Senescence gene signature of radiation fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE41789 | GEO | 2013/11/01
SECONDARY ACCESSION(S): PRJNA178206
REPOSITORIES: GEO
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Project description:Radiation lung injury is characterized by early inflammation and late fibrosis. The causes underlying the chronic, progressive nature of radiation injury are poorly understood. Here, we report that the gene expression of irradiated lung tissue correlates with that observed in the lungs in aged animals. We demonstrate that NOX4 expression and superoxide elaboration is increased in irradiated lungs and pneumocytes in a dose dependent fashion. We used microarrays to detail the global programme of gene expression and report that irradiated lung tissue correlates with that observed in the lungs in aged animals. Female C57Bl/Ncr mice, aged 10 weeks were treated with/ without radiation to the thorax with a X-RAD 320 x-ray irradiator at a dose rate of 2.61 Gy/minute. An age-matched cohort of mice received no IR while additional cohorts received 5 Gy in a single dose, 17.5 Gy in a single dose. RNA was extracted and hybridization done on Affymetrix Mouse430_2 microarrays.
2013-11-01 | E-GEOD-41789 | biostudies-arrayexpress
Project description:Irradiation of the K-rasLA1 mouse model with a fractionated dose of 1.0Gy 56Fe- particles increases the incidence of invasive carcinoma compared to unirradiated controls or those irradiated with an acute dose. Microarray profiling was perfromed on whole lungs from K-rasLA1 mice in order to determine global expression changes in the lung following radiation exposure. RNA was extracted from K-rasLA1 lungs from unirradiated control animals or those irradiated with a fractionated or acute dose of 1.0Gy 56Fe- particles 70 days post-irradiation when lungs are still histologically indistiguishable and only contain benign lesions.
2014-09-22 | GSE42233 | GEO
Project description:Irradiation of the K-rasLA1 mouse model with a fractionated dose of 1.0Gy 56Fe- particles increases the incidence of invasive carcinoma compared to unirradiated controls or those irradiated with an acute dose. Microarray profiling was perfromed on whole lungs from K-rasLA1 mice in order to determine global expression changes in the lung following radiation exposure. RNA was extracted from K-rasLA1 lungs from unirradiated control animals or those irradiated with a fractionated or acute dose of 1.0Gy 56Fe- particles 70 days post-irradiation when lungs are still histologically indistiguishable and only contain benign lesions. 129S2 K-rasLA1 mice were either irradiated with an acute (1.0Gy x1; n = 15) or fractionated (0.2Gy x5; n=13) dose of 1.0Gy 56Fe- particles or left unirradiated (n=13). Animals were euthanized 70 days post-irradiation and RNA was extracted from the whole left lung of each animal.
2014-09-22 | E-GEOD-42233 | biostudies-arrayexpress
Project description:Radiotherapy, a treatment modality received by more than half of all cancer patients, remains one of the most effective approaches to achieve local tumour control. Despite increased accuracy driven by technological advances, healthy tissue injury due to off-target radiation exposure can still occur. In this study, we sought to understand the biological effect of radiation-mediated injury to the lung in the context of cancer metastasis, since we had previously reported that tissue regeneration is a feature of the metastatic microenvironment of this organ. We have exposed healthy mouse lung tissue to radiation prior to the induction of metastasis and observed a strong enhancement of cancer cell growth. Lung tissue was preconditioned into a profoundly tumour-supportive microenvironment governed by enhanced regenerative Notch signalling. Most importantly, we found that locally activated neutrophils were key drivers of these tissue perturbations, significantly increasing the metastatic proficiency of irradiated lung tissue and endowing arriving cancer cells with an augmented stemness phenotype. We show that by preventing neutrophil-dependent Notch activation in the irradiated tissue, we were able to significantly offset the radiation-enhanced metastases. Mechanistically, we identified the release of neutrophil granules as the effectors of the pro-tumorigenic preconditioning of the irradiated lung tissue. These findings not only reveal a novel tumour-supportive function of neutrophils in the context of tissue-injury, but also have important clinical implications by suggesting targeting their activity could maximise the success of radiotherapy for the treatment of cancer.
2021-12-13 | PXD027628 | Pride
Project description:Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts leading to the progressive scarring of the lung. To identify transcriptional gene programs driving persistent fibrosis in aged lungs, we performed a comparative RNA-seq analysis of fibroblasts freshly isolated from young and aged mouse lungs 30 days post-bleomycin injury. We discovered that lung fibroblasts isolated from young animals at this time point post-injury were transcriptionally similar to those isolated from uninjured mice. In contrast, aged lung fibroblasts isolated at the same time point exhibited a sustained pro-fibrotic state characterized by the elevated expression of genes implicated in inflammation, extracellular matrix remodeling, and cell survival. We identified the protein kinase pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its direct target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures observed in aged lung fibroblasts post-injury. PIM1 and NFATc1 transcripts were highly enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was detected in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation and this effect was dependent on NFATc1. Pharmacological inhibition of PIM1 in IPF-derived lung fibroblasts attenuated their activation and sensitized them to apoptotic stimuli. Finally, inhibition of PIM1 strongly reduced the expression of ECM remodeling and pro-survival genes and blocked the secretion of collagen in IPF lung explants ex vivo. Targeting PIM1/NFATc1 axis in pathogenic lung fibroblasts may represent a therapeutic strategy to limit their activation and promote fibrosis resolution in IPF.
2022-01-01 | GSE191208 | 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:The goal of our study is to establish a method to propagate human pneumocytes efficiently in a large scale. While human pneumectomy-derived lung epithelial cells (LECs) showed efficient long-term growth when co-cultured with irradiated NIH-3T3, they do not express molecular markers of mature pneumocytes or airway cells in this condition. Removal of feeders causes differentiation toward airway club cell-like phenotype, and an induction treatment with combination of small molecules and growth factors is required to differentiate them toward pneumocytes. To elucidate the underlying mechanisms, we analyzed gene expression profile of LECs with or without induction treatment. We also included LECs under coculture and the original frozen lung tissue, as a reference.
2018-08-15 | GSE86449 | GEO
Project description:The avian influenza A(H7N9) virus has caused high mortality in humans, especially in the elderly; however, little is known about the mechanistic basis for this. In this study, we employed non-human primates to evaluate the effect of aging on the pathogenicity of A(H7N9) virus. We observed that A(H7N9) virus infection of aged animals (defined as 20–26 years) caused more severe symptoms than infection of young animals (defined as 2 3 years). In aged animals, lung inflammation was weak and virus infection was sustained. Although cytokine and chemokine expression in the lungs of most aged animals was lower than that in the lungs of young animals, one aged animal showed dysregulated proinflammatory cytokine and chemokine production, resulting in it being euthanized. These results suggest that attenuated or dysregulated immune responses in aged animals are responsible for the severe symptoms observed among elderly patients infected with A(H7N9) virus.
2020-06-13 | GSE152406 | GEO
Project description:We used a rat model of whole thorax x-ray irradiation to profile the microRNA (miRNA) in lung and blood up to 4 weeks after radiation. Small RNA from normal and irradiated Wistar rat lungs and blood were analyzed by next-generation sequencing and the changes by radiation were identified by deRNA-seq at 1, 2, 3 and 4 weeks after irradiation. The average total reads/library was 2,703,137 with a mean of 88% mapping to the rat genome. Detailed profiles of 100 of the most abundant miRNA in rat blood and lung are described.
2017-04-25 | GSE86567 | GEO
Project description:In order to elucidate the contribute of the pulmonary vasculature to lung fibrosis, we injured young and aged mice with bleomycine, to create a model of resolving versus persistent lung fibrosis. The animals were sacrificed 30 days after the injury (time point in which we observed a divergent resolving vs persistent lung fibrosis in young vs aged mice). We found that lung fibrosis resolution in young mice was accompained by the activation of transcriptional programs promoting vascular repair and lung fibrosis resolution. Lung endothelial cells from aged mice after injury failed to activate these programs, leading to dysrepair and progressive fibrosis.
2021-09-30 | GSE181508 | GEO