physician blinded to clinical RILT results: Grade 0∼ no abnormality identified in normal tissues within the radiation treatment volume; Grade 1∼increased activity in the pleural reflections and soft tissues within the radiation treatment volume but no parenchymal lung changes; Grade 2 = increased parenchymal lung uptake in the radiation treatment volume of equal or lower intensity than normal soft tissues in the mediastinum or chest wall located outside the radiation field; Grade 3 = increased parenchymal lung uptake in the radiation treatment volume of greater intensity than normal soft tissues in the mediastinum or chest wall. Common Terminology Criteria for Adverse Events version 3.0 was used to score RILT and event was defined as grade 2 or higher. On during-RT PET images, 75 (89.3%), 5 (6.0%), 4 (4.7%) and 0 (0%) patients had grade 0, 1, 2, and 3 changes, respectively. At 3 months after completion of RT, 42.9% patients had visible changes: 12 (24.5%) grade 1, 3 (6.1%) grade 2, and 6 (12.2%) grade 3 on the post-RT PET images. Overall, 11 patients (13.1%) developed RILT and the median time to RILT after radiation therapy was 4.6 months (range, 2-10). Among patients developed clinical RILT, 3 patients (37.5%) grade 1-2, 4 (50%) had grade 3 FDG uptake on the post-RT PET images. In 9 patients with increased FDG uptake during-RT, 5 (55.6 %) developed RILT, and 3 of them had grade 3 and above. Among 8 RILT patients with post-RT PET images available for assessment, 7 (89%) had grade 1-3 changes on FDG uptake. There was a significant correlation between the incidence of severe RILT and FDG uptake changes on during-RT (p = 0.002) and post-RT (p < 0.001) PET images. FDG uptake is commonly increased at 3 months after RT, but infrequently increased on during-RT PET. Increase in FDG uptake in lung either during- or post-RT may be associated with increased risk of RILT. Increased uptake during-RT may identify patients at highest risk for RILT. Visual assessment of PET may identify patients at high risk for toxicity and guide individualized radiation plan to decrease RILT.

Role of Migratory Inhibition Factor in Age-Related Susceptibility to Radiation Lung Injury via NF-E2–Related Factor–2 and Antioxidant Regulation

Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.

Enalapril Mitigates Focal Alveolar Lesions, A Histological Marker of Late Pulmonary Injury by Radiation to the Lung

The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described "late effect" in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25-42 mg/m²/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/RijCmcr rats.

Reactive Oxygen Species and X-Ray Disrupted Spontaneous [Ca2+]iOscillation in Alveolar Macrophages

Radiation leads to a rapid burst of reactive oxygen species (ROS), which is considered to be one of the major causes of radiation-induced injury. ROS have previously been shown to induce changes in cytosolic Ca²⁺ ([Ca²⁺]i) including [Ca²⁺]i oscillation. However, the role of radiation in [Ca²⁺]i oscillation is poorly understood. The purpose of this study was to identify the effect of ROS and X ray on [Ca²⁺]i oscillation, as well as their role in radiation-induced lung injury. Alveolar macrophages were cultured in the absence and presence of different doses of hydrogen peroxide (H₂O₂) or exposed to X-ray irradiation with or without pretreatment of diphenyleneiodonium chloride (DPI, an inhibitor of NADPH oxidases) or tetrandrine (TET, a calcium entry blocker) and cytosolic Ca²⁺ concentration was detected by fluorescent Ca²⁺ indicator Fura-2. Rat radiation lung injury was induced in vivo by using 40 Gy X ray and DPI or TET was used to prevent radiation-induced lung injury. The results showed that there was spontaneous [Ca²⁺]i oscillation in alveolar macrophages under normal conditions, and treatment of H₂O₂ (100-500 μM) or 2 Gy X ray inhibited the spontaneous [Ca²⁺]i oscillation and induced [Ca²⁺]i rise. TET abolished H₂O₂ or X ray induced [Ca²⁺]i rise in alveolar macrophages, and attenuated X ray- induced rat alveolitis in vivo. DPI prevented X-ray-induced inhibition of [Ca²⁺]i oscillation in alveolar macrophages and prevented X-ray-induced rat alveolitis. Taken together, the data suggest that the disruption of [Ca²⁺]i oscillation and induction of [Ca²⁺]i rise through ROS is involved in the mechanism of radiation-induced lung injury.

End-Stage Radiation Pneumonitis After Autologous Stem Cell Transplantation for Refractory Hodgkin Lymphoma

Radiation lung injury typically occurs after treatment for malignancies, including lung, esophagus, breast, and hematopoietic malignancies. The risk has decreased with development of radiation treatment with lower doses to lung fields via intensity modulated and stereotactic procedures. The risk is still substantial in some settings, such as total body radiation in patients with stem cell transplants or stem cell transplants in patients with recurrent Hodgkin lymphoma. Histologically, radiation injury progresses from acute alveolar injury (diffuse alveolar damage) through a fibrotic phase resembling nonspecific interstitial pneumonia. The histologic features are nonspecific, but atypical pneumocytes are especially enlarged and bizarre in the acute and subacute phases of radiation-induced lung injury. We present a case of radiation fibrosis requiring transplant in a patient with relapsing mediastinal Hodgkin lymphoma requiring stem cell transplant and repeat mediastinal radiation.