scispace - formally typeset
Search or ask a question

Showing papers on "Radiation-induced lung injury published in 2017"


Journal ArticleDOI
TL;DR: The progress that has been made in recent years in the understanding of cellular and molecular mechanisms of RILI is summarized in this review.
Abstract: The lung is one of several moderately radiosensitive organs. Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced pulmonary fibrosis, occurs most often in radiotherapy of lung cancer, esophageal cancer, and other thoracic cancers. Clinical symptoms of RILI include dry cough, shortness of breath, chest pain, fever, and even severe respiratory failure and death. The occurrence of RILI is a complex process that includes a variety of cellular and molecular interactions which ultimately leads to large fibroblast accumulation, proliferation, and differentiation, resulting in excessive extracellular matrix deposits, causing pulmonary fibrosis. The progress that has been made in recent years in the understanding of cellular and molecular mechanisms of RILI is summarized in this review.

67 citations


Journal ArticleDOI
TL;DR: It is demonstrated that PD attenuated radiation‐induced lung injury through inhibiting epithelial–mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.
Abstract: Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. It is characterized with two main features including early radiation pneumonitis and fibrosis in later phase. This study was to investigate the potential radioprotective effects of polydatin (PD), which was shown to exert anti-inflammation and anti-oxidative capacities in other diseases. In this study, we demonstrated that PD-mitigated acute inflammation and late fibrosis caused by irradiation. PD treatment inhibited TGF-β1-Smad3 signalling pathway and epithelial-mesenchymal transition. Moreover, radiation-induced imbalance of Th1/Th2 was also alleviated by PD treatment. Besides its free radical scavenging capacity, PD induced a huge increase of Sirt3 in culture cells and lung tissues. The level of Nrf2 and PGC1α in lung tissues was also elevated. In conclusion, our data showed that PD attenuated radiation-induced lung injury through inhibiting epithelial-mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.

49 citations


Journal ArticleDOI
TL;DR: Investigating whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI foundHypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.
Abstract: Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O 2 ) or hypoxic conditions (2.5% O 2 ). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included HE meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

45 citations


Journal ArticleDOI
TL;DR: Preclinical research shows the potential for therapies targeting transforming growth factor-β (TGF-B), Toll like receptor (TLRs), Tumour necrosis factor-alpha (TNF-alpha), Interferon gamma (IFN-γ) and so on that may restore lung function.

38 citations


Journal ArticleDOI
TL;DR: Evaluated manganese superoxide dismutase (MnSOD) gene-modified mesenchymal stem cells (MSCs) were effective in modulating RILI in mice and had great potential for accelerating from bench to bedside.
Abstract: Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene–modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-β1, and the oxidative stress fa...

33 citations


Journal ArticleDOI
TL;DR: GA can protect against early-stage RILI and this protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway.
Abstract: Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway.

20 citations


Journal ArticleDOI
Fei Tang1, Rui Li1, Jianxin Xue1, Jie Lan1, He Xu1, Yongmei Liu1, Lin Zhou1, You Lu1 
TL;DR: Administration with AZM markedly alleviated acute RILI as indicated by hematoxylin and eosin and Masson staining and mitigated the radiation-induced acute lung injury possibly by its anti-inflammatory and anti-fibrotic effects.
Abstract: Radiation-induced lung injury (RILI) is a common and major obstacle in thoracic cancer radiotherapy, resulting in considerable morbidity and limiting the dose of radiation. However, an effective treatment option remains to be established. Therefore, the present study aimed to investigate the effects of azithromycin (AZM) in acute RILI with a mouse model. In the present study, C57BL/6 mice were given a single thoracic irradiation of 16 Gy and administered orally with AZM. The lung histopathological findings, the levels of malondialdehyde (MDA; an indicator of oxidative damage) and the concentration of pro-inflammatory and pro-fibrotic cytokines in plasma were assessed on 28 day following irradiation. In addition, the total cell counts in bronchoalveolar lavage fluid (BALF), the pro-inflammatory and pro-fibrotic cytokine gene expression in lung tissue were evaluated on day 7, 14 and 28 following irradiation. Administration with AZM markedly alleviated acute RILI as indicated by hematoxylin and eosin and Masson staining. The levels of MDA and total cell counts in BALF significantly reduced in AZM treated mice. AZM also down-regulated the concentration and mRNA expression of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1. In addition, AZM attenuated the irradiation-induced increases in the mRNA expression of fibrotic markers (α-smooth muscle actin and α-1 type I collagen). AZM treatment mitigated the radiation-induced acute lung injury possibly by its anti-inflammatory and anti-fibrotic effects.

20 citations


Journal ArticleDOI
TL;DR: Ethyl pyruvate treatment ameliorates RILI, including radiation-induced fibrosis in mice, and the inhibition of production and release of pro-inflammatory or fibrotic cytokines, especially HMGB1, may partly attribute to its attenuating RILi effect.

20 citations


Journal ArticleDOI
TL;DR: In this paper, the authors used magnetic resonance imaging (MRI) of hyperpolarized (HP) 129 Xe dissolved in pulmonary tissue (PT) and red blood cells (RBCs) to detect regional changes to PT structure and perfusion in a partial-lung rat model of radiation-induced lung injury and compare with histology.
Abstract: Purpose The purpose of this work was to use magnetic resonance imaging (MRI) of hyperpolarized (HP) 129 Xe dissolved in pulmonary tissue (PT) and red blood cells (RBCs) to detect regional changes to PT structure and perfusion in a partial-lung rat model of radiation-induced lung injury and compare with histology. Methods and materials The right medial region of the lungs of 6 Sprague-Dawley rats was irradiated (20 Gy, single-fraction). A second nonirradiated cohort served as the control group. Imaging was performed 4 weeks after irradiation to quantify intensity and heterogeneity of PT and RBC 129 Xe signals. Imaging findings were correlated with measures of PT and RBC distribution. Results Asymmetric (right vs left) changes in 129 Xe signal intensity and heterogeneity were observed in the irradiated cohort but were not seen in the control group. PT signal was observed to increase in intensity and heterogeneity and RBC signal was observed to increase in heterogeneity in the irradiated right lungs, consistent with histology. Conclusion Regional changes to PT and RBC 129 Xe signals are detectable 4 weeks following partial-lung irradiation in rats.

17 citations


Journal ArticleDOI
01 Sep 2017-Medicine
TL;DR: Postmastectomy treatment with the IMRT technique can reduce the incidence rate of radiation toxicity by decreasing organs at risk (OARs) irradiation and neoadjuvant chemotherapy and hypertension were the most significant risk factors for acute skin dermatitis and acute radiation induced lung injury.

15 citations


Journal ArticleDOI
TL;DR: Radiologic injuries were frequently found in follow-up CT scans after radiotherapy for NSCLC patients and the risk of a radiologic response increased with increasing time and lung dose metrics, and depended on patient age and smoking status.

Journal ArticleDOI
TL;DR: Pretreatment with Ilomastat, a synthetic inhibitor of MMPs, decreased the expression and activity of M MPs and significantly alleviated the lung inflammation and fibrosis in the irradiated mice, as well as enhanced the survival of irradiation mice.
Abstract: Lung injury is one of the pathological features in human or animal after radiation and the main side effect for patient after lung cancer radiotherapy. The efficient protective strategy still needs to exploit and the underlying mechanisms remain to be investigated. We found that the expression and activity of matrix metalloproteinases (MMPs) significantly increased at the early stage of radiation-induced lung injury (RILI). Pretreatment with Ilomastat, a synthetic inhibitor of MMPs, decreased the expression and activity of MMPs and significantly alleviated the lung inflammation and fibrosis in the irradiated mice, as well as enhanced the survival of irradiated mice. In addition, the levels of TGF-β, IL-6, TNF-α and IL-1β in the tissues dramatically reduced in the irradiated mice pretreated with Ilomastat. Furthermore, our experiments in vitro also showed that radiation significantly increased the MMPs activity, and Ilomastat pretreatment inhibited the activity of MMPs activated by irradiation and increased the cell survival. It is the first report, to our knowledge, to demonstrate that Ilomastat is a potential effective reliever for RILI and MMPs may play important roles in the process of RILI.

Journal Article
Rong Han1, Dong-Ming Wu1, Shi-Hua Deng1, Teng Liu1, Ting Zhang1, Ying Xu1 
TL;DR: The pyroptosis caused by the activation of NLRP3 inflammatory body occurred in the lung tissue of mice after irradiation, and caspase-1 activity increased.
Abstract: Objective To establish a radiation-induced lung injury model and investigate the role of caspase-1-dependent programmed cell death (pyroptosis) in the pathogenesis of radiation pneumonitis. Methods BALB/c mice were sacrificed after receiving 5-day 15 Gy X-ray irradiation at chest cavity. The pathological changes of pulmonary tissues were observed by HE staining. The apoptosis of lung tissues cells after irradiation was detected by TUNEL assay. The expressions of γ-H2AX, ki67, NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC/TMS-1) were detected by Western blot analysis. Real-time quantitative PCR was used to check mRNA levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), NLRP3, caspase-1, IL-1β and IL-18. Immunohistochemical staining was used to determine the expressions of NLRP3, caspase-1 and TMS1 in lung tissues. The activity of caspase-1 was evaluated by caspase-1 assay kit, and the serum levels of IL-1β and IL-18 were detected by ELISA. Results After irradiation, the capillaries of the alveolar wall of the mice were dilated and congested, inflammatory cells infiltrated, the alveolar wall thickened. Positive rate of lung tissue cells was raised in TUNEL staining. The expressions of γ-H2AX and ki67 were elevated, indicating that DNA damage and cell proliferation activity decreased in lung tissues. The mRNA levels of IL-6, IL-8, TNF-α and MCP-1 in lung cells increased; the serum levels of IL-1β and IL-18 increased; the expressions of IL-1β, IL-18, NLRP3, caspase-1 and ASC/TMS-1 in lung tissues were enhanced; and caspase-1 activity increased. Conclusion After irradiation, the pyroptosis caused by the activation of NLRP3 inflammatory body occurred in the lung tissue of mice.

Journal ArticleDOI
Rui Li1, Guo Chen1, Lin Zhou1, He Xu1, Fei Tang1, Jie Lan1, Ruizhan Tong1, Lei Deng1, Jianxin Xue1, You Lu1 
TL;DR: Investigation of the potential protective effects of URB937 using a mouse model of RILI suggested that inhibiting fatty acid amide hydrolase could ameliorate RilI without compromising the efficacy of irradiation on tumor control.
Abstract: Radiation-induced lung injury (RILI) is a potentially life-threatening complication of radiotherapy. In the current study, we examined the potential protective effects of URB937, an inhibitor of fatty acid amide hydrolase using a mouse model of RILI. Briefly, male C57BL/6 mice received 16Gy irradiation to the thoracic region and then intraperitoneal injection of either URB937 (1 mg/kg) or vehicle every 2 days for 30 days. The extent of the lung injury was evaluated histologically at the end of the drug treatment as well as 3 months after the cessation of the treatment. The data showed URB937 attenuated radiation-induced lung injury and increased endocannabinoid concentration in lung tissue. Treatment with URB937 decreased leukocyte migration and inflammatory cytokines in bronchoalveolar lavage fluid and plasma at day 30. Histopathological examination revealed URB937 could restore lung structure and restrain inflammatory cell and fibroblast accumulation caused by irradiation in lung tissue. URB937 also decreased radiation-induced pro-inflammatory (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α) and pro-fibrotic cytokines (e.g., transforming growth factor-β1) level in lung tissue, as well as lipid peroxidation in the lungs. Mouse survival examined in a separate group of experimental subjects indicated that URB937 could prolong animal survival. Experiments using a mouse bearing Lewis lung carcinoma cells showed that URB937 does not affect irradiation-induced inhibition of tumor growth. These results suggest that inhibiting fatty acid amide hydrolase could ameliorate RILI without compromising the efficacy of irradiation on tumor control.

Journal ArticleDOI
TL;DR: Over the last few decades, advances in radiation therapy technology have markedly improved radiation delivery, allow precise delivery of high doses of radiation conformed to the tumor, and result in improved locoregional control while reducing radiation dose to surrounding normal tissue.
Abstract: Over the last few decades, advances in radiation therapy technology have markedly improved radiation delivery. Advancements in treatment planning with the development of image-guided radiotherapy and techniques such as proton therapy, allow precise delivery of high doses of radiation conformed to the tumor. These advancements result in improved locoregional control while reducing radiation dose to surrounding normal tissue. The radiologic manifestations of these techniques can differ from radiation induced lung disease seen with traditional radiation therapy. Awareness of these radiologic manifestations and correlation with radiation treatment plans are important to differentiate expected radiation induced lung injury from recurrence, infection and drug toxicity.

Proceedings ArticleDOI
Jianxin Xue, Shisuo Du, You Lu1, Adam P. Dicker, Bo Lu 
TL;DR: Anti-PD-1 mAbs potentiates the radiation-induced pneumonitis, likely mediated by increased CD8+ cytotoxic T lymphocytes, and should be taken for excessive lung toxicities in ongoing clinical trials of combining thoracic RT and anti-PD1 therapy.
Abstract: Purpose: Combination of radiation therapy and anti-PD1 immunotherapy has been investigated both in the lab and in the clinic. Pneumonitis is a rare but potentially fatal toxicity of ant-programmed death-1 (PD-1) monoclonal antibodies (mAbs). The purpose of our study is to address whether anti-PD-1 mAbs will potentiate radiation-induced lung toxicity and mortality in a murine model using Small Animal Radiation Research Platform (SARRP) for lung-targeting irradiation (IR). Methods: Both lungs of male C57bl/6 mice were targeted for 20Gy using the SARRP. Mice were stratified into 4 treatment groups receiving IgG, anti-PD1, IR + IgG, or IR + anti-PD1. IgG or anti-PD-1 mAbs administrated via i.p. injection, with a dosage of 10mg/kg, twice per week for five doses. Acute lung injury was assessed by HE p Conclusions: Anti-PD-1 mAbs potentiates the radiation-induced pneumonitis, likely mediated by increased CD8+ cytotoxic T lymphocytes. Anti-PD-1 mAbs may increase the radiation-related mortality although it was not statistically significance at the day 120 following IR. Care should be taken for excessive lung toxicities in ongoing clinical trials of combining thoracic RT and anti-PD1 therapy. We will collaborate with NRG to further investigate clinical lung toxicities from combining thoracic radiotherapy with Nivo in the ongoing RTOG 3505 though analyzing the collected biospecimens. Note: This abstract was not presented at the meeting. Citation Format: Jianxin Xue, Shisuo Du, You Lu, Adam Dicker, Bo Lu. Anti-PD-1 treatment may potentiate the radiation-induced lung injury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2017-3671

Journal ArticleDOI
TL;DR: This case confirms that a radiation-induced lung injury is accompanied by acute inflammatory reaction in the lung parenchyma irradiated with a total dose of 12-40 Gy, and this well-defined inflammation component could be exactly characterized with FDG-PET/CT.
Abstract: Visualization and metabolic analysis of acute inflammation in the lung parenchyma plays a crucial role for the prediction and diagnosis of radiation-induced lung injury and is particularly important in medically inoperable patients because of a priori very limited pulmonary function. This case confirms that a radiation-induced lung injury is accompanied by acute inflammatory reaction in the lung parenchyma irradiated with a total dose of 12-40 Gy. This well-defined inflammation component could be exactly characterized with FDG-PET/CT.

Book ChapterDOI
01 Jan 2017
TL;DR: Hyperpolarized MRI, especially 129 Xe, promises to provide new insight into the pathophysiology of RILI and may give an earlier indication of lung injury associated with RT of thoracic tumors, potentially allowing longitudinal monitoring of treatment and adjustment before the onset of severe pneumonitis and irreversible fibrosis.
Abstract: Nonsmall cell lung carcinoma is one of the most fatal cancers and is often treated using thoracic radiotherapy (RT). Unfortunately, the lung is a very radiosensitive organ and radiation-induced lung injury (RILI) is a frequent consequence of thoracic RT, affecting about one in three patients. RILI can significantly limit RT and early detection is vital in order to adjust the treatment plan and improve outcomes. Magnetic resonance imaging (MRI) of hyperpolarized gas ( 3 He and 129 Xe) presents an unprecedented opportunity to map anatomical and functional changes associated with RILI. In particular, inhaled hyperpolarized 3 He and 129 Xe gas are exquisitely sensitive to changes in alveolar microanatomy accompanying radiation pneumonitis and fibrosis through changes in the apparent diffusion coefficient (ADC) of alveolar gas. Additionally, 129 Xe dissolves in the parenchymal tissue and red blood cells (RBCs) of the lung and reflects changes in sizes and gas exchange associated with these compartments. In this chapter, the application of hyperpolarized gas ( 3 He and 129 Xe) MRI to both humans and rat models of RILI is reviewed and results of experiments measuring 129 Xe ADC, gas exchange, and tissue and RBC imaging are presented. These results are consistent with conventional functional (e.g., blood gases) and histological (i.e., tissue density) changes, but with the advantage of noninvasive regional information. Hyperpolarized MRI, especially 129 Xe, promises to provide new insight into the pathophysiology of RILI and may give an earlier indication of lung injury associated with RT of thoracic tumors, potentially allowing longitudinal monitoring of treatment and adjustment before the onset of severe pneumonitis and irreversible fibrosis.