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Cai X, Wei Z, Shen Y, Qian L, Cai J, Yang Y, Chi R, Wang W, Yu S, Li K, Fei Y, Li C, Han Y, Liu M, Zhang J, Wang D, Jiang M, Li YG. Pulmonary artery denervation by noninvasive stereotactic radiotherapy: a pilot study in swine models of pulmonary hypertension. Nat Commun 2025; 16:558. [PMID: 39788963 PMCID: PMC11718002 DOI: 10.1038/s41467-025-55933-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 01/06/2025] [Indexed: 01/12/2025] Open
Abstract
Catheter-based pulmonary artery denervation (PADN) has achieved promising outcomes to treat pulmonary hypertension (PH). We herein present stereotactic body radiotherapy (SBRT) as a novel noninvasive approach for PADN. A single fraction of 15 Gy, 20 Gy or 25 Gy was delivered for PADN in a thromboxane A2 (TxA2) - induced acute PH swine model. We demonstrated that PADN by 20-Gy SBRT reduced mean pulmonary artery (PA) pressure during the TxA2 challenge. All SBRT dosages led to a deeper denervation area compared with radiofrequency ablation (RFA) and reduced sympathetic neural norepinephrine synthesis in the ablation zone. Probable radiation related side effects were mostly found in animals treated with 25-Gy. In subsequent monocrotaline-induced chronic PH animals, PADN by 20-Gy SBRT resulted in more significant improvement in pulmonary hemodynamics and PA remodeling in comparison to RFA. In summary, our findings suggest that appropriate SBRT scheme could balance the efficacy and safety for PADN, potentiating to be a novel strategy to treat PH.
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Affiliation(s)
- Xingxing Cai
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhixing Wei
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yichen Shen
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Li Qian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Cai
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuli Yang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Runmin Chi
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Wang
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shunxuan Yu
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Keke Li
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yudong Fei
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Cheng Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yaqin Han
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ming Liu
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianguo Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Dengbin Wang
- Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Mawei Jiang
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Yi-Gang Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Wiedemann J, Paruchuru SK, den Boef LE, Brouwer U, Silljé HHW, Schouten EM, Dickinson MG, van Goethem MJ, Coppes RP, van Luijk P. Sparing of the Heart Facilitates Recovery From Cardiopulmonary Side Effects After Thoracic Irradiation. Int J Radiat Oncol Biol Phys 2025; 121:191-201. [PMID: 39151832 DOI: 10.1016/j.ijrobp.2024.07.2330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/22/2024] [Accepted: 07/29/2024] [Indexed: 08/19/2024]
Abstract
PURPOSE When irradiating thoracic tumors, dose to the heart or lung has been associated with survival. We previously showed in a rat model that in addition to known side effects such as pericarditis, pneumonitis and fibrosis, heart and/or lung irradiation also impaired diastolic function and increased pulmonary artery pressure. Simultaneous irradiation of both organs strongly intensified these effects. However, the long-term consequences of these interactions are not yet known. Therefore, here, we investigated the long-term effects of combined heart and lung irradiation. METHODS AND MATERIALS Different regions of the rat thorax containing the heart and/or 50% of the lungs were irradiated with protons. Respiratory rate (RR) was measured biweekly as an overall parameter for cardiopulmonary function. Echocardiography of the heart was performed at 8, 26, and 42 weeks after irradiation. Tissue remodeling and vascular changes were assessed using Masson trichrome and Verhoeff-stained lung and left ventricle tissue collected at 8 and 42 weeks after irradiation. RESULTS During the entire experimental period RR was consistently increased after combined heart/lung irradiation. This coincided with persistent effects on lung vasculature and reduced right-ventricle (RV) contraction. In contrast, recovery of RR, pulmonary remodeling and RV contraction was observed after sparing of the heart. These corresponding temporal patterns suggest that the reduction of RV function is related to vascular remodeling in the lung. CONCLUSIONS Combined irradiation of lung and heart leads to an intensified, persistent reduction of cardiopulmonary function. Recovery of the pulmonary vasculature and RV function requires heart sparing.
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Affiliation(s)
- Julia Wiedemann
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sai K Paruchuru
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lisette E den Boef
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Uilke Brouwer
- Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Herman H W Silljé
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Elisabeth M Schouten
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Michael G Dickinson
- Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Marc-Jan van Goethem
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robert P Coppes
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter van Luijk
- Departments of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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3
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English J, Dhanikonda S, Tanaka KE, Koba W, Eichenbaum G, Yang WL, Guha C. Thrombopoietin mimetic reduces mouse lung inflammation and fibrosis after radiation by attenuating activated endothelial phenotypes. JCI Insight 2024; 9:e181330. [PMID: 39513364 PMCID: PMC11601560 DOI: 10.1172/jci.insight.181330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/12/2024] [Indexed: 11/15/2024] Open
Abstract
Radiation-induced lung injury (RILI) initiates radiation pneumonitis and progresses to fibrosis as the main side effect experienced by patients with lung cancer treated with radiotherapy. There is no effective drug for RILI. Sustained vascular activation is a major contributor to the establishment of chronic disease. Here, using a whole thoracic irradiation (WTI) mouse model, we investigated the mechanisms and effectiveness of thrombopoietin mimetic (TPOm) for preventing RILI. We demonstrated that administering TPOm 24 hours before irradiation decreased histologic lung injury score, apoptosis, vascular permeability, expression of proinflammatory cytokines, and neutrophil infiltration in the lungs of mice 2 weeks after WTI. We described the expression of c-MPL, a TPO receptor, in mouse primary pulmonary microvascular endothelial cells, showing that TPOm reduced endothelial cell-neutrophil adhesion by inhibiting ICAM-1 expression. Seven months after WTI, TPOm-treated lung exhibited less collagen deposition and expression of MMP-9, TIMP-1, IL-6, TGF-β, and p21. Moreover, TPOm improved lung vascular structure, lung density, and respiration rate, leading to a prolonged survival time after WTI. Single-cell RNA sequencing analysis of lungs 2 weeks after WTI revealed that TPOm shifted populations of capillary endothelial cells toward a less activated and more homeostatic phenotype. Taken together, TPOm is protective for RILI by inhibiting endothelial cell activation.
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Affiliation(s)
- Jeb English
- Department of Radiation Oncology
- Department of Pathology, and
| | | | | | - Wade Koba
- Department of Radiology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Gary Eichenbaum
- Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, New Jersey, USA
| | | | - Chandan Guha
- Department of Radiation Oncology
- Department of Pathology, and
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4
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Beukema JC, Haveman JW, Langendijk JA, Oldehinkel E, van den Bergh ACM, de Haan JJ, van Melle JP, van Luijk P, Muijs CT. Blood biomarkers for cardiac damage during and after radiotherapy for esophageal cancer: A prospective cohort study. Radiother Oncol 2024; 200:110479. [PMID: 39154840 DOI: 10.1016/j.radonc.2024.110479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE The aim of this study was to test the hypothesis that the levels of High Sensitive Troponin T (HS-TNT) and N-terminal Brain Natriuretic Peptide (NT-ProBNP) increase after radiation therapy in a dose dependent way and are predictive for clinical cardiac events. MATERIALS AND METHODS Blood samples during and after radiotherapy of 87 esophageal cancer patients were analysed regarding the course of HS-TNT and NT-ProBNP levels and their relationship with clinical toxicity endpoints and radiation dose volume parameters. RESULTS HS-TNT values at the end of treatment correlated with the mean heart dose (p = 0.02), whereas the rise of NT-ProBNP correlated with the mean lung dose (p = 0.01). Furthermore, the course of both HS-TNT (p < 0.001) and NT-ProBNP (p < 0.01) levels were significantly different for patients who developed new cardiac events as opposed to those without new cardiac events. CONCLUSION Significant correlations were found for both biomarkers with radiation dose and clinical toxicity endpoints after treatment. Therefore, these markers might be of additional value in NTCP models for cardiac events and might help us unravelling the mechanisms behind these toxicity endpoints.
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Affiliation(s)
- Jannet C Beukema
- Department of Radiation oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Jan-Willem Haveman
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Johannes A Langendijk
- Department of Radiation oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Edwin Oldehinkel
- Department of Radiation oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | | | - Jacco J de Haan
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Joost P van Melle
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Peter van Luijk
- Department of Radiation oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Christina T Muijs
- Department of Radiation oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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5
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Nations JA, Lin J, Park AB, Shriver CD, Zhu K. Pulmonary Hypertension and Survival among Non-Small Cell Lung Cancer Patients: A Retrospective Cohort Study in the U.S. Military Health System. J Clin Med 2024; 13:3217. [PMID: 38892928 PMCID: PMC11173320 DOI: 10.3390/jcm13113217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Background: Lung cancer is one of the most lethal cancers with survival being closely related to stage and influenced by comorbid illness. The survival implications of pulmonary hypertension (PH) on patients with non-small cell lung cancer (NSCLC) have only been evaluated in small cohorts, with limited long-term follow-up. Methods: We conducted a retrospective cohort study of 7946 patients with NSCLC diagnosed in the MHS. This study evaluated the survival impact of PH in patients diagnosed with NSCLC in the MHS. Patients were classified as having and not having PH. We stratified PH into those diagnosed before the diagnosis of NSCLC and those diagnosed after NSCLC diagnosis. Results: Relative to patients without PH, patients with PH diagnosed before NSCLC had an increased risk of death (HR = 1.15 [95% CI, 1.02-1.29]). The increased risk of death was more obvious for patients with PH diagnosed after NSCLC compared with those without PH (HR = 2.74 [95% CI, 2.51-2.99]). The results were similar when stratified by patient demographics. Conclusions: In the MHS, PH is associated with worsened NSCLC survival, regardless of when it is diagnosed. When PH is diagnosed after NSCLC, it is associated with a marked reduction in survival, and this finding may suggest a potential role for monitoring pulmonary pressures in NSCLC patients. Furthermore, as specific PH therapy exists, some NSCLC patients with PH may be candidates for therapy.
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Affiliation(s)
- Joel A. Nations
- Veterans Affairs Medical Center, Washington, DC 20422, USA
- Department of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
| | - Jie Lin
- John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA (C.D.S.); (K.Z.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
- Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Amie B. Park
- John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA (C.D.S.); (K.Z.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
| | - Craig D. Shriver
- John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA (C.D.S.); (K.Z.)
- Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
| | - Kangmin Zhu
- John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA (C.D.S.); (K.Z.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
- Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
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Baumann M, Bacchus C, Aznar MC, Coppes RP, Deutsch E, Georg D, Haustermans K, Hoskin P, Krause M, Lartigau EF, Lee AWM, Löck S, Offersen BV, Thwaites DI, van der Heide UA, Valentini V, Overgaard J. Clinical research for global needs of radiation oncology. Radiother Oncol 2024; 190:110076. [PMID: 38157941 DOI: 10.1016/j.radonc.2023.110076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Affiliation(s)
| | - Carol Bacchus
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marianne C Aznar
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, The Christie NHS Foundation Trust, United Kingdom
| | - Rob P Coppes
- Departments of Radiation Oncology and Biomedical Sciences of Cells & Systems, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Eric Deutsch
- Department of Radiation Oncology, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, France
| | - Dietmar Georg
- Division Medical Radiation Physics, Department of Radiation Oncology, Medical University of Vienna/AKH, Wien, Austria
| | - Karin Haustermans
- Department of Radiation Oncology, University Hospitals Leuven, Belgium
| | - Peter Hoskin
- Mount Vernon Cancer Centre and University of Manchester, United Kingdom
| | - Mechthild Krause
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany
| | - Eric F Lartigau
- Academic Department of Radiotherapy, Oscar Lambret Comprehensive Cancer Center, Lille, France
| | - Anne W M Lee
- Department of Clinical Oncology, University of Hong Kong - Shenzhen Hospital and University of Hong Kong, China
| | - Steffen Löck
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany
| | - Birgitte V Offersen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark
| | - David I Thwaites
- Institute of Medical Physics, School of Physics, The University of Sydney, Australia; Radiotherapy Research Group, Leeds Institute of Medical Research, St James's Hospital and University of Leeds, United Kingdom
| | - Uulke A van der Heide
- Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - Jens Overgaard
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark
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Weiß A, Löck S, Xu T, Liao Z, Hoffmann AL, Troost EGC. Prediction of radiation pneumonitis using the effective α/β of lungs and heart in NSCLC patients treated with proton beam therapy. Radiother Oncol 2024; 190:110013. [PMID: 37972734 DOI: 10.1016/j.radonc.2023.110013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE Radiation pneumonitis (RP) remains a major complication in non-small cell lung cancer (NSCLC) patients undergoing radiochemotherapy (RCHT). Traditionally, the mean lung dose (MLD) and the volume of the total lung receiving at least 20 Gy (V20Gy) are used to predict RP in patients treated with normo-fractionated photon therapy. However, other models, including the actual dose-distribution in the lungs using the effective α/β model or a combination of radiation doses to the lungs and heart, have been proposed for predicting RP. Moreover, the models established for photons may not hold for patients treated with passively-scattered proton therapy (PSPT). Therefore, we here tested and validated novel predictive parameters for RP in NSCLC patient treated with PSPT. METHODS Data on the occurrence of RP, structure files and dose-volume histogram parameters for lungs and heart of 96 NSCLC patients, treated with PSPT and concurrent chemotherapy, was retrospectively retrieved from prospective clinical studies of two international centers. Data was randomly split into a training set (64 patients) and a validation set (32 patients). Statistical analyses were performed using binomial logistic regression. RESULTS The biologically effective dose (BED) of the'lungs - GTV' significantly predicted RP ≥ grade 2 in the training-set using both a univariate model (p = 0.019, AUCtrain = 0.72) and a multivariate model in combination with the effective α/β parameter of the heart (pBED = 0.006, [Formula: see text] = 0.043, AUCtrain = 0.74). However, these results did not hold in the validation-set (AUCval = 0.52 andAUCval = 0.50, respectively). Moreover, these models were found to neither outperform a model built with the MLD (p = 0.015, AUCtrain = 0.73, AUCval = 0.51), nor a multivariate model additionally including the V20Gy of the heart (pMLD = 0.039, pV20Gy,heart = 0.58, AUCtrain = 0.74, AUCval = 0.53). CONCLUSION Using the effective α/β parameter of the lungs and heart we achieved similar performance to commonly used models built for photon therapy, such as MLD, in predicting RP ≥ grade 2. Therefore, prediction models developed for photon RCHT still hold for patients treated with PSPT.
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Affiliation(s)
- Albrecht Weiß
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Steffen Löck
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ting Xu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhongxing Liao
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aswin L Hoffmann
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany
| | - Esther G C Troost
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany.
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8
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Isobe S, Nair RV, Kang HY, Wang L, Moonen JR, Shinohara T, Cao A, Taylor S, Otsuki S, Marciano DP, Harper RL, Adil MS, Zhang C, Lago-Docampo M, Körbelin J, Engreitz JM, Snyder MP, Rabinovitch M. Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension. Nat Commun 2023; 14:7578. [PMID: 37989727 PMCID: PMC10663616 DOI: 10.1038/s41467-023-43039-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 10/30/2023] [Indexed: 11/23/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.
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Affiliation(s)
- Sarasa Isobe
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ramesh V Nair
- Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Helen Y Kang
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lingli Wang
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jan-Renier Moonen
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Tsutomu Shinohara
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aiqin Cao
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Shalina Taylor
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Shoichiro Otsuki
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - David P Marciano
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Rebecca L Harper
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mir S Adil
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Chongyang Zhang
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mauro Lago-Docampo
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jakob Körbelin
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jesse M Engreitz
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael P Snyder
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Marlene Rabinovitch
- Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
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9
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Bedi R, Ahmad A, Horbal P, Mar PL. Radiation-associated Arrhythmias: Putative Pathophysiological Mechanisms, Prevalence, Screening and Management Strategies. Arrhythm Electrophysiol Rev 2023; 12:e24. [PMID: 37680206 PMCID: PMC10481379 DOI: 10.15420/aer.2022.44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/16/2023] [Indexed: 09/09/2023] Open
Abstract
Radiation-associated cardiovascular disease, an increasingly recognised disease process, is a significant adverse effect of radiation therapy for common malignancies that involve the chest, and include lymphomas, lung, mediastinal and breast cancers. Two factors contribute to the increasing incidence of radiation-associated cardiovascular disease: advances in malignancy detection and the improved survival of cancer patients, by which many symptoms of radiation-associated cardiovascular disease, specifically radiation-associated arrhythmias, present years and/or decades following initial radiotherapy. We present a focused overview of the currently understood pathophysiology, prevalence and management strategies of radiation-associated arrhythmias, which include bradyarrhythmias, tachyarrhythmias and autonomic dysfunction.
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Affiliation(s)
- Rohil Bedi
- Department of Internal Medicine, Saint Louis University School of Medicine St Louis, Missouri, US
| | - Ali Ahmad
- Department of Internal Medicine, Saint Louis University School of Medicine St Louis, Missouri, US
| | - Piotr Horbal
- Department of Internal Medicine, Saint Louis University School of Medicine St Louis, Missouri, US
- Division of Cardiovascular Medicine, Department of Internal Medicine, Ohio State University Columbus, Ohio, US
| | - Philip L Mar
- Division of Cardiology, Department of Internal Medicine, Saint Louis University School of Medicine St Louis, Missouri, US
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10
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Fan JF, Wang YK, Liu M, Liu GS, Min TJ, Chen RY, He Y. Effect of angiotensin II on irradiation exacerbated decompression sickness. Sci Rep 2023; 13:11659. [PMID: 37468556 DOI: 10.1038/s41598-023-38752-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/14/2023] [Indexed: 07/21/2023] Open
Abstract
In some complicated situations, decompression sickness (DCS) combined with other injuries, such as irradiation, will seriously endanger life safety. However, it is still unclear whether irradiation will increase the incidence of DCS. This study was designed to investigate the damage effects of irradiation on decompression injury and the underlying mechanism. Sprague-Dawley rats were exposed to irradiation followed by hyperbaric decompressing and the mortality and decompression symptoms were observed. Lung tissue and bronchoalveolar lavage fluid were collected to detect the lung lesion, inflammation response, activity of the angiotensin system, oxidative stress, and relative signal pathway by multiple methods, including Q-PCR, western blot, and ELISA. As a result, pre-exposure to radiation significantly exacerbated disease outcomes and lung lesions of DCS. Mechanically, the up-regulation of angiotensin-converting enzyme expression and angiotensin II levels was responsible for the exacerbated DCS and lung lesions caused by predisposing irradiation exposure. Oxidative stress and PI3K/AKT signal pathway activation in pulmonary tissue were enhanced after irradiation plus decompression treatment. In conclusion, our results suggested that irradiation could exacerbate lung injury and the outcomes of DCS by activating the angiotensin system, which included eliciting oxidative stress and activation of the PI3K/AKT signal pathway.
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Affiliation(s)
- Jie-Fu Fan
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yang-Kai Wang
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Min Liu
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Guang-Sheng Liu
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Tian-Jiao Min
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Rui-Yong Chen
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China.
| | - Ying He
- Naval Medical Center of PLA, Naval Medical University (Second Military Medical University), Shanghai, China.
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11
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Miller R, Castillo R, Castillo E, Jones BL, Miften M, Kavanagh B, Lu B, Werner-Wasik M, Ghassemi N, Lombardo J, Barta J, Grills I, Rusthoven CG, Guerrero T, Vinogradskiy Y. Characterizing Pulmonary Function Test Changes for Patients With Lung Cancer Treated on a 2-Institution, 4-Dimensional Computed Tomography-Ventilation Functional Avoidance Prospective Clinical Trial. Adv Radiat Oncol 2023; 8:101133. [PMID: 36618762 PMCID: PMC9816902 DOI: 10.1016/j.adro.2022.101133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/17/2022] [Indexed: 12/05/2022] Open
Abstract
Purpose Four-dimensional computed tomography (4DCT)-ventilation-based functional avoidance uses 4DCT images to generate plans that avoid functional regions of the lung with the goal of reducing pulmonary toxic effects. A phase 2, multicenter, prospective study was completed to evaluate 4DCT-ventilation functional avoidance radiation therapy. The purpose of this study was to report the results for pretreatment to posttreatment pulmonary function test (PFT) changes for patients treated with functional avoidance radiation therapy. Methods and Materials Patients with locally advanced lung cancer receiving chemoradiation were accrued. Functional avoidance plans based on 4DCT-ventilation images were generated. PFTs were obtained at baseline and 3 months after chemoradiation. Differences for PFT metrics are reported, including diffusing capacity for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). PFT metrics were compared for patients who did and did not experience grade 2 or higher pneumonitis. Results Fifty-six patients enrolled on the study had baseline and posttreatment PFTs evaluable for analysis. The mean change in DLCO, FEV1, and FVC was -11.6% ± 14.2%, -5.6% ± 16.9%, and -9.0% ± 20.1%, respectively. The mean change in DLCO was -15.4% ± 14.4% for patients with grade 2 or higher radiation pneumonitis and -10.8% ± 14.1% for patients with grade <2 radiation pneumonitis (P = .37). The mean change in FEV1 was -14.3% ± 22.1% for patients with grade 2 or higher radiation pneumonitis and -3.9% ± 15.4% for patients with grade <2 radiation pneumonitis (P = .09). Conclusions The current work is the first to quantitatively characterize PFT changes for patients with lung cancer treated on a prospective functional avoidance radiation therapy study. In comparison with patients treated with standard thoracic radiation planning, the data qualitatively show that functional avoidance resulted in less of a decline in DLCO and FEV1. The presented data can help elucidate the potential pulmonary function improvement with functional avoidance radiation therapy.
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Affiliation(s)
- Ryan Miller
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Richard Castillo
- Department of Radiation Oncology, Emory University, Atlanta, Georgia
| | - Edward Castillo
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas
| | - Bernard L. Jones
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado
| | - Moyed Miften
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado
| | - Brian Kavanagh
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado
| | - Bo Lu
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Maria Werner-Wasik
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Nader Ghassemi
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Joseph Lombardo
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Julie Barta
- Department of Thoracic Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Inga Grills
- Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan
| | - Chad G. Rusthoven
- Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan
| | - Thomas Guerrero
- Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan
| | - Yevgeniy Vinogradskiy
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
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12
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Hou G, Li J, Liu W, Wei J, Xin Y, Jiang X. Mesenchymal stem cells in radiation-induced lung injury: From mechanisms to therapeutic potential. Front Cell Dev Biol 2022; 10:1100305. [PMID: 36578783 PMCID: PMC9790971 DOI: 10.3389/fcell.2022.1100305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Radiotherapy (RT) is an effective treatment option for multiple thoracic malignant tumors, including lung cancers, thymic cancers, and tracheal cancers. Radiation-induced lung injury (RILI) is a serious complication of radiotherapy. Radiation causes damage to the pulmonary cells and tissues. Multiple factors contribute to the progression of Radiation-induced lung injury, including genetic alterations, oxidative stress, and inflammatory responses. Especially, radiation sources contribute to oxidative stress occurrence by direct excitation and ionization of water molecules, which leads to the decomposition of water molecules and the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS). Subsequently, reactive oxygen species and reactive nitrogen species overproduction can induce oxidative DNA damage. Immune cells and multiple signaling molecules play a major role in the entire process. Mesenchymal stem cells (MSCs) are pluripotent stem cells with multiple differentiation potentials, which are under investigation to treat radiation-induced lung injury. Mesenchymal stem cells can protect normal pulmonary cells from injury by targeting multiple signaling molecules to regulate immune cells and to control balance between antioxidants and prooxidants, thereby inhibiting inflammation and fibrosis. Genetically modified mesenchymal stem cells can improve the natural function of mesenchymal stem cells, including cellular survival, tissue regeneration, and homing. These reprogrammed mesenchymal stem cells can produce the desired products, including cytokines, receptors, and enzymes, which can contribute to further advances in the therapeutic application of mesenchymal stem cells. Here, we review the molecular mechanisms of radiation-induced lung injury and discuss the potential of Mesenchymal stem cells for the prevention and treatment of radiation-induced lung injury. Clarification of these key issues will make mesenchymal stem cells a more fantastic novel therapeutic strategy for radiation-induced lung injury in clinics, and the readers can have a comprehensive understanding in this fields.
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Affiliation(s)
- Guowen Hou
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, and Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China,Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Jinjie Li
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Wenyun Liu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Jinlong Wei
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, and Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China,Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China,*Correspondence: Ying Xin, ; Xin Jiang,
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, and Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China,Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China,*Correspondence: Ying Xin, ; Xin Jiang,
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13
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Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms232314959. [PMID: 36499287 PMCID: PMC9735580 DOI: 10.3390/ijms232314959] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.
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14
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Wiedemann J, Coppes RP, van Luijk P. Radiation-induced cardiac side-effects: The lung as target for interacting damage and intervention. Front Oncol 2022; 12:931023. [PMID: 35936724 PMCID: PMC9354542 DOI: 10.3389/fonc.2022.931023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/28/2022] [Indexed: 11/16/2022] Open
Abstract
Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated. The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable.
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Affiliation(s)
- Julia Wiedemann
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Robert P. Coppes
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Peter van Luijk
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- *Correspondence: Peter van Luijk,
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15
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Prolonged Inhalation Exposure to Coal Dust on Irradiated Rats and Consequences. ScientificWorldJournal 2022; 2022:8824275. [PMID: 35153629 PMCID: PMC8828334 DOI: 10.1155/2022/8824275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 11/21/2022] Open
Abstract
The purposes of this study were to research immune system changes and liver and lung tissues in irradiated rats after prolonged exposure to coal dust. A study was carried out on 30 male Wistar rats that were divided into 3 groups: group I, intact animals; group II, exposure to coal dust and 0.2 Gy γ-irradiation; and group III, combined exposure to 6 Gy γ-irradiation and coal dust. The combination of a low and sublethal dose of γ-irradiation with coal dust leads to a significant change in immunity at the remote period. Particularly, the increase in radioactivity at the combined effect causes weakening of phagocytosis, and reduction in T lymphocytes by a factor of 2, immunoglobulin imbalance, and cytokine dysfunction develop secondary immune failure. During prolonged inhalation with coal dust of irradiated animals with the dose of 0.2 Gy, fibrosis and perivascular sclerosis of the bronchial wall of the lungs are formed, and perivascular fibrosis is formed in the liver. The increase in exposure dose up to 6 Gy in combination with coal, in the distant period, caused pulmonary hypertension amid hypertrophy of light arterial vessels and fibrous changes in arteriole, and destructive changes and collection necrosis develop in liver parenchyma. In the case of dust radiation synergy, the increase in doses leads to a significant immune deficiency, which occurs according to the “dose effect” principle; increases damage to animal tissues; and leads to liver tissue necrosis, pulmonary fibrosis, and pulmonary hypertension.
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16
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Paganetti H. Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy. Int J Radiat Oncol Biol Phys 2022; 112:222-236. [PMID: 34407443 PMCID: PMC8688199 DOI: 10.1016/j.ijrobp.2021.08.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/14/2021] [Accepted: 08/10/2021] [Indexed: 01/03/2023]
Abstract
Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tissue constraints. Potential variations in RBE have been assessed in several published reviews but have mostly focused on data from clonogenic cell survival experiments with unclear relevance for clinical proton therapy. The goal of this review is to put in vitro findings in relation to clinical observations. Relevant in vivo pathways determining RBE for tumors and normal tissues are outlined, including not only damage to tumor cells and parenchyma but also vascular damage and immune response. Furthermore, the current clinical evidence of varying RBE is reviewed. The assessment can serve as guidance for treatment planning, personalized dose prescriptions, and outcome analysis.
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Affiliation(s)
- Harald Paganetti
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
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17
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Lei X, He N, Zhu L, Zhou M, Zhang K, Wang C, Huang H, Chen S, Li Y, Liu Q, Han Z, Guo Z, Han Z, Li Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Radiation-Induced Lung Injury via miRNA-214-3p. Antioxid Redox Signal 2021; 35:849-862. [PMID: 32664737 DOI: 10.1089/ars.2019.7965] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Aims: Radiotherapy is an effective treatment for thoracic malignancies, but it can cause pulmonary injury and may lead to respiratory failure in a subset of patients. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are now recognized as a new candidate for cell-free treatment of lung diseases. Here, we investigated whether MSC-derived EVs (MSC-EVs) could ameliorate radiation-induced lung injury. Results: We exposed mice to thoracic radiation with a total dose of 15 Gy and assessed the protective effects of MSC-EVs on endothelial cells damage, vascular permeability, inflammation, and fibrosis. We found that MSC-EVs attenuated radiation-induced lung vascular damage, inflammation, and fibrosis. Moreover, MSC-EVs reduced the levels of radiation-induced DNA damage by downregulating ATM/P53/P21 signaling. Our results confirmed that the downregulation of ataxia telangiectasia mutated (ATM) was regulated by miR-214-3p, which was enriched in MSC-EVs. Further analysis demonstrated that MSC-EVs inhibited the senescence-associated secretory phenotype development and attenuated the radiation-induced injury of endothelial cells. Innovation and Conclusion: Our study reveals that MSC-EVs can reduce pulmonary radiation injury through transferring miR-214-3p, providing new avenues to minimize lung injury from radiation therapy. Antioxid. Redox Signal. 35, 849-862.
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Affiliation(s)
- Xudan Lei
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China.,The Key Laboratory of Bioactive Materials, Ministry of Education, The College of Life Science, Nankai University, Tianjin, China
| | - Ningning He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Department of Radiobiology, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Lihong Zhu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Manqian Zhou
- Department of Radiation Oncology, Tianjin Union Medical Center, Tianjin, China
| | - Kaiyue Zhang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Chen Wang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Haoyan Huang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Shang Chen
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Yuhao Li
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Qiang Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Department of Radiobiology, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Zhibo Han
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China.,Jiangxi Engineering Research Center for Stem Cell, Shangrao, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Zhongchao Han
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China.,Jiangxi Engineering Research Center for Stem Cell, Shangrao, China
| | - Zongjin Li
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China.,The Key Laboratory of Bioactive Materials, Ministry of Education, The College of Life Science, Nankai University, Tianjin, China.,State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
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18
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Aqeel M, Medhora M, Gore E, Borkenhagen J, Klawikowski S, Eastwood D, Banerjee A, Jacobs ER. Evaluation of Radiation-induced Pleural Effusions after Radiotherapy to Support Development of Animal Models of Radiation Pneumonitis. HEALTH PHYSICS 2021; 121:434-443. [PMID: 34546223 PMCID: PMC8500166 DOI: 10.1097/hp.0000000000001462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
ABSTRACT Not all animal models develop radiation-induced pleural effusions (RIPEs) as a form of radiation-induced lung injury (RILI). Such effusions are also not well characterized in humans. The purpose of this study is to identify occurrences of RIPE in humans, provide justification for development of relevant animal models, and further characterize its risk factors in cancer patients. We also aim to identify dose thresholds for cardiopulmonary toxicity in humans to shed light on possible pathogenic mechanisms for RIPEs. We carried out a retrospective review of medical records of 96 cancer patients receiving thoracic irradiation (TRT) at our institution. Fifty-three (53%) patients developed a new pleural effusion post TRT; 18 (19%) had RIPE; and 67% developed RIPE ipsilateral to the site irradiated. None developed "contralateral only" effusions. Median time to development was 6 mo (IQR; 4-8 mo). Of 18, 8 patients (44%) had concomitant asymptomatic (radiographic only) or symptomatic radiation pneumonitis and pericardial effusion. Dosimetric factors, including combined and ipsilateral mean lung dose (MLD), were significantly associated with increased risk of RIPE. Angiotensin converting enzyme inhibition, steroids, or concurrent chemotherapy did not modify incidence of RIPE. Our results substantiate the occurrence and incidence of RIPEs in humans. In cancer patients, a median time to development of effusions around 6 mo also supports the onset of RIPEs concurrent with radiation pneumonitis. Future work needs to include large populations of cancer survivors in whom delayed RIPEs can be tracked and correlated with cardiovascular changes in the context of injury to multiple organs.
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Affiliation(s)
- Masooma Aqeel
- Current Affiliation: Section of Pulmonary & Critical
Care Medicine, Department of Medicine, Aga Khan University, Karachi, Pakistan.
Formerly at Division of Pulmonary Medicine, Department of Medicine, Froedtert
Hospital & Medical College of Wisconsin, Milwaukee, WI, United States
| | - Meetha Medhora
- Division of Pulmonary Medicine, Department of Medicine,
Froedtert Hospital & Medical College of Wisconsin, Milwaukee, WI, United
States
- Department of Radiation Oncology, Froedtert Hospital &
Medical College of Wisconsin, Milwaukee, WI, United States
- Research Service, Department of Veteran’s Affairs,
Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States
| | - Elizabeth Gore
- Department of Radiation Oncology, Froedtert Hospital &
Medical College of Wisconsin, Milwaukee, WI, United States
- Research Service, Department of Veteran’s Affairs,
Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States
| | - Jenna Borkenhagen
- Department of Radiation Oncology, Froedtert Hospital &
Medical College of Wisconsin, Milwaukee, WI, United States
| | - Slade Klawikowski
- Department of Radiation Oncology, Froedtert Hospital &
Medical College of Wisconsin, Milwaukee, WI, United States
| | - Daniel Eastwood
- Department of Biostatistics, Medical College of Wisconsin,
Milwaukee, WI, United States
| | - Anjishnu Banerjee
- Department of Biostatistics, Medical College of Wisconsin,
Milwaukee, WI, United States
| | - Elizabeth R. Jacobs
- Division of Pulmonary Medicine, Department of Medicine,
Froedtert Hospital & Medical College of Wisconsin, Milwaukee, WI, United
States
- Research Service, Department of Veteran’s Affairs,
Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States
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19
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Nanduri LSY, Duddempudi PK, Yang WL, Tamarat R, Guha C. Extracellular Vesicles for the Treatment of Radiation Injuries. Front Pharmacol 2021; 12:662437. [PMID: 34084138 PMCID: PMC8167064 DOI: 10.3389/fphar.2021.662437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023] Open
Abstract
Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.
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Affiliation(s)
- Lalitha Sarad Yamini Nanduri
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Phaneendra K. Duddempudi
- Department of Biochemistry, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Weng-Lang Yang
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Urology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Institute for Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
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20
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Collie D, Wright SH, Del-Pozo J, Kay E, Schwarz T, Parys M, Lawrence J. Regional and organ-level responses to local lung irradiation in sheep. Sci Rep 2021; 11:9553. [PMID: 33953285 PMCID: PMC8099861 DOI: 10.1038/s41598-021-88863-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 04/14/2021] [Indexed: 11/30/2022] Open
Abstract
Lung is a dose-limiting organ in radiotherapy. This may limit tumour control when effort is made in planning to limit the likelihood of radiation-induced lung injury (RILI). Understanding the factors that dictate susceptibility to radiation-induced pulmonary fibrosis will aid in the prevention and management of RILI, and may lead to more effective personalized radiotherapy treatment. As the interaction of regional and organ-level responses may shape the chronic consequences of RILI, we sought to characterise both aspects of the response in an ovine model. A defined volume of left pulmonary parenchyma was prescribed 5 fractions of 6 Gy within 14 days while the contralateral lung dose was constrained. Radiographic changes via computed tomography (CT) were documented to define differences in radio-exposed lung relative to non-exposed lung at d21, d63 and d171 (n = 2), and at d21, d147 and d227 (n = 2). Gross and histologic lung changes were evaluated in samples derived at necropsy examination to define the chronic pulmonary response to radiation. Irradiated lung demonstrated reduced radio-density and increased homogeneity as evidenced from texture based radiomic feature analysis, relative to the control lung. At necropsy, the radiation field was readily defined by pallor on the pleural surface, which was also evident on the cut surface of fixed lung specimens. The degree and homogeneity of pallor reflected the sparse presence of erythrocytes in alveolar septal capillaries of radiation-exposed lung. These changes contrasted with dilated and congested microvasculature in the contralateral control lung. Referencing data to measurements made in control lung volumes of sheep experiencing acute RILI indicated that interstitial collagen continues to deposit in the radio-exposed lung field. Overall lung vascularity increased during the chronic response, as evidenced by increased expression of endothelial cell marker (CD31); however, vascularity was consistently decreased in irradiated lung and was negatively correlated with lung collagen. Other organ-level responses included increased expression of alpha smooth muscle actin (ASMA), increased numbers of proliferating cells (Ki67 positive), and cells expressing the dendritic cell-lysosomal associated membrane protein (DC-LAMP) antigen. The chronic response to RILI in this model is effected at both the whole organ and local lung level. Whilst the long-term consequences of exposure to radiation involved the continued deposition of collagen in the radiation field, organ-level responses also included increased vascularization and increased expression of ASMA, Ki67 and DC-LAMP. Interrupting the interplay between these aspects may influence susceptibility to pulmonary fibrosis after radiotherapy. We advocate for the importance of large animal model systems in pursuing these opportunities to target local, organ-level and systemic mechanisms in parallel within the same subject over time.
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Affiliation(s)
- David Collie
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK.
| | - Steven H Wright
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
| | - Jorge Del-Pozo
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
| | - Elaine Kay
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
- Small Animal Clinical Sciences, School of Veterinary Medicine, University of Glasgow, Glasgow, UK
| | - Tobias Schwarz
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
| | - Magdalena Parys
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
| | - Jessica Lawrence
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Edinburgh, EH25 9RG, UK
- Department of Veterinary Clinical Sciences, University of Minnesota, St Paul, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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21
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Voshart DC, Wiedemann J, van Luijk P, Barazzuol L. Regional Responses in Radiation-Induced Normal Tissue Damage. Cancers (Basel) 2021; 13:cancers13030367. [PMID: 33498403 PMCID: PMC7864176 DOI: 10.3390/cancers13030367] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 12/16/2022] Open
Abstract
Normal tissue side effects remain a major concern in radiotherapy. The improved precision of radiation dose delivery of recent technological developments in radiotherapy has the potential to reduce the radiation dose to organ regions that contribute the most to the development of side effects. This review discusses the contribution of regional variation in radiation responses in several organs. In the brain, various regions were found to contribute to radiation-induced neurocognitive dysfunction. In the parotid gland, the region containing the major ducts was found to be critical in hyposalivation. The heart and lung were each found to exhibit regional responses while also mutually affecting each other's response to radiation. Sub-structures critical for the development of side effects were identified in the pancreas and bladder. The presence of these regional responses is based on a non-uniform distribution of target cells or sub-structures critical for organ function. These characteristics are common to most organs in the body and we therefore hypothesize that regional responses in radiation-induced normal tissue damage may be a shared occurrence. Further investigations will offer new opportunities to reduce normal tissue side effects of radiotherapy using modern and high-precision technologies.
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Affiliation(s)
- Daniëlle C. Voshart
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.C.V.); (J.W.)
- Department of Biomedical Sciences of Cells & Systems–Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Julia Wiedemann
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.C.V.); (J.W.)
- Department of Biomedical Sciences of Cells & Systems–Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Peter van Luijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.C.V.); (J.W.)
- Department of Biomedical Sciences of Cells & Systems–Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
- Correspondence: (P.v.L.); (L.B.)
| | - Lara Barazzuol
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.C.V.); (J.W.)
- Department of Biomedical Sciences of Cells & Systems–Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
- Correspondence: (P.v.L.); (L.B.)
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22
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Bryant AJ, Pham A, Gogoi H, Mitchell CR, Pais F, Jin L. The Third Man: DNA sensing as espionage in pulmonary vascular health and disease. Pulm Circ 2021; 11:2045894021996574. [PMID: 33738095 PMCID: PMC7934053 DOI: 10.1177/2045894021996574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 01/01/2023] Open
Abstract
For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic material, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of DNA sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expression of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condition is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circulation of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immunology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.
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Affiliation(s)
- Andrew J. Bryant
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
| | - Ann Pham
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
| | - Himanshu Gogoi
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
| | - Carly R. Mitchell
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
| | - Faye Pais
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
| | - Lei Jin
- University of Florida College of Medicine, Department of Medicine, Gainesville, FL, USA
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23
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Current and Future Perspectives of the Use of Organoids in Radiobiology. Cells 2020; 9:cells9122649. [PMID: 33317153 PMCID: PMC7764598 DOI: 10.3390/cells9122649] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
The majority of cancer patients will be treated with radiotherapy, either alone or together with chemotherapy and/or surgery. Optimising the balance between tumour control and the probability of normal tissue side effects is the primary goal of radiation treatment. Therefore, it is imperative to understand the effects that irradiation will have on both normal and cancer tissue. The more classical lab models of immortal cell lines and in vivo animal models have been fundamental to radiobiological studies to date. However, each of these comes with their own limitations and new complementary models are required to fill the gaps left by these traditional models. In this review, we discuss how organoids, three-dimensional tissue-resembling structures derived from tissue-resident, embryonic or induced pluripotent stem cells, overcome the limitations of these models and thus have a growing importance in the field of radiation biology research. The roles of organoids in understanding radiation-induced tissue responses and in moving towards precision medicine are examined. Finally, the limitations of organoids in radiobiology and the steps being made to overcome these limitations are considered.
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24
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MacVittie TJ, Farese AM, Parker GA, Bennett AW, Jackson W. 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 2020; 119:559-587. [PMID: 33009295 PMCID: PMC9440605 DOI: 10.1097/hp.0000000000001346] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
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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Affiliation(s)
| | - Ann M. Farese
- University of Maryland School of Medicine, Baltimore, MD
| | | | - Alexander W. Bennett
- Louisville, KY, formerly at University of Maryland School of Medicine, Baltimore, MD
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25
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Barazzuol L, Coppes RP, van Luijk P. Prevention and treatment of radiotherapy-induced side effects. Mol Oncol 2020; 14:1538-1554. [PMID: 32521079 PMCID: PMC7332214 DOI: 10.1002/1878-0261.12750] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 01/10/2023] Open
Abstract
Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.
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Affiliation(s)
- Lara Barazzuol
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Rob P. Coppes
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Peter van Luijk
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
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26
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Lambin P, Lieverse RIY, Eckert F, Marcus D, Oberije C, van der Wiel AMA, Guha C, Dubois LJ, Deasy JO. Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy. Semin Radiat Oncol 2020; 30:187-193. [PMID: 32381298 PMCID: PMC8412054 DOI: 10.1016/j.semradonc.2019.12.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There is now strong clinical and preclinical evidence that lymphocytes, for example, CD8+ T cells, are key effectors of immunotherapy and that irradiation of large blood vessels, the heart, and lymphoid organs (including nodes, spleen, bones containing bone marrow, and thymus in children) causes transient or persistent lymphopenia. Furthermore, there is extensive clinical evidence, across multiple cancer sites and treatment modalities, that lymphopenia correlates strongly with decreased overall survival. At the moment, we lack quantitative evidence to establish the relationship between dose-volume and dose-rate to critical normal structures and lymphopenia. Therefore, we propose that data should be systematically recorded to characterise a possible quantitative relationship. This might enable us to improve the efficacy of radiotherapy and develop strategies to predict and prevent treatment-related lymphopenia. In anticipation of more quantitative data, we recommend the application of the principle of As Low As Reasonably Achievable to lymphocyte-rich regions for radiotherapy treatment planning to reduce the radiation doses to these structures, thus moving toward "Lymphocyte-Sparing Radiotherapy."
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Affiliation(s)
- Philippe Lambin
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
| | - Relinde I Y Lieverse
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Franziska Eckert
- Department of Radiation Oncology, University Hospital and Medical Faculty Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Damiënne Marcus
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Cary Oberije
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Alexander M A van der Wiel
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY
| | - Ludwig J Dubois
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY
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27
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De Ruysscher D, Faivre-Finn C, Nackaerts K, Jordan K, Arends J, Douillard J, Ricardi U, Peters S. Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer. Ann Oncol 2020; 31:41-49. [DOI: 10.1016/j.annonc.2019.10.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/06/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022] Open
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28
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Venema CM, de Vries EFJ, van der Veen SJ, Dorrius MD, van Kruchten M, Schröder CP, Hospers GAP, Glaudemans AWJM. Enhanced pulmonary uptake on 18F-FES-PET/CT scans after irradiation of the thoracic area: related to fibrosis? EJNMMI Res 2019; 9:82. [PMID: 31444658 PMCID: PMC6708021 DOI: 10.1186/s13550-019-0549-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 08/05/2019] [Indexed: 12/29/2022] Open
Abstract
Rationale The use of 16α-[18F]fluoro-17β-estradiol (FES) positron emission tomography (PET) in clinical dilemmas and for therapy decision-making in lesions expressing estrogen receptors is growing. However, on a considerable number of FES PET scans, previously performed in a research and clinical setting in our institution, FES uptake was noticed in the lungs without an oncologic substrate. We hypothesized that this uptake was related to pulmonary fibrosis as a result of radiation therapy. This descriptive study therefore aimed to investigate whether radiation therapy in the thoracic area is possibly related to enhanced pulmonary, non-tumor FES uptake. Methods All FES-PET/CT scans performed in our institution from 2008 to 2017 were retrospectively analyzed. Scans from patients who had received irradiation in the thoracic area prior to the scan were compared to scans of patients who had never received irradiation in the thoracic area. The primary outcome was the presence of enhanced non-tumor FES uptake in the lungs, defined as visually increased FES uptake in the absence of an oncologic substrate on the concordant (contrast-enhanced) CT scan. All CT scans were evaluated for the presence of fibrosis or oncologic substrates. Results A total of 108 scans were analyzed: 70 scans of patients with previous irradiation in the thoracic area and 38 of patients without. Enhanced non-tumor FES uptake in the lungs was observed in 39/70 irradiated patients (56%), versus in 9/38 (24%) of non-irradiated patients. Fibrosis was present in 37 of the 48 patients with enhanced non-tumor FES uptake (77%), versus in 15 out of 60 (25%) patients without enhanced non-tumor uptake, irrespective of radiotherapy (p < 0.001). Conclusion After irradiation of the thorax, enhanced non-tumor uptake on FES-PET can be observed in the radiation field in a significant proportion of patients. This seems to be related to fibrosis. When observing enhanced FES uptake in the lungs, this should not be interpreted as metastases. Information on recent radiation therapy or history of pulmonary fibrosis should therefore be taken into consideration.
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Affiliation(s)
- C M Venema
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - E F J de Vries
- Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - S J van der Veen
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - M D Dorrius
- Medical Imaging Center, Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - M van Kruchten
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - C P Schröder
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - G A P Hospers
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - A W J M Glaudemans
- Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.
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29
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van der Feen DE, Berger RMF, Bartelds B. Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence. Am J Respir Cell Mol Biol 2019; 61:11-20. [DOI: 10.1165/rcmb.2018-0329tr] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Diederik E. van der Feen
- Center for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Rolf M. F. Berger
- Center for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Beatrijs Bartelds
- Center for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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30
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Medhora M, Gao F, Gasperetti T, Narayanan J, Hye Khan MA, Jacobs ER, Fish BL. Delayed Effects of Acute Radiation Exposure (Deare) in Juvenile and Old Rats: Mitigation by Lisinopril. HEALTH PHYSICS 2019; 116:529-545. [PMID: 30624354 PMCID: PMC6384142 DOI: 10.1097/hp.0000000000000920] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Our goal is to develop lisinopril as a mitigator of delayed effects of acute radiation exposure in the National Institute of Allergy and Infectious Diseases program for radiation countermeasures. Published studies demonstrated mitigation of delayed effects of acute radiation exposure by lisinopril in adult rats. However, juvenile or old rats beyond their reproductive lifespans have never been tested. Since no preclinical models of delayed effects of acute radiation exposure were available in these special populations, appropriate rat models were developed to test lisinopril after irradiation. Juvenile (42-d-old, prepubertal) female and male WAG/RijCmcr (Wistar) rats were given 13-Gy partial-body irradiation with only part of one hind limb shielded. Lethality from lung injury between 39-58 d and radiation nephropathy between 106-114 d were recorded. All irradiated-only juvenile rats were morbid from delayed effects of acute radiation exposure by 114 d, while lisinopril (24 mg m d) started 7 d after irradiation and continued improved survival to 88% (p = 0.0015, n ≥ 8/group). Old rats (>483-d-old, reproductively senescent) were irradiated with 13-Gy partial-body irradiation keeping part of one leg shielded and additionally shielding the head in some animals. Irradiated old females developed lethal nephropathy, and all became morbid by 170 d after irradiation, though no rats displayed lethal radiation pneumonitis. Similar results were observed for irradiated geriatric males, though 33% of rats remained alive at 180 d after irradiation. Lisinopril mitigated radiation nephropathy in old rats of both sexes. Finally, comparison of delayed effects of acute radiation exposure between irradiated juvenile, adult, and old rats showed younger rats were more sensitive to delayed effects of acute radiation exposure with earlier manifestation of injuries to some organs.
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Affiliation(s)
- Meetha Medhora
- Department of Radiation Oncology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
- Department of Medicine, Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
- Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295
| | - Feng Gao
- Department of Radiation Oncology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Tracy Gasperetti
- Department of Radiation Oncology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Jayashree Narayanan
- Department of Radiation Oncology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Md. Abdul Hye Khan
- Department of Pharmacology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
| | - Elizabeth R. Jacobs
- Department of Medicine, Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
- Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295
| | - Brian L. Fish
- Department of Radiation Oncology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
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Zhou C, Moustafa MR, Cao L, Kriegsmann M, Winter M, Schwager C, Jones B, Wang S, Bäuerle T, Zhou PK, Schnölzer M, Weichert W, Debus J, Abdollahi A. Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation. Int J Cancer 2019; 144:3160-3173. [PMID: 30536712 PMCID: PMC6590477 DOI: 10.1002/ijc.32059] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 11/15/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022]
Abstract
Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose‐limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose–response series of fractionated irradiation was utilized to develop a non‐invasive and quantitative measure for the degree of fibrosis – the fibrosis index (FI). The correlation of FI with histopathology, blood‐gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24‐week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro‐inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state toward a macrophage/T‐helper cell type 2‐like (M2/Th2) polarized phenotype. Together, the multiscale characterization of FI in radiation‐induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need. What's new? The development of fibrosis scar tissue in the lungs is a dose‐limiting effect of radiotherapy for thoracic malignancies. Molecular mechanisms driving radiation‐induced lung fibrosis (RILF), however, remain unclear. In this study, a fibrosis index (FI) was devised to quantitatively detect spatial and temporal kinetics of lung fibrosis development. Multi‐scale characterization of FI uncovered mechanisms governing lung fibrosis, including perturbation of immune balance and microvascular integrity. Radiation dose and FI were correlated with an inflammatory switch toward a macrophage/T‐helper cell type 2‐like polarized phenotype. The findings open the way for further mechanistic study and the discovery of therapeutic targets for RILF.
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Affiliation(s)
- Cheng Zhou
- Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Centre (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.,Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany.,Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mahmoud R Moustafa
- Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Centre (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.,Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany.,Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt
| | - Liji Cao
- Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mark Kriegsmann
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Winter
- Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany.,Department of Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Schwager
- Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Centre (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.,Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany
| | - Bleddyn Jones
- Gray Laboratory, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Shijun Wang
- Department of Pediatric Nephrology, Gastroenterology & Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Tobias Bäuerle
- Institute of Radiology, University Hospital Erlangen, Erlangen, Germany
| | - Ping-Kun Zhou
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Martina Schnölzer
- Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany.,Department of Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Juergen Debus
- Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Centre (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.,Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany
| | - Amir Abdollahi
- Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Centre (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.,Division of Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation research in Oncology (NCRO), Heidelberg, Germany
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Abstract
Soy isoflavones have demonstrated chemopreventive and anticancer properties in epidemiology and biological studies, in addition to their function as antioxidants in prevention of cardiovascular disease. We have explored the potential of soy isoflavones, as a safe biological approach, to enhance the efficacy of radiotherapy for local tumor control and limit normal tissue damage in solid tumors. This review presents studies investigating the interaction between soy isoflavones and radiation in different malignancies, including prostate cancer, renal cell carcinoma, and nonsmall cell lung cancer. Soy isoflavones were found to be potent sensitizers of cancer cells to radiation causing increased cell killing in vitro in human tumor cell lines and greater tumor inhibition in vivo in preclinical orthotopic murine tumor models. In the course of these studies, radioprotection of normal tissues and organs in the field of radiation was observed both in a clinical trial for prostate cancer and in preclinical models. The mechanisms of radiosensitization and radioprotection mediated by soy isoflavones are discussed and emphasize the role of soy isoflavones in increasing radiation effect on tumor and mitigating inflammatory responses induced by radiation in normal tissues. Soy isoflavones could be used as a safe, nontoxic complementary strategy that simultaneously increases radiation effectiveness on the malignancy while reducing damage in normal tissues in the field of radiation.
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Affiliation(s)
- Gilda G Hillman
- Department of Oncology, Radiation Oncology Division, and Department of Biochemistry, Microbiology and Immunology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.
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Defraene G, La Fontaine M, van Kranen S, Reymen B, Belderbos J, Sonke JJ, De Ruysscher D. Radiation-Induced Lung Density Changes on CT Scan for NSCLC: No Impact of Dose-Escalation Level or Volume. Int J Radiat Oncol Biol Phys 2018; 102:642-650. [PMID: 30244882 DOI: 10.1016/j.ijrobp.2018.06.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 05/23/2018] [Accepted: 06/20/2018] [Indexed: 12/25/2022]
Abstract
PURPOSE Dose-escalation for patients with non-small cell lung cancer (NSCLC) in the positron emission tomography (PET)-boost trial (NCT01024829) exposes portions of normal lung tissue to high radiation doses. The relationship between lung parenchyma dose and density changes on computed tomography (CT) was analyzed. MATERIALS AND METHODS The CT scans of 59 patients with stage IB to III NSCLC, randomized between a boost to the whole primary tumor and an integrated boost to its 50% SUVmax (maximum standardized uptake value) volume. Patients were treated with concurrent or sequential chemoradiation or radiation only. Deformable registration mapped the 3-month follow-up CT to the planning CT. Hounsfield unit differences (ΔHU) were extracted to assess lung parenchyma density changes. Equivalent dose in 2 Gy fractions (EQD2)-ΔHU response was described sigmoidally, and regional response variation was studied by polar analysis. Prognostic factors of ΔHU were obtained through generalized linear modeling. RESULTS Saturation of ΔHU was observed above 60 Gy. No interaction was found between boost dose distribution (D1cc and V70Gy) and ΔHU at lower doses. ΔHU was lowest peripherally from the tumor and peaked posteriorly at 3 cm from the tumor border (3.1 HU/Gy). Right lung location was an independent risk factor for ΔHU (P = .02). CONCLUSIONS No apparent increase of lung density changes at 3-month follow-up was observed above 60 Gy EQD2 for patients with NSCLC treated with (concurrent or sequential chemo) radiation. The mild response observed peripherally in the lung parenchyma might be exploited in plan optimization routines minimizing lung damage.
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Affiliation(s)
- Gilles Defraene
- Department of Oncology, Experimental Radiation Oncology, KU Leuven-University of Leuven, Belgium.
| | - Matthew La Fontaine
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Simon van Kranen
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bart Reymen
- Maastricht University Medical Center, Maastricht, The Netherlands
| | - José Belderbos
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jan-Jakob Sonke
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Dirk De Ruysscher
- Department of Oncology, Experimental Radiation Oncology, KU Leuven-University of Leuven, Belgium; Maastricht University Medical Center, Maastricht, The Netherlands; Department of Radiation Oncology (Maastro Clinic), GROW School for Developmental Biology and Oncology, Maastricht, The Netherlands
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Zanette B, Stirrat E, Jelveh S, Hope A, Santyr G. Physiological gas exchange mapping of hyperpolarized 129
Xe using spiral-IDEAL and MOXE in a model of regional radiation-induced lung injury. Med Phys 2018; 45:803-816. [DOI: 10.1002/mp.12730] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/17/2017] [Accepted: 11/28/2017] [Indexed: 12/20/2022] Open
Affiliation(s)
- Brandon Zanette
- Department of Medical Biophysics; University of Toronto, Toronto; 101 College St Toronto ON M5G1L7 Canada
- Translational Medicine Program; Peter Gilgan Centre for Research and Learning; The Hospital for Sick Children; 686 Bay St Toronto ON M5G0A4 Canada
| | - Elaine Stirrat
- Translational Medicine Program; Peter Gilgan Centre for Research and Learning; The Hospital for Sick Children; 686 Bay St Toronto ON M5G0A4 Canada
| | - Salomeh Jelveh
- Radiation Medicine Program; Princess Margaret Cancer Centre; 610 University Ave Toronto ON M5G2M9 Canada
| | - Andrew Hope
- Radiation Medicine Program; Princess Margaret Cancer Centre; 610 University Ave Toronto ON M5G2M9 Canada
- Department of Radiation Oncology; University of Toronto; 149 College St Toronto ON M5T1P5 Canada
| | - Giles Santyr
- Department of Medical Biophysics; University of Toronto, Toronto; 101 College St Toronto ON M5G1L7 Canada
- Translational Medicine Program; Peter Gilgan Centre for Research and Learning; The Hospital for Sick Children; 686 Bay St Toronto ON M5G0A4 Canada
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Prado C, MacVittie TJ, Bennett AW, Kazi A, Farese AM, Prado K. Organ Doses Associated with Partial-Body Irradiation with 2.5% Bone Marrow Sparing of the Non-Human Primate: A Retrospective Study. Radiat Res 2017; 188:615-625. [PMID: 28985133 DOI: 10.1667/rr14804.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
A partial-body irradiation model with approximately 2.5% bone marrow sparing (PBI/BM2.5) was established to determine the radiation dose-response relationships for the prolonged and delayed multi-organ effects of acute radiation exposure. Historically, doses reported to the entire body were assumed to be equal to the prescribed dose at some defined calculation point, and the dose-response relationship for multi-organ injury has been defined relative to the prescribed dose being delivered at this point, e.g., to a point at mid-depth at the level of the xiphoid of the non-human primate (NHP). In this retrospective-dose study, the true distribution of dose within the major organs of the NHP was evaluated, and these doses were related to that at the traditional dose-prescription point. Male rhesus macaques were exposed using the PBI/BM2.5 protocol to a prescribed dose of 10 Gy using 6-MV linear accelerator photons at a rate of 0.80 Gy/min. Point and organ doses were calculated for each NHP from computed tomography (CT) scans using heterogeneous density data. The prescribed dose of 10.0 Gy to a point at midline tissue assuming homogeneous media resulted in 10.28 Gy delivered to the prescription point when calculated using the heterogeneous CT volume of the NHP. Respective mean organ doses to the volumes of nine organs, including the heart, lung, bowel and kidney, were computed. With modern treatment planning systems, utilizing a three-dimensional reconstruction of the NHP's CT images to account for the variations in body shape and size, and using density corrections for each of the tissue types, bone, water, muscle and air, accurate determination of the differences in dose to the NHP can be achieved. Dose and volume statistics can be ascertained for any body structure or organ that has been defined using contouring tools in the planning system. Analysis of the dose delivered to critical organs relative to the total-body target dose will permit a more definitive analysis of organ-specific effects and their respective influence in multiple organ injury.
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Affiliation(s)
- C Prado
- a Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and
| | - T J MacVittie
- a Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and
| | - A W Bennett
- a Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and
| | - A Kazi
- b Veterans Administration, Maryland Health Care System, Baltimore, Maryland
| | - A M Farese
- a Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and
| | - K Prado
- a Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and
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Niezink AGH, de Jong RA, Muijs CT, Langendijk JA, Widder J. Pulmonary Function Changes After Radiotherapy for Lung or Esophageal Cancer: A Systematic Review Focusing on Dose-Volume Parameters. Oncologist 2017; 22:1257-1264. [PMID: 28550029 DOI: 10.1634/theoncologist.2016-0324] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 03/28/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Despite technical developments in treatment delivery, radiation-induced lung toxicity (RILT) remains a crucial problem in thoracic radiotherapy. Clinically based RILT scores have their limitations, and more objective measures such as pulmonary functions tests (PFTs) might help to improve treatment strategies. PURPOSE To summarize the available evidence about the effect of dose to the lung in thoracic radiotherapy on forced expiratory volume in one second (FEV1) and diffusion capacity (DLCO) in patients with lung and esophageal cancer treated with curative intent. MATERIAL AND METHODS A systematic review following the PRISMA guidelines was performed, using MEDLINE and including clinical studies using (chemo)radiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) for lung or CRT for esophageal cancer that reported both lung dose-volume histogram (DVH) parameters and changes in PFT results. Search terms included lung and esophageal neoplasms, respiratory function tests, and radiotherapy. RESULTS Fifteen studies met the inclusion criteria. Seven out of 13 studies on lung cancer reported significant declines (defined as a p value < .05) in PFT results. Both esophageal studies reported significant DLCO declines. One SABR study found a correlation between low lung-dose parameters and FEV1 decline. Relations between decline of FEV1 (three studies) or decline of DLCO (five studies), respectively, and DVH parameters were found in eight studies analyzing CRT. Furthermore, a heterogeneous range of clinical risk factors for pulmonary function changes were reported in the selected studies. CONCLUSIONS There is evidence that pulmonary function declines after RT in a dose-dependent manner, but solid data about lung DVH parameters predicting changes in PFT results are scarce. A major disadvantage was the wide variety of methods used, frequently lacking multivariable analyses. Studies using prospective high-quality data, analyzed with appropriate statistical methods, are needed. The Oncologist 2017;22:1257-1264 IMPLICATIONS FOR PRACTICE: Radiation-induced lung toxicity remains crucial in thoracic radiotherapy. To prevent this toxicity in the future and individualize patient treatment, objective measures of pulmonary toxicity are needed. Pulmonary function tests may provide such objective measures. This systematic review, included all available clinical studies using external beam radiotherapy for lung or esophageal cancer reporting pulmonary function combined with dose-volume histogram parameters. There is preliminary evidence that pulmonary function declines post radiotherapy in a dose-dependent manner. Data quality and analyses were generally limited. Analyses of high-quality data are therefore urgently needed to improve individualization of advanced radiation therapy.
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Affiliation(s)
- Anne G H Niezink
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Renske A de Jong
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Christina T Muijs
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Joachim Widder
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
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Abstract
OPINION STATEMENT Pulmonary hypertension is caused by cancer and its therapeutic agents including chemotherapy, radiotherapy, and even the targeted therapies. Ironically, some of the cancer therapies that cause one type of pulmonary hypertension (PH) could potentially be employed in the treatment of another PH type. Greater awareness on the role of cancer therapeutic agents in causing PH is required. Conversely, since PH is mostly incurable, the potential role of some of these cancer therapeutic agents in the cure of PH should be recognized. In short, the relationship between cancer, cancer therapy, and PH is an interesting one requiring further attention, education, and research.
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Mathew R, Huang J, Wu JM, Fallon JT, Gewitz MH. Hematological disorders and pulmonary hypertension. World J Cardiol 2016; 8:703-718. [PMID: 28070238 PMCID: PMC5183970 DOI: 10.4330/wjc.v8.i12.703] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/07/2016] [Accepted: 10/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.
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Outcomes After Curative Thoracic Radiotherapy in Patients With Coronary Artery Disease and Existing Cardiac Stents. Am J Clin Oncol 2016; 39:549-555. [DOI: 10.1097/coc.0000000000000092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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40
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Williams JP, Calvi L, Chakkalakal JV, Finkelstein JN, O’Banion MK, Puzas E. Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury. Radiat Res 2016; 186:1-16. [PMID: 27332954 PMCID: PMC4991354 DOI: 10.1667/rr14473.1] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Jacqueline P. Williams
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York
| | - Laura Calvi
- Department of Medicine, University of Rochester Medical Center, Rochester, New York
| | - Joe V. Chakkalakal
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York
| | - Jacob N. Finkelstein
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York
- Department of Pediatrics and Neonatology, University of Rochester Medical Center, Rochester, New York
| | - M. Kerry O’Banion
- Department of Neuroscience, University of Rochester Medical Center, Rochester, New York
| | - Edward Puzas
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York
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Borgdorff MAJ, Dickinson MG, Berger RMF, Bartelds B. Right ventricular failure due to chronic pressure load: What have we learned in animal models since the NIH working group statement? Heart Fail Rev 2016; 20:475-91. [PMID: 25771982 PMCID: PMC4463984 DOI: 10.1007/s10741-015-9479-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Right ventricular (RV) failure determines outcome in patients with pulmonary hypertension, congenital heart diseases and in left ventricular failure. In 2006, the Working Group on Cellular and Molecular Mechanisms of Right Heart Failure of the NIH advocated the development of preclinical models to study the pathophysiology and pathobiology of RV failure. In this review, we summarize the progress of research into the pathobiology of RV failure and potential therapeutic interventions. The picture emerging from this research is that RV adaptation to increased afterload is characterized by increased contractility, dilatation and hypertrophy. Clinical RV failure is associated with progressive diastolic deterioration and disturbed ventricular–arterial coupling in the presence of increased contractility. The pathobiology of the failing RV shows similarities with that of the LV and is marked by lack of adequate increase in capillary density leading to a hypoxic environment and oxidative stress and a metabolic switch from fatty acids to glucose utilization. However, RV failure also has characteristic features. So far, therapies aiming to specifically improve RV function have had limited success. The use of beta blockers and sildenafil may hold promise, but new therapies have to be developed. The use of recently developed animal models will aid in further understanding of the pathobiology of RV failure and development of new therapeutic strategies.
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Affiliation(s)
- Marinus A J Borgdorff
- Department of Pediatrics, Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands,
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Nagle PW, Hosper NA, Ploeg EM, van Goethem MJ, Brandenburg S, Langendijk JA, Chiu RK, Coppes RP. The In Vitro Response of Tissue Stem Cells to Irradiation With Different Linear Energy Transfers. Int J Radiat Oncol Biol Phys 2016; 95:103-111. [PMID: 27084633 DOI: 10.1016/j.ijrobp.2016.02.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 02/03/2016] [Accepted: 02/04/2016] [Indexed: 01/17/2023]
Abstract
PURPOSE A reduction in the dose, irradiated volume, and sensitivity of, in particular, normal tissue stem cells is needed to advance radiation therapy. This could be obtained with the use of particles for radiation therapy. However, the radiation response of normal tissue stem cells is still an enigma. Therefore, in the present study, we developed a model to investigate the in vitro response of stem cells to particle irradiation. METHODS AND MATERIALS We used the immortalized human salivary gland (HSG) cell line resembling salivary gland (SG) cells to translate the radiation response in 2-dimensional (2D) to 3-dimensional (3D) conditions. This response was subsequently translated to the response of SG stem cells (SGSCs). Dispersed single cells were irradiated with photons or carbon ions at different linear energy transfers (LETs; 48.76 ± 2.16, 149.9 ± 10.8, and 189 ± 15 keV/μm). Subsequently, 2D or 3D clonogenicity was determined by counting the colonies or secondary stem cell-derived spheres in Matrigel. γH2AX immunostaining was used to assess DNA double strand break repair. RESULTS The 2D response of HSG cells showed a similar increase in dose response to increasing higher LET irradiation as other cell lines. The 3D response of HSG cells to increasing LET irradiation was reduced compared with the 2D response. Finally, the response of mouse SGSCs to photons was similar to the 3D response of HSG cells. The response to higher LET irradiation was reduced in the stem cells. CONCLUSIONS Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.
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Affiliation(s)
- Peter W Nagle
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Nynke A Hosper
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Emily M Ploeg
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marc-Jan van Goethem
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; KVI-Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands
| | - Sytze Brandenburg
- KVI-Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Roland K Chiu
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert P Coppes
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Klein D, Schmetter A, Imsak R, Wirsdörfer F, Unger K, Jastrow H, Stuschke M, Jendrossek V. Therapy with Multipotent Mesenchymal Stromal Cells Protects Lungs from Radiation-Induced Injury and Reduces the Risk of Lung Metastasis. Antioxid Redox Signal 2016; 24:53-69. [PMID: 26066676 DOI: 10.1089/ars.2014.6183] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIMS Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypothesized that vascular damage facilitates lung metastasis after thorax irradiation and that therapeutically applied multipotent mesenchymal stromal cells (MSCs) with reported repair activity may prevent these adverse effects of ionizing radiation by protecting lung endothelia from radiation-induced damage. RESULTS Previous whole-thorax irradiation (WTI) with 15 Gy significantly enhanced seeding and metastatic growth of tumor cells in the lung. WTI was further associated with endothelial cell damage, senescence of lung epithelial cells, and upregulation of invasion- and inflammation-promoting soluble factors, for example, endothelial matrix metalloproteinase 2 (Mmp2), its activator Mmp14, the cofactor tissue inhibitor of metalloproteinases 2 (Timp2), chemokine (C-C motif) ligand 2 (Ccl2), and urokinase-type plasminogen activator (Plau/uPA), and recruitment of CD11b+CD11c- myelomonocytic cells. Inhibition of Mmp2 counteracted radiation-induced vascular dysfunction without preventing increased metastasis. In contrast, therapy with bone marrow or aorta-derived MSCs within 2 weeks postirradiation antagonized radiation-induced damage to resident cells as well as the resulting secretome changes and abrogated the metastasis-promoting effects of WTI. INNOVATION Therapy with MSCs protects lungs from radiation-induced injury and reduces the risk of lung metastasis. MSC-mediated inhibition of Mmp2 mediates their protective effects at the vasculature. Furthermore, local and systemic effects such as inhibition of radiation-induced senescence of bronchial epithelial cells and associated secretion of immunomodulatory factors may participate in the inhibitory effect of MSCs on lung metastasis. CONCLUSION MSC therapy is a promising strategy to prevent radiation-induced lung injury and the resulting increased risk of metastasis.
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Affiliation(s)
- Diana Klein
- 1 Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Alexandra Schmetter
- 1 Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Roze Imsak
- 1 Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Florian Wirsdörfer
- 1 Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Kristian Unger
- 2 Research Unit Radiation Cytogenetics, Helmholtz-Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany and Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz-Zentrum München, Neuherberg, Germany
| | - Holger Jastrow
- 3 Institute of Anatomy, University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Martin Stuschke
- 4 Department of Radiotherapy, University Hospital, University of Duisburg-Essen , Essen, Germany
| | - Verena Jendrossek
- 1 Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen , Essen, Germany
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van der Veen SJ, Faber H, Ghobadi G, Brandenburg S, Langendijk JA, Coppes RP, van Luijk P. Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects. Int J Radiat Oncol Biol Phys 2015; 94:163-171. [PMID: 26700710 DOI: 10.1016/j.ijrobp.2015.09.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 09/16/2015] [Accepted: 09/21/2015] [Indexed: 12/25/2022]
Abstract
PURPOSE Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity. METHODS AND MATERIALS A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. RESULTS Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. CONCLUSIONS In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.
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Affiliation(s)
- Sonja J van der Veen
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hette Faber
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ghazaleh Ghobadi
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Sytze Brandenburg
- KVI Center for Advanced Radiation Research, University of Groningen, Groningen, The Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert P Coppes
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter van Luijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Russell NS, Floot B, van Werkhoven E, Schriemer M, de Jong-Korlaar R, Woerdeman LA, Stewart FA, Scharpfenecker M. Blood and lymphatic microvessel damage in irradiated human skin: The role of TGF-β, endoglin and macrophages. Radiother Oncol 2015; 116:455-61. [DOI: 10.1016/j.radonc.2015.08.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 08/18/2015] [Accepted: 08/20/2015] [Indexed: 02/01/2023]
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Kreuzer M, Auvinen A, Cardis E, Hall J, Jourdain JR, Laurier D, Little MP, Peters A, Raj K, Russell NS, Tapio S, Zhang W, Gomolka M. Low-dose ionising radiation and cardiovascular diseases – Strategies for molecular epidemiological studies in Europe. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015; 764:90-100. [DOI: 10.1016/j.mrrev.2015.03.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 03/25/2015] [Accepted: 03/26/2015] [Indexed: 12/31/2022]
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Medhora M, Gao F, Glisch C, Narayanan J, Sharma A, Harmann LM, Lawlor MW, Snyder LA, Fish BL, Down JD, Moulder JE, Strande JL, Jacobs ER. Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling. JOURNAL OF RADIATION RESEARCH 2015; 56:248-60. [PMID: 25368342 PMCID: PMC4380043 DOI: 10.1093/jrr/rru095] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/11/2014] [Accepted: 09/19/2014] [Indexed: 05/20/2023]
Abstract
To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy.
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Affiliation(s)
- Meetha Medhora
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Pulmonary Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Research Service, Department of Veteran's Affairs, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, USA
| | - Feng Gao
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Chad Glisch
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Jayashree Narayanan
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Ashish Sharma
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Leanne M Harmann
- Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Michael W Lawlor
- Division of Pediatric Pathology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Laura A Snyder
- Marshfield Laboratories; Wisconsin Veterinary Referral Hospital, Waukesha, Wisconsin, USA
| | - Brian L Fish
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Julian D Down
- Harvard-Massachusetts Institute of Technology Division of Health Sciences Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - John E Moulder
- Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Jennifer L Strande
- Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Elizabeth R Jacobs
- Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Pulmonary Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Research Service, Department of Veteran's Affairs, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, USA
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van Loon RLE, Bartelds B, Wagener FADTG, Affara N, Mohaupt S, Wijnberg H, Pennings SWC, Takens J, Berger RMF. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase. Front Pediatr 2015; 3:71. [PMID: 26380246 PMCID: PMC4551834 DOI: 10.3389/fped.2015.00071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 07/31/2015] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1). METHODS Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the presence or absence of the selective HO-activity inhibitor tin-mesoporphyrin (SnMP). HO activity, circulating EPCs and pulmonary vascular lesions were assessed after 3 weeks. RESULTS In PAH rats, circulating EPCs were decreased and HO activity was increased compared to control. EPO treatment restored circulating EPCs and improved pulmonary vascular remodeling, as shown by a reduced wall thickness and occlusion rate of the intra-acinar vessels. Inhibition of HO activity with SnMP aggravated PAH. Moreover, SnMP treatment abrogated EPO-induced amelioration of pulmonary vascular remodeling, while surprisingly further increasing circulating EPCs as compared with EPO alone. CONCLUSION In experimental PAH, EPO treatment restored the number of circulating EPCs to control level, improved pulmonary vascular remodeling, and showed important interplay with HO activity. Inhibition of increased HO activity in PAH rats exacerbated progression of pulmonary vascular remodeling, despite the presence of restored number of circulating EPCs. We suggest that both EPO-induced HO-1 and EPCs are promising targets to ameliorate the pulmonary vasculature in PAH.
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Affiliation(s)
- Rosa Laura E van Loon
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands
| | - Beatrijs Bartelds
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands
| | - Frank A D T G Wagener
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center , Nijmegen , Netherlands
| | - Nada Affara
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands
| | - Saffloer Mohaupt
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands
| | - Hans Wijnberg
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands
| | - Sebastiaan W C Pennings
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center , Nijmegen , Netherlands
| | - Janny Takens
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands
| | - Rolf M F Berger
- Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands
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van der Veen SJ, Ghobadi G, de Boer RA, Faber H, Cannon MV, Nagle PW, Brandenburg S, Langendijk JA, van Luijk P, Coppes RP. ACE inhibition attenuates radiation-induced cardiopulmonary damage. Radiother Oncol 2014; 114:96-103. [PMID: 25465731 DOI: 10.1016/j.radonc.2014.11.017] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 11/04/2014] [Accepted: 11/10/2014] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND PURPOSE In thoracic irradiation, the maximum radiation dose is restricted by the risk of radiation-induced cardiopulmonary damage and dysfunction limiting tumor control. We showed that radiation-induced sub-clinical cardiac damage and lung damage in rats mutually interact and that combined irradiation intensifies cardiopulmonary toxicity. Unfortunately, current clinical practice does not include preventative measures to attenuate radiation-induced lung or cardiac toxicity. Here, we investigate the effects of the ACE inhibitor captopril on radiation-induced cardiopulmonary damage. MATERIAL AND METHODS After local irradiation of rat heart and/or lungs captopril was administered orally. Cardiopulmonary performance was assessed using biweekly breathing rate measurements. At 8 weeks post-irradiation, cardiac hemodynamics were measured, CT scans and histopathology were analyzed. RESULTS Captopril significantly improved breathing rate and cardiopulmonary density/structure, but only when the heart was included in the radiation field. Consistently, captopril reduced radiation-induced pleural and pericardial effusion and cardiac fibrosis, resulting in an improved left ventricular end-diastolic pressure only in the heart-irradiated groups. CONCLUSION Captopril improves cardiopulmonary morphology and function by reducing acute cardiac damage, a risk factor in the development of radiation-induced cardiopulmonary toxicity. ACE inhibition should be evaluated as a strategy to reduce cardiopulmonary complications induced by radiotherapy to the thoracic area.
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Affiliation(s)
- Sonja J van der Veen
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Ghazaleh Ghobadi
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Rudolf A de Boer
- Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Hette Faber
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Megan V Cannon
- Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Peter W Nagle
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | | | - Johannes A Langendijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Peter van Luijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Robert P Coppes
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
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50
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Effects of γ-irradiation on Na,K-ATPase in cardiac sarcolemma. Mol Cell Biochem 2013; 388:241-7. [DOI: 10.1007/s11010-013-1915-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 12/06/2013] [Indexed: 10/25/2022]
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