Showing papers on "Radiation-induced lung injury published in 2013"
TL;DR: The data suggest that the FVB/N mouse strain is sensitive to thoracic radiation, aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury, and the epithelial-to-mesenchymal transition may play an important role in the development of radiation -induced lung fibrosis.
Abstract: Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11–13 Gy) and fractionated doses (24–36 Gy) of 137Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c), the number of pro-SP-c+ cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis.
75 citations
TL;DR: MSC-based HGF gene therapy not only reduces inflammation but also inhibits lung fibrosis, as suggested by results of this study.
Abstract: Effective therapeutic strategies for radiation-induced lung injury (RILI) are lacking. Mesenchymal stem cells (MSCs), as gene therapy delivery vehicles, possess the ability to repair injured lung. In this study, we conducted MSC-based hepatocyte growth factor (HGF) gene therapy for RILI. Mice received single-dose radiation with 20 Gy of γ rays locally to the lung, and then were administered normal sodium, Ad-HGF-modified MSCs, or Ad-Null-modified MSCs. Ad-HGF-modified MSCs (MSCs-HGF) improved histopathological and biochemical markers of lung injury. MSCs-HGF could reduce secretion and expression of proinflammatory cytokines, including tumor necrosis factor-α, interferon-γ, interleukin (IL)-6, and intercellular adhesion molecule-1, and increase the expression of antiinflammatory cytokine IL-10. It could also decrease expression levels of profibrosis factors transforming growth factor-β, Col1a1 (collagen type 1, α1), and Col3a1, and inhibit fibrosis progress. MSCs-HGF could promote proliferation of...
74 citations
TL;DR: The results provide a novel insight for RILI therapy that currently lack efficient treatments, and MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response.
65 citations
TL;DR: It is suggested that melatonin reduces radiation-induced lung injury via a significant reduction of oxidative stress and of the production of cytokines, such as TGF-β1 and TNF-α, theProduction of which increased following lung irradiation.
Abstract: Purpose: The modification of radiation-induced lung injuries by melatonin was studied by measuring changes in oxidative stress, cytokine expression and histopathology in the lung tissue of mice following irradiation.Materials and methods: The thoraces of C57BL/6 mice were exposed to a single X-ray radiation dose of 12 Gy with or without 200 mg/kg of melatonin pretreatment. The level and localization of transforming growth factor (TGF)-β1 protein were measured using an enzyme-linked immunosorbent assay (ELISA) method and immunohistochemical staining, respectively. Real-time quantitative polymerase chain reaction (PCR) was established to evaluate the relative mRNA expression levels of TGF-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6.Results: Malondialdehyde (MDA) levels increased after irradiation and then significantly reduced (1.9-fold) under melatonin treatment. Changes in superoxide dismutase (SOD) and catalase activities, as well as glutathione (GSH) levels, after irradiation...
44 citations
TL;DR: In this article, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized (13)C-pyruvate and C-lactate were performed in the thorax and kidney regions of rats 2 weeks following whole-thorax irradiation (14 Gy).
Abstract: Radiation-induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation-induced lung injury (2-4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized (13)C-pyruvate (pyruvate) and (13)C-lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole-thorax irradiation (14 Gy). Lactate-to-pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age-matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate-to-pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized (13)C metabolic MR spectroscopy and imaging for detection of early radiation-induced lung injury.
40 citations
TL;DR: In conclusion, sivelestat reduced radiation‑induced lung injury in the mice by suppressing NE activity and excessive inflammatory reactions.
Abstract: The aim of this study was to investigate whether sivelestat, a neutrophil elastase (NE) inhibitor, mitigates radiation-induced lung injury in mice. C57BL/6J mice were administered a dose of 20 Gy to the bilateral whole lungs. Sivelestat was administered immediately before and 1 h after irradiation in group RE2, and immediately before and 1, 3 and 6 h after irradiation in group RE4. Group R received irradiation without sivelestat injection. Mice that did not receive sivelestat injection or irradiation were used as controls. NE activity was measured 24 and 48 h after irradiation, and the mice were sacrificed 24 h, 48 h and 15 weeks after irradiation for histopathological examination. In groups RE2 and RE4, NE activity was significantly suppressed until 48 h after irradiation compared to group R. The degree of lung damage in each group was scored during histopathological examination. Results showed that the scores of groups RE2 and RE4 were significantly lower compared to those of group R 15 weeks after irradiation. In conclusion, sivelestat reduced radiation‑induced lung injury in the mice by suppressing NE activity and excessive inflammatory reactions.
16 citations
TL;DR: These data are the first to show that GRP blockade decreases inflammatory and fibrotic responses to radiation in mice, and are a novel radiation fibrosis mitigating agent that could be clinically useful in humans exposed to radiation therapeutically or unintentionally.
Abstract: 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/cm2. 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.
16 citations
TL;DR: Ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation- induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.
Abstract: Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.
13 citations
TL;DR: It is hypothesized that Halofuginone may be able to ameliorate the radiation induced lung fibrosis through inhibiting various members of TFG-β signaling pathway.
12 citations
Patent•
17 Jul 2013
TL;DR: In this article, a gene modified mesenchymal stem cell (MSC) was obtained through: in-vitro isolated culture and amplification of a MSC, deriving from bone marrow and an umbilical cord, and recombinant adenovirus Ad-HGF mediated in vitro modification of the MSC by a hepatocyte growth factor (HGF).
Abstract: Relating to the fields of biotechnologies and gene therapy, the invention provides application of a gene modified mesenchymal stem cell in pulmonary fibrosis treatment. The gene modified mesenchymal stem cells are obtained through: in-vitro isolated culture and amplification of a mesenchymal stem cell (MSC) deriving from bone marrow and an umbilical cord, and recombinant adenovirus Ad-HGF mediated in-vitro modification of the MSC by a hepatocyte growth factor (HGF). By transplanting the gene modified MSC to a C57 mouse to intervene in radiation induced lung injury and fibrosis, exudation of a plurality proteins including albumin, IgM and the like from an alveolar space can be reduced, local inflammatory responses of the lung can be alleviated, and expression of TNF-alpha, soluble ICAM-1 and multiple factors is inhibited, expression of the profibrotic factor TGF-beta, the collagen gene col1 alpha 1 and col 3 alpha 1 can be inhibited, and pulmonary tissue collagen fiber deposition is reduced. The expression results of endogenous HGF and its receptor cmet show that endogenous HGF expression can be induced and endogenous MSC can home to injured parts. Therefore, the employment of HGF modified MSC in treatment of lung injury and fibrosis brought by various pathogenic causes is of great significance.
7 citations
TL;DR: The clinical animal model of chronic radiation-induced lung injury which corresponds to practical conditions in clinic can be successfully established.
TL;DR: There appeared to be no relationship between the mast cell response and the strain-dependent susceptibility towards pneumonitis or fibrosis, and further investigations are required to explore the possible participation of mast cells in mediating specific vascular responses and whether a genetically diverse mastcell response occurs in humans.
Abstract: The role of mast cell infiltrates in the pathology of radiation damage to the lung has been a subject of continuing investigation over the past four decades. This has been accompanied by a number of proposals as to how mast cells and the secretory products thereof participate in the generation of acute inflammation (pneumonitis) and the chronic process of collagen deposition (fibrosis). An additional pathophysiology examines the possible connection between mast cell hyperplasia and pulmonary hypertension through the release of vasoactive mediators. The timing and magnitude of pneumonitis and fibrosis are known to vary tremendously among different genetic mouse strains and animal species. Therefore, we have systematically compared mast cell numbers in lung sections from nine mouse strains, two rat strains and nonhuman primates (NHP) after whole thorax irradiation (WTI) at doses ranging from 10–15 Gy and at the time of entering respiratory distress. Mice of the BALB/c strain had a dramatic increase in inter...
TL;DR: The data suggest that infusion of marrow fibroblasts stimulates mobilization of ELC, which is associated with a reduction in otherwise progressive radiation-induced lung injury, and circulating ELC contribute to increased angiogenesis, which facilitates endogenous lung repair.
Abstract: In the current study, we used a canine model of radiation-induced lung injury to test the effect of a single i.v. infusion of 10×106/kg of marrow fibroblasts on the progression of damage following 15 Gy exposure to the right lung. The fibroblasts, designated DS1 cells, are a cloned population of immortalized cells isolated from a primary culture of marrow stromal cells. DS1 cells were infused at week 5 post-irradiation when lung damage was evident by imaging with high-resolution computed tomography (CT). At 13 weeks post-irradiation we found that 4 out of 5 dogs receiving DS1 cells had significantly improved pulmonary function compared to 0 out of 5 control dogs (p = 0.047, Fisher’s Exact). Pulmonary function was measured as the single breath diffusion capacity-hematocrit (DLCO-Hct), the total inspiratory capacity (IC), and the total lung capacity (TLC), which differed significantly between control and DS1-treated dogs; p = 0.002, p = 0.005, and p = 0.004, respectively. The DS1-treated dogs also had less pneumonitis detected by CT imaging and an increased number of TTF-1 (thyroid transcription factor 1, NKX2-1) positive cells in the bronchioli and alveoli compared to control dogs. Endothelial-like progenitor cells (ELC) of host origin, detected by colony assays, were found in peripheral blood after DS1 cell infusion. ELC numbers peaked one day after infusion, and were not detectable by 7 days. These data suggest that infusion of marrow fibroblasts stimulates mobilization of ELC, which is associated with a reduction in otherwise progressive radiation-induced lung injury. We hypothesize that these two observations are related, specifically that circulating ELC contribute to increased angiogenesis, which facilitates endogenous lung repair.
10 May 2013
01 Jan 2013
01 Jan 2013
TL;DR: This paper presents a meta-analysis of lung cancer and radiation-Induced Lung Injury using positron emission tomography and X-ray diffraction analysis as a guide to diagnosis and treatment.
Abstract: .............................................................................................................................. ii Co-Authorship Statement ................................................................................................... iii Acknowledgments ............................................................................................................... v Table of Contents .............................................................................................................. vii List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii List of Appendices .......................................................................................................... xvii List of Abbreviations ..................................................................................................... xviii Chapter 1: Introduction ....................................................................................................... 1 1.1 Overview and Motivation ....................................................................................... 1 1.2 Healthy Lung Physiology ....................................................................................... 2 1.3 Lung Function Tests ............................................................................................... 2 1.4 Radiation Therapy of Lung Cancer ......................................................................... 3 1.4.1 Lung Cancer ................................................................................................ 3 1.4.2 Treatment of Lung Cancer .......................................................................... 3 1.4.3 Radiation-Induced Lung Injury (RILI) ....................................................... 4 1.4.4 Radiopathology of Irradiated Lung Tissue ................................................. 5 1.5 Clinical Diagnosis of Radiation-Induced Lung Injury ............................................ 7 1.5.1 Epidemiology and Risk Factors .................................................................. 7 1.5.2 Dose Volume Histogram Parameters .......................................................... 8 1.5.3 Signs, Symptoms and Radiographic Findings .......................................... 10 1.6 Functional Imaging of Radiation-Induced Lung Injury ........................................ 11 1.6.1 Nuclear Medicine Imaging Methods ........................................................ 11 1.6.2 Magnetic Resonance Imaging Methods .................................................... 11
01 Jan 2013