An interactive murine single cell atlas of the lung responses to radiation injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE211713 | GEO | 2023/03/20
REPOSITORIES: GEO
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Project description:Acute exposure to high-dose gamma radiation can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used to model acute, early stage RILI in vitro. Both lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6h of radiation exposure, and greater damage is observed in the endothelium. The alveolus chips are exposed to radiation injury at 16 Gy and shows effects that resemble the human lung greater than animal preclinical models. The Alveolus Chip is also used to evaluate the potential ability of two drugs to suppress the effects of acute RILI. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative approach for studying the molecular basis of acute RILI towards screening radiation countermeasure therapeutics.
2023-09-13 | GSE242706 | GEO
Project description:Acute exposure to high-dose gamma radiation often results in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip device consisting of human lung alveolar epithelium and pulmonary endothelium (Lung Alveolus Chip) is used to recapitulate acute, early stage RILI in vitro. This RNA-seq data captures that both the lung epithelium and endothelium in this model capture key hallmarks of this disease particularly, DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6h of radiation exposure. The data also suggests that radiation affects the alveolar endothelium more significantly than the epithelium. The alveolus chips are exposed to radiation injury at 16 Gy and shows effects that resemble the human lung greater than animal preclinical models. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative approach for studying the molecular basis of acute RILI towards screening radiation countermeasure therapeutics.
2023-09-11 | GSE242840 | GEO
Project description:Purpose: Radiation-induced lung injury (RILI) is a progressive condition, with an early phase, radiation pneumonitis (RP), and a late phase, lung fibrosis (LF). RILI may occur after partial body ionizing radiation exposures or by internal radioisotope exposure, with wide individual variability in timing and extent of lung injury. This study aims to provide new insights into the pathogenesis and progression of RILI in the non-human primate (NHP) rhesus macaque model. Methods:We used an integrative approach to understand RILI and its evolution at clinical and molecular levels in seventeen NHPs exposed to10 Gy of whole thorax irradiation in comparison to three sham-irradiated control NHPs. Lung samples were collected at necropsy for molecular and histopathological analyses using RNA sequencing and immunohistochemistry Results: Our data enhances understanding of RILI in non-survivors and survivors in a NHP model. RNA sequencing highlighted the role of SERPINA3, ATP12A, GJB2, CLDN10, TOX3, LPA as possible biomarkers and potential therapeutic targets of RILI. Their differential expression in nonsurvivors and survivors correlated with the severity of the disease.
2021-05-11 | GSE174196 | GEO
Project description:Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancerâ??associated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI. Methods: C57BL6/J mice receiving single dose exposure to 18, 20, 22, or 25 Gy, (n=10/group) were temporally assessed (4-12 weeks) for cellular and biochemical indices of injury present in both bronchoalveolar lavage (BAL) and lung tissues (cytokines, tyrosine nitrosylated proteins, leukocytes, extravasation of Evans blue dye or EBD, BAL albumin, histology). In specific experiments, irradiated mice (25Gy) received simvastatin (10 mg/kg) via intraperitoneal injection three times a week (pre and post irradiation) for 2- 6 weeks post irradiation. Results. Acute RILI evolved in a dose- and time-dependent fashion. Mice irradiated with 25Gy exhibited modest increases in BAL leukocytes but significant increases in BAL IL-6 (p=0.03) and TNF-a (p=0.01) at 4 weeks compared to controls. Increases in BAL nitrotyrosine content peaked at 6 weeks (p=0.03) and was accompanied by marked nitrotyrosine immunostaining in lung tissues. Indices of increase lung vascular permeability such as EBD extravasation, BAL protein and BAL albumin significantly increased over time beginning at 6 weeks (p>0.002 all) with histological evidence of severe edema formation and airway inflammation. Simvastatin- treated irradiated mice were noted to exhibit marked attenuation of vascular leak with significantly decreased BAL protein (p=0.01) and inflammatory cell infiltration (50% reduction). Conclusion: Simvastatin is a potentially important therapeutic strategy to limit RILI and may influence radiation associated morbidity and mortality. We used microarrays to detail the global programme of gene expression induced by radiation in Wild type and the protection of SIMVA Experiment Overall Design: animals were treated by Vehical, Radiation (25Gy), SIMVA(10mg/kg), or both.
2009-03-07 | E-GEOD-14431 | biostudies-arrayexpress
Project description:Intrinsic variations in the development of lung injury among patients undergoing radiotherapy for tumors in the thoracic region suggest there are one or more genes that influence the development and severity of radiation pneumonitis and/or fibrosis. We hypothesized well-characterized murine strain differences in pulmonary response to radiation may offer a novel method to extract the specific genes and/or pathways participating in the development of pneumonitis and/or fibrosis.
2017-02-08 | GSE85359 | GEO
Project description:Thoracic radiation therapy is limited by the development of acute (i.e. pneumonitis) and late (i.e. pulmonary fibrosis) side-effects. The goal of this study is to analyze, at the single cell level, the molecular impact of two radiation treatments : a conventional/clinical (CONV) modality vs. FLASH, a new radiation method that spares healthy tissue from late radiation-induced toxicities (Science Translational Medicine 6: 245ra293, 2014). We analyzed by single cell RNA sequencing (scRNAseq) dissociated lung cells from a non-irradiated control mouse (NI), a mouse 4 days after CONV thoracic irradiation (CONV) and a mouse 4 days after FLASH irradiation (FLASH). We identify transcriptional alterations induced in the distinct lung cell types after irradiation and show that FLASH irradiated lung cells present a reduced pro-inflammatory phenotype as well as a diminished activation of epithelial lung progenitor cells. In line with previous report (Radiother Oncol 124: 365-9, 2017), this study indicates that FLASH radiation therapy limits inflammation and preserves the regenerative capcity of the lung.
2019-12-07 | GSE133992 | GEO
Project description:Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancer–associated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI. Methods: C57BL6/J mice receiving single dose exposure to 18, 20, 22, or 25 Gy, (n=10/group) were temporally assessed (4-12 weeks) for cellular and biochemical indices of injury present in both bronchoalveolar lavage (BAL) and lung tissues (cytokines, tyrosine nitrosylated proteins, leukocytes, extravasation of Evans blue dye or EBD, BAL albumin, histology). In specific experiments, irradiated mice (25Gy) received simvastatin (10 mg/kg) via intraperitoneal injection three times a week (pre and post irradiation) for 2- 6 weeks post irradiation. Results. Acute RILI evolved in a dose- and time-dependent fashion. Mice irradiated with 25Gy exhibited modest increases in BAL leukocytes but significant increases in BAL IL-6 (p=0.03) and TNF-a (p=0.01) at 4 weeks compared to controls. Increases in BAL nitrotyrosine content peaked at 6 weeks (p=0.03) and was accompanied by marked nitrotyrosine immunostaining in lung tissues. Indices of increase lung vascular permeability such as EBD extravasation, BAL protein and BAL albumin significantly increased over time beginning at 6 weeks (p>0.002 all) with histological evidence of severe edema formation and airway inflammation. Simvastatin- treated irradiated mice were noted to exhibit marked attenuation of vascular leak with significantly decreased BAL protein (p=0.01) and inflammatory cell infiltration (50% reduction). Conclusion: Simvastatin is a potentially important therapeutic strategy to limit RILI and may influence radiation associated morbidity and mortality. We used microarrays to detail the global programme of gene expression induced by radiation in Wild type and the protection of SIMVA
2009-03-02 | GSE14431 | GEO
Project description:Utilizing an established model of Radiation Induced Pulmonary Fibrosis, low input RNA sequencing was performed on whole lung cell suspensions obtained from 12.5 Gy thorax only radiation treated C57BL/6J mice and compareed to 0 Gy (Sham irradiation) age matched controls
2017-02-14 | GSE94852 | GEO
Project description:Total lung RNA from 3 mouse strains after 18Gy thoracic irradiation. Thoracic cavity radiotherapy is limited by the development of alveolitis and fibrosis in susceptible patients. To define the response to 18 Gy pulmonary irradiation in mice, at the expression level, and to identify pathways which may influence the alveolitis and fibrosis phenotypes expression profiling was completed. Male mice of three strains, A/J (late alveolitis response), C3H/HeJ (C3H, early alveolitis response) and C57BL/6J (B6, fibrosis response) were exposed to thoracic radiation, euthanised when moribund and lung tissue gene expression was assessed with microarrays. treated vs. control in 3 strains
2009-09-11 | E-GEOD-2250 | biostudies-arrayexpress
Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI. Four mice were treated with PBS as a control. Three mice were treated with (S)-FTY-phosphonate (0.1mg/kg) as a drug control. Three mice were treated with SEW-2871 (0.1mg/kg) as a drug control. Three mice were treated with FTY720 (0.1mg/kg) as a drug control. Three mice were treated with administered radiation (25 Gy) alone. Three mice were treated with both administered radiation (25 Gy) and (S)-FTY-phosphonate (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and SEW-2871 (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and FTY720 (0.1mg/kg).
2010-11-17 | E-GEOD-25295 | biostudies-arrayexpress