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Xin Qi - One of the best experts on this subject based on the ideXlab platform.
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paeoniflorin protects human ea hy926 endothelial cells against gamma radiation induced oxidative Injury by activating the nf e2 related factor 2 heme oxygenase 1 pathway
Toxicology Letters, 2013Co-Authors: Jing Yu, Xin QiAbstract:Abstract Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of Radiation-Induced Lung Injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from Radiation-Induced oxidative Injury. This study was designed to confirm the protective effect of Paeoniflorin against Radiation-Induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against Radiation-Induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against Radiation-Induced Injury through the Nrf2/HO-1 pathway.
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paeoniflorin protects human ea hy926 endothelial cells against gamma radiation induced oxidative Injury by activating the nf e2 related factor 2 heme oxygenase 1 pathway
Toxicology Letters, 2013Co-Authors: Jing Yu, Xin QiAbstract:Abstract Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of Radiation-Induced Lung Injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from Radiation-Induced oxidative Injury. This study was designed to confirm the protective effect of Paeoniflorin against Radiation-Induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against Radiation-Induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against Radiation-Induced Injury through the Nrf2/HO-1 pathway.
Jing Yu - One of the best experts on this subject based on the ideXlab platform.
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paeoniflorin protects human ea hy926 endothelial cells against gamma radiation induced oxidative Injury by activating the nf e2 related factor 2 heme oxygenase 1 pathway
Toxicology Letters, 2013Co-Authors: Jing Yu, Xin QiAbstract:Abstract Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of Radiation-Induced Lung Injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from Radiation-Induced oxidative Injury. This study was designed to confirm the protective effect of Paeoniflorin against Radiation-Induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against Radiation-Induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against Radiation-Induced Injury through the Nrf2/HO-1 pathway.
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paeoniflorin protects human ea hy926 endothelial cells against gamma radiation induced oxidative Injury by activating the nf e2 related factor 2 heme oxygenase 1 pathway
Toxicology Letters, 2013Co-Authors: Jing Yu, Xin QiAbstract:Abstract Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of Radiation-Induced Lung Injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from Radiation-Induced oxidative Injury. This study was designed to confirm the protective effect of Paeoniflorin against Radiation-Induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against Radiation-Induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against Radiation-Induced Injury through the Nrf2/HO-1 pathway.
Zeljko Vujaskovic - One of the best experts on this subject based on the ideXlab platform.
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cerium oxide nanoparticles a potential medical countermeasure to mitigate radiation induced Lung Injury in cba j mice
Radiation Research, 2016Co-Authors: Vlado Antonic, Isabel L Jackson, S Das, Andrew Zodda, Xiuwu Zhang, Sudipta Seal, Zeljko VujaskovicAbstract:Cerium oxide nanoparticles (CNPs) have a unique surface regenerative property and can efficiently control reactive oxygen/nitrogen species. To determine whether treatment with CNPs can mitigate the delayed effects of Lung Injury after acute radiation exposure, CBA/J mice were exposed to 15 Gy whole-thorax radiation. The animals were either treated with nanoparticles, CNP-18 and CNP-ME, delivered by intraperitoneal injection twice weekly for 4 weeks starting 2 h postirradiation or received radiation treatment alone. At the study's end point of 160 days, 90% of the irradiated mice treated with high-dose (10 μM) CNP-18 survived, compared to 10% of mice in the radiation-alone (P < 0.0001) and 30% in the low-dose (100 nM) CNP-18. Both low- and high-dose CNP-ME-treated irradiated mice showed increased survival rates of 40% compared to 10% in the radiation-alone group. Multiple Lung functional parameters recorded by flow-ventilated whole-body plethysmography demonstrated that high-dose CNP-18 treatment had a significant radioprotective effect on lethal dose Radiation-Induced Lung Injury. Lung histology revealed a significant decrease (P < 0.0001) in structural damage and collagen deposition in mice treated with high-dose CNP-18 compared to the irradiated-alone mice. In addition, significant reductions in inflammatory response (P < 0.01) and vascular damage (P < 0.01) were observed in the high-dose CNP-18-treated group compared to irradiated-alone mice. Together, the findings from this preclinical efficacy study clearly demonstrate that CNPs have both clinically and histologically significant mitigating and protective effects on lethal dose Radiation-Induced Lung Injury.
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radiation induced Lung Injury is mitigated by blockade of gastrin releasing peptide
American Journal of Pathology, 2013Co-Authors: Shutang Zhou, Zeljko Vujaskovic, Frank Cuttitta, Esther Nissao, Isabel L Jackson, Wei Leong, Lindsay Dancy, Mary E SundayAbstract:Gastrin-releasing peptide (GRP), secreted by pulmonary neuroendocrine cells, mediates oxidant-induced Lung Injury in animal models. Considering that GRP blockade abrogates pulmonary inflammation and fibrosis in hyperoxic baboons, we hypothesized that ionizing radiation triggers GRP secretion, contributing to inflammatory and fibrotic phases of Radiation-Induced Lung Injury (RiLI). Using C57BL/6 mouse model of pulmonary fibrosis developing ≥20 weeks after high-dose thoracic radiation (15 Gy), we injected small molecule 77427 i.p. approximately 1 hour after radiation then twice weekly for up to 20 weeks. Sham controls were anesthetized and placed in the irradiator without radiation. Lung paraffin sections were immunostained and quantitative image analyses performed. Mice exposed to radiation plus PBS had increased interstitial CD68 + macrophages 4 weeks after radiation and pulmonary neuroendocrine cells hyperplasia 6 weeks after radiation. Ten weeks later radiation plus PBS controls had significantly increased pSmad2/3 + nuclei/cm 2 . GRP blockade with 77427 treatment diminished CD68 + , GRP + , and pSmad2/3 + cells. Finally, interstitial fibrosis was evident 20 weeks after radiation by immunostaining for α-smooth muscle actin and collagen deposition. Treatment with 77427 abrogated interstitial α-smooth muscle actin and collagen. Sham mice given 77427 did not differ significantly from PBS controls. Our data are the first to show that GRP blockade decreases inflammatory and fibrotic responses to radiation in mice. GRP blockade is a novel radiation fibrosis mitigating agent that could be clinically useful in humans exposed to radiation therapeutically or unintentionally.
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a preclinical rodent model of radiation induced Lung Injury for medical countermeasure screening in accordance with the fda animal rule
Health Physics, 2012Co-Authors: Isabel L Jackson, Zeljko Vujaskovic, Puting Xu, Caroline Hadley, Barry P Katz, R Mcgurk, Julian D DownAbstract:The purpose of pre-clinical murine model development is to establish that the pathophysiological outcome of our rodent model of Radiation-Induced Lung Injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation Lung Injury in humans. In this study, we assessed this issue by evaluating the relationship between morbidity (pulmonary function, histopathologic damage) and mortality among three strains of mice, C57BL/6J, CBA/J, and C57L/J. These different strains display variations in latency and phenotypic expression of Radiation-Induced Lung damage. By comparing the response of each strain to the human pulmonary response, we established an appropriate animal model(s) of human Radiation-Induced pulmonary Injury. Observations in the C57L/J and CBA/J murine models can be extrapolated to the human Lung for evaluation of mechanisms of action of radiation as well as future efficacy testing and approving agents that fall under the “Animal Rule” of the US Food and Drug Administration (FDA) (21 CFR Parts 314 and 601).
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overexpression of extracellular superoxide dismutase protects mice from radiation induced Lung Injury
International Journal of Radiation Oncology Biology Physics, 2002Co-Authors: Song K Kang, Rodney J Folz, Zahid N Rabbani, Mitchell S Anscher, Hong Huang, Maria L Golson, T Samulski, Mark W Dewhirst, Zeljko VujaskovicAbstract:Abstract Purpose The purpose of this study was to determine if Radiation-Induced Lung Injury is associated with prolonged oxidative stress, and whether chronic overexpression of extracellular superoxide dismutase (EC-SOD) in the Lung of transgenic mice protects against Radiation-Induced Lung Injury. Methods and materials Whole-Lung radiation was delivered to EC-SOD overexpressing B6C3 transgenic (XRT-TG) mice and wild-type littermates (XRT-WT). Pulmonary function was assessed by breathing frequency. Right Lung wet weight was used as a gross indicator of Lung damage. Histopathology was used to assess collagen deposition and tissue fibrosis according to an established grading system. Immunohistochemistry was used to stain and quantify the number of macrophages. ELISA was used to measure activated TGF-β1. Oxidative stress was assessed by measuring lipid oxidation products (malondialic acid) by HPLC. Results Four of six XRT-WT mice required euthanasia at 15–19 weeks postradiation because of respiratory distress, whereas no XRT-TG mouse developed distress. All assessments of Lung damage at 15–20 weeks postradiation were higher for XRT-WT mice compared with the XRT-TG mice, including breathing frequency (380 vs. 286 bpm, p ≤ 0.0004), right Lung weight (228 vs. 113 mg, p ≤ 0.06), macrophage count (48 vs. 5 per 40× field, p ≤ 0.06), and percent activated TGF-β1 (37 vs. 11%, p ≤ 0.06). Semiquantitative measures, including fibrosis and collagen deposition, were also higher for XRT-WT mice, with an exact Fisher p value of ≤0.03 for both variables. In addition, malondialic acid was elevated in XRT-WT mice 15–20 weeks after radiation delivery, and levels were lower in the XRT-TG mice (624 vs. 323 pmol/mg protein, p ≤ 0.06). Conclusions After radiation therapy, oxidative stress is present at 15–20 weeks after initial exposure, which correlates with the delayed clinical onset of Radiation-Induced Lung damage. Overexpression of EC-SOD in transgenic mice appears to confer protection against this Radiation-Induced Lung Injury, with a corresponding decrease in oxidative stress. EC-SOD may be a potential therapeutic agent for radioprotection in the treatment of thoracic malignancies. Further investigation is needed to confirm and expand on the current results.
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a small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase sod mimetic properties protects Lungs from radiation induced Injury
Free Radical Biology and Medicine, 2002Co-Authors: Zeljko Vujaskovic, Qin Fu Feng, Zahid N Rabbani, Thaddeus V Samulski, Mark W Dewhirst, Song K Kang, Ines Batinichaberle, Ivan Spasojevic, Irwin Fridovich, Mitchell S AnscherAbstract:Radiation therapy (RT) is an important therapeutic modality in the treatment of thoracic tumors. The maximum doses to these tumors are often limited by the radiation tolerance of Lung tissues. Lung Injury from ionizing radiation is believed to be a consequence of oxidative stress and a cascade of cytokine activity. Superoxide dismutase (SOD) is a key enzyme in cellular defenses against oxidative damage. The objective of this study was to determine whether the SOD mimetic AEOL 10113 [manganese (III) mesotetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP(5+))] increases the tolerance of Lung to ionizing radiation. AEOL 10113 was able to significantly reduce the severity of RT-induced Lung Injury. This was strongly supported with histopathology results and measurements of collagen deposition (hydroxyproline content). There was a significant reduction in the plasma level of the profibrogenic cytokine transforming growth factor-beta (TGF-beta) in the group of rats receiving RT + AEOL 10113. In conclusion, the novel SOD mimetic, AEOL 10113, demonstrates a significant protective effect from Radiation-Induced Lung Injury.
Mitchell S Anscher - One of the best experts on this subject based on the ideXlab platform.
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overexpression of extracellular superoxide dismutase protects mice from radiation induced Lung Injury
International Journal of Radiation Oncology Biology Physics, 2002Co-Authors: Song K Kang, Rodney J Folz, Zahid N Rabbani, Mitchell S Anscher, Hong Huang, Maria L Golson, T Samulski, Mark W Dewhirst, Zeljko VujaskovicAbstract:Abstract Purpose The purpose of this study was to determine if Radiation-Induced Lung Injury is associated with prolonged oxidative stress, and whether chronic overexpression of extracellular superoxide dismutase (EC-SOD) in the Lung of transgenic mice protects against Radiation-Induced Lung Injury. Methods and materials Whole-Lung radiation was delivered to EC-SOD overexpressing B6C3 transgenic (XRT-TG) mice and wild-type littermates (XRT-WT). Pulmonary function was assessed by breathing frequency. Right Lung wet weight was used as a gross indicator of Lung damage. Histopathology was used to assess collagen deposition and tissue fibrosis according to an established grading system. Immunohistochemistry was used to stain and quantify the number of macrophages. ELISA was used to measure activated TGF-β1. Oxidative stress was assessed by measuring lipid oxidation products (malondialic acid) by HPLC. Results Four of six XRT-WT mice required euthanasia at 15–19 weeks postradiation because of respiratory distress, whereas no XRT-TG mouse developed distress. All assessments of Lung damage at 15–20 weeks postradiation were higher for XRT-WT mice compared with the XRT-TG mice, including breathing frequency (380 vs. 286 bpm, p ≤ 0.0004), right Lung weight (228 vs. 113 mg, p ≤ 0.06), macrophage count (48 vs. 5 per 40× field, p ≤ 0.06), and percent activated TGF-β1 (37 vs. 11%, p ≤ 0.06). Semiquantitative measures, including fibrosis and collagen deposition, were also higher for XRT-WT mice, with an exact Fisher p value of ≤0.03 for both variables. In addition, malondialic acid was elevated in XRT-WT mice 15–20 weeks after radiation delivery, and levels were lower in the XRT-TG mice (624 vs. 323 pmol/mg protein, p ≤ 0.06). Conclusions After radiation therapy, oxidative stress is present at 15–20 weeks after initial exposure, which correlates with the delayed clinical onset of Radiation-Induced Lung damage. Overexpression of EC-SOD in transgenic mice appears to confer protection against this Radiation-Induced Lung Injury, with a corresponding decrease in oxidative stress. EC-SOD may be a potential therapeutic agent for radioprotection in the treatment of thoracic malignancies. Further investigation is needed to confirm and expand on the current results.
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a small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase sod mimetic properties protects Lungs from radiation induced Injury
Free Radical Biology and Medicine, 2002Co-Authors: Zeljko Vujaskovic, Qin Fu Feng, Zahid N Rabbani, Thaddeus V Samulski, Mark W Dewhirst, Song K Kang, Ines Batinichaberle, Ivan Spasojevic, Irwin Fridovich, Mitchell S AnscherAbstract:Radiation therapy (RT) is an important therapeutic modality in the treatment of thoracic tumors. The maximum doses to these tumors are often limited by the radiation tolerance of Lung tissues. Lung Injury from ionizing radiation is believed to be a consequence of oxidative stress and a cascade of cytokine activity. Superoxide dismutase (SOD) is a key enzyme in cellular defenses against oxidative damage. The objective of this study was to determine whether the SOD mimetic AEOL 10113 [manganese (III) mesotetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP(5+))] increases the tolerance of Lung to ionizing radiation. AEOL 10113 was able to significantly reduce the severity of RT-induced Lung Injury. This was strongly supported with histopathology results and measurements of collagen deposition (hydroxyproline content). There was a significant reduction in the plasma level of the profibrogenic cytokine transforming growth factor-beta (TGF-beta) in the group of rats receiving RT + AEOL 10113. In conclusion, the novel SOD mimetic, AEOL 10113, demonstrates a significant protective effect from Radiation-Induced Lung Injury.
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assessment of the protective effect of amifostine on radiation induced pulmonary toxicity
Experimental Lung Research, 2002Co-Authors: Zeljko Vujaskovic, Qin Fu Feng, Zahid N Rabbani, Thaddeus V Samulski, Mitchell S Anscher, David M BrizelAbstract:The objective of this study was to assess the radioprotective effects of amifostine in the rat model of Radiation-Induced Lung Injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)- β correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right Lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was meas...
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predicting the risk of symptomatic radiation induced Lung Injury using both the physical and biologic parameters v30 and transforming growth factor β
International Journal of Radiation Oncology Biology Physics, 2001Co-Authors: Hong Huang, Gunilla C Bentel, Robert W Clough, Randy L Jirtle, Feng Ming Kong, Lawrence B Marks, Mitchell S AnscherAbstract:Abstract Purpose: To correlate the volume of Lung irradiated with changes in plasma levels of the fibrogenic cytokine transforming growth factor β (TGFβ) during radiotherapy (RT), such that this information might be used to predict the development of symptomatic Radiation-Induced Lung Injury (SRILI). Methods and Materials: The records of all patients with Lung cancer treated with RT with curative intent from 1991 to 1997 on a series of prospective normal tissue Injury studies were reviewed. A total of 103 patients were identified who met the following inclusion criteria: ( 1 ) newly diagnosed Lung cancer of any histology treated with RT ± chemotherapy with curative intent; ( 2 ) no evidence of distant metastases or malignant pleural effusion; ( 3 ) no thoracic surgery after Lung RT; ( 4 ) no endobronchial brachytherapy; ( 5 ) follow-up time more than 6 months; ( 6 ) plasma TGFβ1 measurements obtained before and at the end of RT. The concentration of plasma TGFβ1 was measured by an enzyme-linked immunosorbent assay. Seventy-eight of the 103 patients were treated with computed tomography based 3-dimensional planning and had dose–volume histogram data available. The endpoint of the study was the development of SRILI (modified NCI [National Cancer Institute] common toxicity criteria). Results: The 1-year and 2-year actuarial incidence of SRILI for all 103 patients was 17% and 21%, respectively. In those patients whose TGFβ level at the end of RT was higher than the pre-RT baseline, SRILI occurred more frequently (2-year incidence = 39%) than in patients whose TGFβ1 level at the end of RT was less than the baseline value (2-year incidence = 11%, p = 0.007). On multivariate analysis, a persistent elevation of plasma TGFβ1 above the baseline concentration at the end of RT was an independent risk factor for the occurrence of SRILI ( p = 0.004). The subgroup of 78 patients treated with 3-dimensional conformal radiotherapy, who consequently had dose–volume histogram data, were divided into groups according to their TGFβ1 kinetics and whether their V 30 level was above or below the median of 30%. Group I ( n = 29), with both a TGFβ1 level at the end of RT that was below the pre-RT baseline and V 30 n = 35), with a TGFβ1 level at the end of irradiation that was below the baseline but a V 30 ≥ 30% or with a TGFβ1 level at the end of RT that was above the pre-RT baseline but V 30 n = 14), with both a TGFβ1 level at the end of RT that was above the baseline and V 30 ≥ 30%. A significant difference was found in the incidence of SRILI among these three groups (6.9%, 22.8%, 42.9%, respectively, p = 0.02). Conclusions: ( 1 ) An elevated plasma TGFβ1 level at the end of RT is an independent risk factor for SRILI; ( 2 ) The combination of plasma TGFβ1 level and V 30 appears to facilitate stratification of patients into low, intermediate, and high risk groups. Thus, combining both physical and biologic risk factors may allow for better identification of patients at risk for the development of symptomatic Radiation-Induced Lung Injury.
Thomas J Macvittie - One of the best experts on this subject based on the ideXlab platform.
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acute radiation induced Lung Injury in the non human primate a review and comparison of mortality and co morbidities using models of partial body irradiation with marginal bone marrow sparing and whole thorax Lung irradiation
Health Physics, 2020Co-Authors: Thomas J Macvittie, Ann M Farese, George A Parker, Alexander Bennett, William E JacksonAbstract:The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of Radiation-Induced Lung Injury. Herein, a literature review of published studies showing the evolution of lethal Lung Injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax Lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature. The primary studies conducted at two research sites benefitted from the similarity of major variables; namely, both sites used rhesus macaques of approximate age and body weight and radiation exposure by LINAC-derived 6 MV photons at dose rates of 0.80 Gy min and 1.00 Gy min delivered to the midline tissue via bilateral, anterior/posterior, posterior/anterior geometry. An advantage relative to sex difference resulted from the use of male and female macaques by the Maryland and the Washington sites, respectively. Subject-based medical management was used for all macaques. The primary studies (6) provided adequate data to establish dose response relationships within 180 d for the Radiation-Induced Lung Injury consequent to whole thorax Lung irradiation (male vs. female) and partial-body irradiation with bone marrow sparing exposure protocols (male). The dose response relationships established by probit analyses vs. linear dose relationships were characterized by two main parameters or dependent variables, a slope and LD50/180. Respective LD50/180 values for the primary studies that used whole thorax Lung irradiation for respective male and female nonhuman primates were 10.24 Gy [9.87, 10.52] (n = 76, male) and 10.28 Gy [9.68, 10.92] (n = 40, female) at two different research sites. The respective slopes were steep at 1.73 [0.841, 2.604] and 1.15 [0.65, 1.65] probits per linear dose. The LD50/180 value and slope derived from the dose response relationships for the partial-body irradiation with bone marrow sparing exposure was 9.94 Gy [9.35, 10.29] (n = 87) and 1.21 [0.70, 1.73] probits per linear dose. A secondary study (1) provided data on limited control cohort of nonhuman primates exposed to whole thorax Lung irradiation. The data supported the incidence of clinical, radiographic, and histological indices of the dose-dependent Lung Injury in the nonhuman primates. Tertiary studies (6) provided data derived from collaboration with the noted primary and secondary studies on control cohorts of nonhuman primates exposed to whole thorax Lung irradiation and partial-body irradiation with bone marrow sparing exposure. These studies provided a summary of histological evidence of fibrosis, inflammation and reactive/proliferative changes in pneumonocytes characteristic of Lung Injury and data on biomarkers for Radiation-Induced Lung Injury based on matrix-assisted laser desorption ionization-mass spectrometry imaging and gene expression approaches. The available database in young rhesus macaques exposed to whole thorax Lung irradiation or partial-body irradiation with bone marrow sparing using 6 MV LINAC-derived radiation with medical management showed that the dose response relationships were equivalent relative to the primary endpoint all-cause mortality. Additionally, the latency, incidence, severity, and progression of the clinical, radiographic, and histological indices of Lung Injury were comparable. However, the differences between the exposure protocols are remarkable relative to the demonstrated time course between the multiple organ Injury of the acute radiation syndrome and that of the delayed effects of acute radiation exposure, respectively.
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haplodeletion of follistatin like 1 attenuates radiation induced pulmonary fibrosis in mice
International Journal of Radiation Oncology Biology Physics, 2019Co-Authors: Zhongjie Chen, Yinshan Fang, Si Zhang, Li Wang, Aixu Zhang, Zhiyong Yuan, Ping Wang, Honggang Zhou, Wanchang Cui, Thomas J MacvittieAbstract:Purpose Radiation-Induced pulmonary fibrosis (RIPF) is a severe and life-threatening complication of radiation therapy in patients with thoracic cancer; however, the exact molecular mechanisms remain unknown, and there is no effective treatment method in clinic. Here, we assessed the role of follistatin-like 1 (Fstl1) in RIPF. Methods and Materials Protein and messenger RNA levels of Fstl1 in Lung tissues from symptomatic RIPF patients, Rhesus macaques, and mice were assessed. Fibrotic and inflammatory responses to Radiation-Induced Lung Injury and accumulation of myofibroblasts in Fstl1 haplodeficient (Fstl1+/–) mice were determined. Finally, Radiation-Induced differentiation and activation of fibroblasts in primary Fstl1+/– Lung fibroblasts were evaluated. Results FSTL1 amounts were significantly increased in serum and/or radiation-injured Lung specimens from symptomatic RIPF patients, Rhesus macaques, and mice. Haplodeletion of Fstl1 in Fstl1+/– mice was protective against x-ray–induced Lung Injury in mice in vivo, as well as myofibroblast activation in vitro. Conclusions These findings suggest that Fstl1 plays an important role in Lung fibrosis and may offer a potential approach to attenuate RIPF in radiation therapy of patients with thoracic cancer.
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lipidomic dysregulation within the Lung parenchyma following whole thorax Lung irradiation markers of Injury inflammation and fibrosis detected by maldi msi
Scientific Reports, 2017Co-Authors: Claire L Carter, Thomas J Macvittie, Ann M Farese, Jace W Jones, Maureen A KaneAbstract:Radiation-Induced Lung Injury (RILI) is a delayed effect of acute radiation exposure that can limit curative cancer treatment therapies and cause lethality following high-dose whole-thorax Lung irradiation (WTLI). To date, the exact mechanisms of Injury development following insult remain ill-defined and there are no FDA approved pharmaceutical agents or medical countermeasures. Traditionally, RILI development is considered as three phases, the clinically latent period, the intermediate acute pneumonitis phase and the later fibrotic stage. Utilizing matrix-assisted laser desorption ionization mass spectrometry imaging, we identified a number of lipids that were reflective of disease state or Injury. Lipids play central roles in metabolism and cell signaling, and thus reflect the phenotype of the tissue environment, making these molecules pivotal biomarkers in many disease processes. We detected decreases in specific surfactant lipids irrespective of the different pathologies that presented within each sample at 180 days post whole-thorax Lung irradiation. We also detected regional increases in ether-linked phospholipids that are the precursors of PAF, and global decreases in lipids that were reflective of severe fibrosis. Taken together our results provide panels of lipids that can differentiate between naive and irradiated samples, as well as providing potential markers of inflammation and fibrosis.
