Biomarkers Associated with Radiation-Induced Lung Injury in Cancer Patients

Radiotherapy (RT) is a common and effective non-surgical treatment for thoracic solid tumors, and radiation-induced lung injury (RILI) is the most common side effect of radiotherapy. Even if RT is effective in the treatment of cancer patients, severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) can reduce the quality of life of patients and may even lead to serious consequences of death. Therefore, how to overcome the problem of accurate prediction and early diagnosis of RT for pulmonary toxicity is very important. This review summarizes the related factors of RILI and the related biomarkers for early prediction of RILI.

Treatment of radiation-induced brain injury with bisdemethoxycurcumin

Radiation therapy is considered the most effective non-surgical treatment for brain tumors.However,there are no available treatments for radiation-induced brain injury.Bisdemethoxycurcumin(BDMC)is a demethoxy derivative of curcumin that has anti-proliferative,anti-inflammatory,and anti-oxidant properties.To determine whether BDMC has the potential to treat radiation-induced brain injury,in this study,we established a rat model of radiation-induced brain injury by administe ring a single 30-Gy vertical dose of irradiation to the whole brain,followed by intraperitoneal injection of 500μL of a 100 mg/kg BDMC solution every day for 5 successive weeks.Our res ults showed that BDMC increased the body weight of rats with radiation-induced brain injury,improved lea rning and memory,attenuated brain edema,inhibited astrocyte activation,and reduced oxidative stress.These findings suggest that BDMC protects against radiationinduced brain injury.

TLD calibration and absorbed dose measurement in a radiation-induced liver injury model under a linear accelerator

The application of a thermoluminescent detector(TLD) for dose detection at the liver irradiation site in mice under linear accelerator precision radiotherapy and the use of a single high dose to irradiate the mouse liver to construct a biological model of a radiation-induced liver injury(RILD) in mice were to determine the feasibility of constructing a precision radiotherapy model in small animals under a linear accelerator. A 360° arc volumetric rotational intensity-modulated radiotherapy(VMAT) plan with a prescribed dose of 2 Gy was developed for the planned target volume(PTV) at the location of the TLD within solid water to compare the difference between the measured dose of TLD and the assessed parameters in the TPS system. The TLD was implanted in the livers of mice, and VMAT was planned based on TLD to compare the measured and prescribed doses. C57BL/6 J mice were randomly divided into control and 25-Gy radiation groups and were examined daily for changes in body weight. They were euthanized at 3 and 10 weeks after radiation, and the levels of liver serum enzymes such as alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) were measured to observe any pathological histological changes in the irradiated areas of the mouse liver. The measured values of solid underwater TLD were within ± 3% of the Dmean value of the evaluation parameter in the TPS system. The mice in the 25-Gy radiation group demonstrated pathological signs of radiation-induced liver injury at the site of liver irradiation. The deviation in the measured and prescribed doses of TLD in the mouse liver ranged from-1.5 to 6%;construction of an accurate model of RILD using the VMAT technique under a linear accelerator is feasible.

Relationship between Ulcerative Colitis and Lung Injuries

Objective To explore the relationship between ulcerative colitis(UC) and lung injuries by assessing their clinical manifestations and characteristics. Methods From July 2009 to April 2012, 91 UC patients presenting to Longhua Hospital who met the established inclusion and exclusion criteria were enrolled in this retrospective study. According to the scores of disease activity index, the patients were divided into the mild, moderate, and severe groups. Meanwhile, the records of pulmonary symptoms, chest X-ray image, and pulmonary function were reviewed. Results Sixty-eight(74.7%) patients had at least 1 pulmonary symptom, such as cough(38.5%), shortness of breath(27.5%), and expectoration(17.6%). And 77(84.6%) had at least 1 ventilation abnormality. Vital capacity value was significantly lower in the severe group than that in the mild group(91.82%±10.38% vs. 98.92%±12.12%, P<0.05). Conclusions Lung injury is a common extraintestinal complication of UC. According to the theory in Traditional Chinese Medicine that the lung and large intestine are related, both the lungs and large intestine should be treated simultaneously.

Correlation between miR-564, TGF-β1, and radiation-induced lung injury

Objective Our study aimed to analyze the expression of miR-564 and TGF-β1 in cancer tissues and the serum of patients with radiation-induced lung injury,and to investigate the relationship between them and radiation-induced lung injury.Methods In situ hybridization and real-time fluorescence quantitative method were used to detect the expression of miR-564.Additionally,immunohistochemistry and enzyme-linked immunosorbent assay(ELISA)were performed to detect the expression of TGF-β1.Results The overall incidence of acute radiation pneumonia was 55.9%(100/179).The incidence of≥grade 2 radioactive pneumonia was 24.0%(43/179)and that of grade 1 was 31.8%(57/179).The expression of miR-564 in grade≥2 was slightly higher than that in patients without or with grade 1,but there was no statistical difference(P=0.86).The serum level and ratio of miR-564 in patients with grade≥2 were significantly higher than those without or with grade 1(P=0.005,P=0.025,respectively).The expression of TGF-β1 in grade≥2 was significantly higher than that of patients without or with grade 1(P=0.017).The serum levels of TGF-β1 in grade≥2 were significantly higher than those in patients without or with grade 1(P=0.038).Although the ratio of TGF-β1 in radiation pneumonia of grade≥2 was significantly higher than that of without or with grade 1,there was no significant difference(P=0.24).Moreover,patients with higher expression of miR-564 and lower expression of TGF-β1 had better prognosis.Conclusion MiR-564 and TGF-β1 are predictors of radiation-induced lung injury.Monitoring its changing trend can improve the accuracy of predicting radiation-induced lung injury.The levels and ratio of serum miR-564 and TGF-β1 in patients with radiation-induced lung injury are related to the severity of radiationinduced lung injury.

Rabbit model of radiation-induced lung injury

Objective:To explore the feasibility of establishing an animal model of chronic radiationinduced lung injury.Methods:Twenty-eight New Zealand white rabbits were randomly divided into 3 groups(the right lung irradiation group,the whole lung irradiation group and the control group).Animal model of radiation-induced lung injury was established b) highdoes radiotherapy in the irradiation groups,then all rabbits underwent CT and pathological examinations at 1.2.4.8.12.16 weeks,respectively after radiation.Results:Within 4 weeks of irradiation,some rabbits in the right lung irradiation group and whole lung irradiation group died. CT and pathological examinations all showed acute radiation pneumonitis.At 8-12 weeks after irradiation,CT scanning showed ground glass samples signs,patchy shadows and fibrotic stripes. Pathological examination showed the fibrosis pulmonary alveolar wall thickened obviously. Conclusions:The clinical animal model of chronic radiation-induced lung injury which corresponds to practical conditions in clinic can be successfully established.

Prevention and treatment of radiation-induced lung injury by hydroxypiperquin phosphate: a clinical and experimental study

Objective: To evaluate the hydroxypiperquin phosphate (HPQP) as a modifier of radiation-induced injury in human and rat lungs. Methods: Sixty-five patients with lung cancer treated with conventional radiotherapy were divided into 2 groups randomly: Thirty cases were treated with HPQP and the others were in a control group. The changes of X - ray manifestation before, after and during taking drug were compared. An animal model of radiation-induced fibrosis of lungs was also established. Hydroxyproling (HP) content in lung tissue and the pathological changes in rat lungs were checked with microscope and electron microscope after 4 months and 6 months respectively. Results: The changes of lung X-ray manifestation in treatment group were much lighter than that in control group. The HP content and the change of pathology in the lungs of those rats with HPQP treatment were obviously less than that in control group. Conclusion: HPQP plays an important role in prevention and treatment of radiation-induced injury in lungs.

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

Expression of Angiotensin Ⅱ and Aldosterone in Radiation-induced Lung Injury

Objective Radiation-induced lung injury(RILI) is the most common,dose-limiting complication in thoracic malignancy radiotherapy.Considering its negative impact on patients and restrictions to efficacy,the mechanism of RILI was studied. Methods Wistar rats were locally irradiated with a single dose of 0,16,and 20 Gy to the right half of the lung to establish a lung injury model.Two and six months after irradiation,the right half of the rat lung tissue was removed,and the concentrations of TGF-β1,angiotensinⅡ,and aldosterone were determined via enzyme-linked immunosorbent assay. Results Statistical differences were observed in the expression levels of angiotensinⅡand aldosterone between the non-irradiation and irradiation groups.Moreover,the expression level of the angiotensinⅡ-aldosterone system increased with increasing doses,and the difference was still observed as time progressed. Conclusions AngiotensinⅡ-aldosterone system has an important pathophysiological function in the progression of RILI.

Research Progress on the Pathogenesis of Acute Lung Injury(ALI)

In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.

Role of Active Principles of Podophyllum hexandrum in Amelioration of Radiation Mediated Lung Injuries by Reactive Oxygen/Nitrogen Species Reduction

Radiation induced reactive oxygen/nitrogen species (ROS/RNS) are reported to cause lung injuries such as pneumonitis and fibrosis which may be fatal at times. Current study is designed to analyse the radioprotective efficacy of P. hexandrum active principles (G-002M) on lungs of mice exposed to high dose of gamma irradiation (7 Gy). Cellular profiles and inflammatory cell infiltrates of irradiated bronchoalveolar lavage fluid (BALF) have shown correlations with lung pathology. Cell counts were determined in BALF of control, 7 Gy radiation exposed and radiation with G-002M pretreated mice. ROS/Nitric Oxide (NO) production was measured by 2,7?dichlorodihydrofluorescein diacetate (DCF-DA) and diaminofluorescein diacetate (DAF-2DA) through microscopy and flow cytometry respectively. Immunostaining of inducible nitric oxide synthase (iNOS) in BALF cells and lung sections was also observed microscopically. iNOS ex- pression was observed in lungs by western blotting. BALF was also processed to estimate total protein, LDH, and phospholipids content. Catalase, reduced Glutathione (GSH), Glutathione reductase (GR) and lipid peroxidation were estimated in lung tissues. Pre-administration of G-002M significantly decreased radiation mediated neutrophils count in BALF of irradiated mice. ROS generation, iNOS expression, total protein, LDH and phospholipids were found less affected in G-002M pretreated group in comparison to radiation alone group. Radiation exposure to mice was found apparently leading to parenchymal fibrosis, an architectural distortion of the lung tissue with edema, infiltration of inflammatory blood cells with increased immunolabeling of iNOS. G-002M pretreatment significantly countered radiation mediated increased lipid peroxidation and decreased GR, catalase and GSH in mice. Current study demonstrates possible role of P. hexandrum (G-002M) in minimizing lung damage induced by radiation mediated ROS/RNS generation.

Research Progress on the Prevention of Premature Infant Lung Injury and Neonatal Respiratory Support

In the past 40 years,advances in neonatal intensive care unit(NICU)technology have enabled premature infants with lower birth weight and younger gestational age to survive.But with it comes an increase in the incidence of long-term respiratory dysfunction,mainly in the form of bronchopulmonary dysplasia(BPD).Preventing lung injury is crucial for preventing BPD and improving the long-term prognosis of premature infants.Therefore,how to avoid ventilator-associated lung injury has become a focus of clinical and scientific research in premature infants in recent years.This article will elaborate on the susceptibility and pathophysiology of premature infant lung injury,ventilation strategies for preventing lung injury,and new advances in neonatal respiratory support.

Modulating the crosstalk between macrophage and Th17: potential mechanism of natural products on acute lung injury

Sepsis is a life-threatening multiple organ dysfunction syndrome caused by the imbalance of the immune response to infection,featuring complex and variable conditions,and is one of the leading causes of mortality in ICU patients.Lung injury is a common organ damage observed in sepsis patients.Macrophages and Th17 cells,as crucial components of innate and adaptive immunity,play pivotal roles in the development of sepsis-induced acute lung injury(ALI).This review summarizes the alterations and mechanisms of macrophages and Th17 cells in sepsis-induced ALI.By focusing on the“cross-talk”between macrophages and Th17 cells,this review aims to provide a solid theoretical foundation for further exploring the therapeutic targets of traditional Chinese medicine formulas in the treatment of sepsis complicated with ALI,thereby offering insights and guidance for the clinical application of traditional Chinese medicine in managing sepsis-associated ALI.

GSN antibody pretreatment aggravates radiation-induced lung injury in mice

Radiation-induced lung injury is one of the main dose limiting factors for thoracic radiation therapy.Gelsolin(GSN) is a widespread,multifunctional regulator of cellular structure and metabolism.In this work,the roles of GSN in radiation-induced lung injury in Balb/c mice were studied.The GSN levels in plasma reduced progressively in 72 hours after irradiation,and then increased gradually.GSN contents in the bronchoalveolar lavage(BAL) fluid increased after thoracic irradiation,whereas mRNA levels of GSN in the lung tissue decreased significantly within 24 hours after irradiation and then increased again.Mice were intravenously injected with 50 ug GSN antibody 0.5 hour before 20 Gy of thoracic irradiation.GSN antibody pretreatment increased lung inflammation,protein concentration in the BAL fluid and leukocytes infiltration in the irradiated mice.The activities of superoxidase dismutase(SOD) in the plasma and the BAL fluid in irradiated mice injected with GSN antibody were less than that of control groups,whereas the levels of malondialdehyde(MDA)increased.These results suggest that pretreatment of GSN antibody may aggravate radiation-induced pneumonitis.

Neuron-specific enolase expression in a rat model of radiation-induced brain injury following vascular endothelial growth factor-modified neural stem cell transplantation

BACKGROUND： Previous studies have shown that transplantation of vascular endothelial growth factor （VEGF）-modified neural stem cells （NSC） provides better outcomes, compared with neural stem cells, in the treatment of brain damage. OBJECTIVE： To compare the effects of VEGF-modified NSC transplantation and NSC transplantation on radiation-induced brain injury, and to determine neuron-specific enolase （NSE） expression in the brain. DESIGN, TIME, AND SETTING： The randomized, controlled study was performed at the Linbaixin Experimental Center, Second Affiliated Hospital, Sun Yat-sen University, China from November 2007 to October 2008. MATERIALS： VEGF-modified C17.2 NSCs were supplied by Harvard Medical School, USA. Streptavidin-biotin-peroxidase-complex kit （Boster, China） and 5, 6-carboxyfluorescein diacetate succinimidyl ester （Fluka, USA） were used in this study. METHODS： A total of 84 Sprague Dawley rats were randomly assigned to a blank control group （n = 20）, model group （n = 20）, NSC group （n = 20）, and a VEGF-modified NSC group （n = 24）. Rat models of radiation-induced brain injury were established in the model, NSC, and VEGF-modified NSC groups. At 1 week following model induction, 10 pL （5 ×10^4 cells/μL） VEGF-modified NSCs or NSCs were respectively infused into the striatum and cerebral cortex of rats from the VEGF-modified NSC and NSC groups. A total of 10μL saline was injected into rats from the blank control and model groups. MAIN OUTCOME MEASURES： NSE expression in the brain was detected by immunohistochemistry following VEGF-modified NSC transplantation. RESULTS： NSE expression was significantly decreased in the brains of radiation-induced brain injury rats （P 〈 0.05）. The number of NSE-positive neurons significantly increased in the NSC and VEGF-modified NSC groups, compared with the model group （P 〈 0.05）. NSE expression significantly increased in the VEGF-modified NSC group, compared with the NSC group, at 6 weeks following transplantation （P 〈 0.05）. CONCLUSION： VEGF-modified NSC transplantation increased NSE expression in rats with radiation-induced brain injury, and the outcomes were superior to NSC transplantation.

Radiation-induced brain injury after a conventional dose of intensity-modulated radiotherapy for nasopharyngeal carcinoma:a case report and literature review

A 61-year-old female nasopharyngeal carcinoma patient was admitted to the hospital with sudden cognitive dysfunction one month after Volumetric Intensity Modulated Arc Therapy(VMAT)conventional dose radiotherapy,and the initial diagnosis was radiation-induced brain injury(RBI).After comprehensive treatment with steroid hormones,the patient’s condition rapidly improved.Typically,in nasopharyngeal carcinoma patients treated with VMAT,the incidence of RBI is extremely low when the temporal lobe dose is less than 65 Gy or 1%of the volume is less than 65 Gy.When this limit is exceeded,RBI may occur in varying degrees.However,in this case,even though the temporal lobe dose was under the prescribed limit,the patient still experienced RBI.The rare observations in this case can be used as a reference,and clinicians should seriously consider the possibility of RBI in similar cases.

Periplaneta Americana Extract Ameliorates LPS-induced Acute Lung Injury Via Reducing Inflammation and Oxidative Stress

Objective Acute lung injury(ALI)is an acute clinical syndrome characterized by uncontrolled inflammation response,which causes high mortality and poor prognosis.The present study determined the protective effect and underlying mechanism of Periplaneta americana extract(PAE)against lipopolysaccharide(LPS)-induced ALI.Methods The viability of MH-S cells was measured by MTT.ALI was induced in BALB/c mice by intranasal administration of LPS(5 mg/kg),and the pathological changes,oxidative stress,myeloperoxidase activity,lactate dehydrogenase activity,inflammatory cytokine expression,edema formation,and signal pathway activation in lung tissues and bronchoalveolar lavage fluid(BALF)were examined by H&E staining,MDA,SOD and CAT assays,MPO assay,ELISA,wet/dry analysis,immunofluorescence staining and Western blotting,respectively.Results The results revealed that PAE obviously inhibited the release of proinflammatory TNF-α,IL-6 and IL-1βby suppressing the activation of MAPK/Akt/NF-κB signaling pathways in LPS-treated MH-S cells.Furthermore,PAE suppressed the neutrophil infiltration,permeability increase,pathological changes,cellular damage and death,pro-inflammatory cytokines expression,and oxidative stress upregulation,which was associated with its blockage of the MAPK/Akt/NF-κB pathway in lung tissues of ALI mice.Conclusion PAE may serve as a potential agent for ALI treatment due to its anti-inflammatory and anti-oxidative properties,which correlate to the blockage of the MAPK/NF-κB and AKT signaling pathways.

Time-dependent Changes in CT of Radiation-induced Liver Injury:A Preliminary Study in Gastric Cancer Patients

In this study, the time-dependent changes on dynamic computed tomograph (CT) of radiation-induced liver injury in gastric cancer patients was examined.The CT images of 52 gastric cancer patients who had received chemoradiotherapies were reviewed on the PACS system.Dynamic CT scan was performed in all the subjects.Our results showed that 18 patients were found to have radiation-induced liver injury.The CT findings of radiation-induced liver injury in gastric cancer patients tend to show up one month after radiation treatment.The damaged area was of low density on all three phases, and then it was enhanced on portal vein phase or delay phase.The focal radiation reaction of liver without basic disease vanished 9-11 months later after treatment.We are led to conclude that dynamic CT is of help in the diagnosis of CRT-induced liver injury, and it may be the method of choice for following up the whole course of the CRT-induced liver injury, i.e., form hepatic damage to healing.The classification of CT findings we recommend can avoid the influence of technological factors, and thereby serve as a better guide for treatment of CRT-induced liver injury.

Glycolysis and acute lung injury:A review

Acute lung injury is featured as diffuse pulmonary edema and persistent hypoxemia caused by lung or systemic injury.It is believed that these pathological changes are associated with damage to the alveolar epithelium and vascular endothelium,recruitment of inflammatory cells,and inflammatory factor storms.In recent years,the metabolic reprogramming of lung parenchymal cells and immune cells,particularly alterations in glycolysis,has been found to occur in acute lung injury.Inhibition of glycolysis can reduce the severity of acute lung injury.Thus,this review focuses on the interconnection between acute lung injury and glycolysis and the mechanisms of interaction,which may bring hope for the treatment of acute lung injury.

The therapeutic mechanism of dexamethasone in lung injury induced by hydrogen sulfide

The lung is one of the primary target organs of hydrogen sulfide(H2S),as exposure to H2S can cause acute lung injury(ALI)and pulmonary edema.Dexamethasone(Dex)exerts a protective effect on ALI caused by exposure to toxic gases and is commonly used in the clinic;however,the underlying mechanisms remain elusive,and the dose is unclear.Methods:In vivo experiments:divided C57BL6 mice into 6 groups at random,12 in each group.The mice were exposed to H2S for 3 h and 5 or 50 mg/kg Dex pretreated before exposure,sacrificed 12 h later.The morphological changes of HE staining and the ultrastructural changes of lungs under transmission electron microscopy were evaluated.The wet/dry ratio of lung tissue was measured.Bronchial alveolar lavage fluid(BALF)protein content and lung permeability index were detected.The expression of AQP5 protein was measured by immunohistochemistry and Western Blot(WB).In vitro experiments:divided human lung adenocarcinoma cell line A549 into 4 groups.1μmol/L dexamethasone was added to pre-incubation.The WB analyzed the protein of p-ERK1/2,p-JNK,and p-p38 in MAPK pathway after 1 h of NaHS exposure;six hours after NaHS exposure,the AQP5 protein was measured by WB.Results:Dex treatment could significantly attenuate the H2S-induced destruction to the alveolar wall,increase the wet-to-dry weight ratio and decrease pulmonary permeability index,with high-dose dexamethasone seemingly functioning better.Additionally,our previous studies showed that aquaporin 5(AQP 5),a critical protein that regulates water flux,decreased both in a mouse and cell model following the exposure to H2S.This study indicates that tThe decrease in AQP 5 can be alleviated by Dex treatment.Additionally,the mitogen activated protein kinase(MAPK)pathway may be involved in the protective effects of Dex in ALI caused by exposure to H2S since H2Sinduced MAPK activation could be inhibited by Dex.Conclusion:The present results indicate that AQP 5 may be considered a therapeutic target for Dex in H2S or other hazardous gases-induced ALI.