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Sample records for rat lung tumours

  1. Boron uptake measurements in a rat model for Boron Neutron Capture Therapy of lung tumours.

    PubMed

    Bortolussi, S; Bakeine, J G; Ballarini, F; Bruschi, P; Gadan, M A; Protti, N; Stella, S; Clerici, A; Ferrari, C; Cansolino, L; Zonta, C; Zonta, A; Nano, R; Altieri, S

    2011-02-01

    Lung carcinoma is the leading cause of cancer mortality in the Western countries. Despite the introduction over the last few years of new therapeutic agents, survival from lung cancer has shown no discernible improvement in the last 20 years. For these reasons any efforts to find and validate new effective therapeutic procedures for lung cancer are very timely. The selective boron uptake in the tumour with respect to healthy tissues makes Boron Neutron Capture Therapy a potentially advantageous option in the treatment of tumours that affect whole vital organs, and that are surgically inoperable. To study the possibility of applying BNCT to the treatment of diffuse pulmonary tumours, an animal model for boron uptake measurements in lung metastases was developed. Both healthy and tumour-bearing rats were infused with Boronophenylalanine (BPA) and sacrificed at different time intervals after drug administration. The lungs were extracted, and prepared for boron analysis by neutron autoradiography and α-spectroscopy. The boron concentrations in tumour and normal lung were plotted as a function of the time elapsed after BPA administration. The concentration in tumour is almost constant within the error bars for all the time intervals of the experiment (1-8 h), while the curve in normal lung decreases after 4 h from BPA infusion. At 4 h, the ratio of boron concentration in tumour to boron concentration in healthy lung is higher than 3, and it stays above this level up to 8 h. Also the images of boron distribution in the samples, obtained by neutron autoradiography, show a selective absorption in the metastases. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. [New TNM classification of malignant lung tumours].

    PubMed

    Wohlschläger, J; Wittekind, C; Theegarten, D

    2010-09-01

    The staging system for lung tumours is now recommended for the classification of both non-small-cell and small-cell lung cancer as well as for carcinoid tumours of the lung. The T classifications have been redefined: T1 has been subclassified as T1a (≤ 2 cm in size) and T1b (> 2-3 cm in size). T2 has been subclassified as T2a (> 3-5 cm in size) and T2b (> 5-7 cm in size). T2 (> 7 cm in size) has been reclassified as T3. Multiple tumour nodules in the same lobe have been reclassified from T4 to T3. Multiple tumour nodules in the same lung but a different lobe have been reclassified from M1 to T4. No changes have been made in the N classification. The M classification has been redefined: M1 has been subdivided into M1a and M1b. Malignant pleural and pericardial effusions have been reclassified from T4 to M1a. Separate tumour nodules in the contralateral lung have been reclassified from T4 to M1a. M1b designates distant metastasis.

  3. Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model

    PubMed Central

    Reed, M D; Tellez, C S; Grimes, M J; Picchi, M A; Tessema, M; Cheng, Y S; March, T H; Kuehl, P J; Belinsky, S A

    2013-01-01

    Background: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. Methods: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. Results: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. Conclusion: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer. PMID:24045660

  4. Pharmacological inhibition of caspase-8 limits lung tumour outgrowth

    PubMed Central

    Terlizzi, Michela; Di Crescenzo, Vincenzo Giuseppe; Perillo, Giuseppe; Galderisi, Antonio; Pinto, Aldo; Sorrentino, Rosalinda

    2015-01-01

    Background and Purpose Lung cancer is one of the leading causes of cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis. Experimental Approach To elucidate the role of caspase-8 in lung carcinoma, we used human samples of non-small cell lung cancer (NSCLC) and a mouse model of carcinogen-induced lung cancer. Key Results Healthy and cancerous NSCLC samples had similar levels of the active form of caspase-8. Similarly, lung tumour-bearing mice had high levels of the active form of caspase-8. Pharmacological inhibition of caspase-8 by z-IETD-FMK robustly reduced tumour outgrowth and this was closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-α, IL-18, IL-1α, IL-33, but not IL-1β. Furthermore, inhibition of caspase-8 reduced the recruitment of innate suppressive cells, such as myeloid-derived suppressor cells, but not of regulatory T cells to lungs of tumour-bearing mice. However, despite the well-known role of caspase-8 in cell death, the apoptotic cascade (caspase-3, caspase-9 and Bcl-2 dependent) was not active in lungs of z-IETD-treated tumour-bearing mice, but instead higher levels of the short segment of c-FLIP (c-FLIPs) were detected. Similarly, human healthy lung samples had higher levels of c-FLIPs than cancerous samples. Conclusions and Implications Our data suggest that caspase-8 is an important orchestrator of cancer-associated inflammation and the presence of short segment of c-FLIP determines whether caspase-8 induces tumour proliferation or tumour arrest/regression in the lung. PMID:25917370

  5. Lung flooding enables efficient lung sonography and tumour imaging in human ex vivo and porcine in vivo lung cancer model

    PubMed Central

    2013-01-01

    Background Sonography has become the imaging technique of choice for guiding intraoperative interventions in abdominal surgery. Due to artefacts from residual air content, however, videothoracoscopic and open intraoperative ultrasound-guided thermoablation of lung malignancies are impossible. Lung flooding is a new method that allows complete ultrasound imaging of lungs and their tumours. Methods Fourteen resected tumourous human lung lobes were examined transpleurally with B-mode ultrasound before (in atelectasis) and after lung flooding with isotonic saline solution. In two swine, the left lung was filled with 15 ml/kg isotonic saline solution through the left side of a double-lumen tube. Lung tumours were simulated by transthoracic ultrasound-guided injection of 5 ml of purified bovine serum albumin in glutaraldehyde, centrally into the left lower lung lobe. The rate of tumour detection, the severity of disability caused by residual gas, and sonomorphology of the lungs and tumours were assessed. Results The ex vivo tumour detection rate was 100% in flooded human lung lobes and 43% (6/14) in atelectatic lungs. In all cases of atelectasis, sonographic tumour imaging was impaired by residual gas. Tumours and atelectatic tissue were isoechoic. In 28% of flooded lungs, a little residual gas was observed that did not impair sonographic tumour imaging. In contrast to tumours, flooded lung tissue was hyperechoic, homogeneous, and of fine-grained structure. Because of the bronchial wall three-laminar structure, sonographic differentiation of vessels and bronchi was possible. In all cases, malignant tumours in the flooded lung appeared well-demarcated from the lung parenchyma. Adenocarcinoma, squamous, and large cell carcinomas were hypoechoic. Bronchioloalveolar cell carcinoma was slightly hyperechoic. Transpleural sonography identifies endobronchial tumour growth and bronchial wall destruction. With transthoracic sonography, the flooded animal lung can be completely

  6. Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth.

    PubMed Central

    McCulloch, P.; George, W. D.

    1989-01-01

    Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mM. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P less than 0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 microM. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells. PMID:2930682

  7. Mechanism of tumour vascularization in experimental lung metastases.

    PubMed

    Szabo, Vanessza; Bugyik, Edina; Dezso, Katalin; Ecker, Nora; Nagy, Peter; Timar, Jozsef; Tovari, Jozsef; Laszlo, Viktoria; Bridgeman, Victoria L; Wan, Elaine; Frentzas, Sophia; Vermeulen, Peter B; Reynolds, Andrew R; Dome, Balazs; Paku, Sandor

    2015-02-01

    The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularization process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (ie vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26, and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularized desmoplastic tissue columns. Finally, we examined the process of arterialization in lung metastases and found that they became arterialized when their diameter grew to exceed 5 mm. In conclusion, our data show that lung metastases can vascularize by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti-angiogenic therapies.

  8. Monitoring of lung tumour cell growth in artificial membranes.

    PubMed

    Yang, Ying; Sulé-Suso, Josep; El Haj, Alicia J; Hoban, Paul R; Wang, Ruikang

    2004-10-15

    Morbidity of many tumour types is associated with invasion of tumour cells through the basement membrane and subsequent metastasis to vital organs. Tumour invasion is frequently detected late on as many patients present with advanced disease. The method of detecting invasion is through conventional histological staining techniques, which are time consuming and require processing of the sample. This can affect interpretation of the results. In this study, a new imaging technique, optical coherence tomography (OCT), was used to monitor lung tumour cell growth in two artificial membranes composed of either collagen type I or Matrigel. In parallel, standard histological section analysis was performed to validate the accuracy of the monitoring by OCT. Cross-sectional images from OCT revealed that lung tumour cells infiltrated only when low cell seeding density (5 x 10(5)) and low collagen concentration (1.5 mg/ml) were combined. The cells could be easily differentiated from the artificial membranes and appeared as either a brighter layer on the top of the membrane or brighter foci embedded within the darker membrane. These cell-membrane morphologies matched remarkably to the standard histological section images. Our results suggest that OCT has a great potential to become a useful tool for fast and robust imaging of cell growth in vivo and as a potential assessment of cell invasion.

  9. pH distributions in spontaneous and isotransplanted rat tumours.

    PubMed Central

    Kallinowski, F.; Vaupel, P.

    1988-01-01

    Spontaneous mammary tumours of the rat with various degrees of malignancy exhibit similar tissue pH distributions. The mean pH (+/- s.d.) of dysplasia is 7.05 +/- 0.20. In benign tumours the mean pH is 6.95 +/- 0.19 and in malignant tumours it is 6.94 +/- 0.19. In contrast, tumours with the same degree of malignancy but different histologies show different pH distributions. Benign tumours with a higher percentage of fibrous tissue exhibit less acidic pH values than those with larger portions of epithelial cells (delta pH = 0.38 pH units). The pH distribution in the benign tumours is independent of the tumour wet weight up to stages of very advanced growth. In the malignant tumours, a trend towards more acidic pH values is observed as the tumour mass enlarges. However, in tissue areas within a malignant tumour with gross, long-established necrosis the pH distribution is shifted towards more alkaline pH values. The pH distributions in spontaneous rat tumours are not significantly different from those obtained in isotransplanted Yoshida sarcomas (6.87 +/- 0.21). In the Yoshida sarcomas, mean pH values do not correlate with tumour size. However, a pH gradient from the rim to the centre of the tumours is found which coincides with the development of small, disseminated necroses in the tumour centre. It is concluded that pathology-related variations of tumour pH may be more important than the mode of tumour origin or the degree of malignancy. PMID:3179183

  10. Tumour markers in rheumatoid arthritis-associated interstitial lung disease.

    PubMed

    Wang, Ting; Zheng, Xing-Ju; Ji, Yu-Lin; Liang, Zong-An; Liang, Bin-Miao

    2016-01-01

    Interstitial lung disease (ILD) is the most common pulmonary extra-articular manifestations of rheumatoid arthritis (RA), but the pathogenesis of RA-ILD is unknown. The purpose of this study was to investigate the tumour markers levels in patients of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to explore the diagnostic value of serum tumour markers for RA-ILD. Twenty-eight patients with RA-ILD and 83 patients with RA only were included. Serum levels of tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 15-3, CA125, and CA19-9 were measured. Tumour markers CA15-3, CA125 and CA19-9 were increased in RA-ILD patients compared with RA without ILD patients. Logistic regression analysis revealed that older age (OR=1.06, 95% CI=[1.02-1.11]) and higher CA125 (OR=1.03, 95% CI=[1.01-1.05]) related to the increased risk of RA-ILD. ROC curve analysis showed the relationship between CA125 and RA-ILD was moderate (area under ROC curve (AUC)=0.78, 95% CI=[0.68-0.88]). In addition, CA125 levels above the normal reference (<35 U/ml) raised the risk of RA-ILD (OR=6.00, 95% CI=[2.37-15.16]). RA patient with older age and elevated tumour markers especially CA125 levels should be evaluated to check whether there is a potential of ILD.

  11. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study.

    PubMed

    Nijsen, F; Rook, D; Brandt, C; Meijer, R; Dullens, H; Zonnenberg, B; de Klerk, J; van Rijk, P; Hennink, W; van het Schip, F

    2001-06-01

    Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-microm poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was < or =0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little 166Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6. 1+/-2.9 for rats with tumour (n=15) versus 0.7+/-0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma.

  12. Interstitial laser photocoagulation of normal lung parenchyma in rats

    PubMed Central

    Fielding, D; Buonaccorsi, G; Hanby, A; Hetzel, M; Bown, S

    1998-01-01

    BACKGROUND—Management of peripheral lung tumours may be risky in patients with poor lung function or in the elderly. A new possibility is interstitial laser photocoagulation (ILP) in which tumours are gently coagulated using thin laser fibres placed percutaneously under radiological guidance. This could have a useful palliative role in selected patients, but to be safe the effects on normal lung parenchyma must first be understood. This paper describes the creation and healing of ILP lesions in the normal rat lung.
METHODS—ILP was performed using single laser fibres placed percutaneously in the left lung of normal rats under general anaesthetic with radiological guidance (laser power 1-3 W at 805 nm, treatment time 250-1000 s). The lesion size and healing were studied in rats killed at times from three days to six months after treatment, the bursting pressure was measured, and any complications noted.
RESULTS—Zones of necrosis up to 12 mm in diameter were produced, the size depending on the laser power and treatment time. Histological examination showed typical thermal effects with complete healing with fibrosis by two months. The effect was very localised with remarkably little effect on the structure and function of the rest of the lung. Adverse effects in the lung parenchyma only occurred if the ILP lesion involved the hilar vessels or the oesophagus, causing pulmonary congestion and perforation, respectively. Pneumothorax was seen in 6% of cases.
CONCLUSIONS—ILP with a single fibre can produce a localised zone of necrosis in normal lung parenchyma which heals safely and which has little effect on the rest of the lung. Further study of this technique using multiple fibres in a larger animal model is warranted to see if it is feasible and safe to produce a large enough volume of necrosis to be of value in the treatment of small peripheral lung tumours in patients who are unsuitable for surgery or palliative radiotherapy.

 PMID:9828858

  13. The profile of melatonin production in tumour-bearing rats.

    PubMed

    Ferreira, Ana Carolina Franco; Martins, Eivor; Afeche, Solange Castro; Cipolla-Neto, José; Costa Rosa, Luís Fernando Bicudo Pereira

    2004-09-24

    The pineal gland is involved in the regulation of tumour growth through the anticancer activity of melatonin, which presents immunomodulatory, anti-proliferative and anti-oxidant effects. In this study we measured melatonin content directly in the pineal gland, in an attempt to clarify the modulation of pineal melatonin secretory activity during tumour growth. Different groups of Walker 256 carcinosarcoma bearing rats were sacrificed at 12 different time points during 24h (12h:12h light/dark cycle) on different days during the tumour development (on the first, seventh and fourteenth day after tumour inoculation). Melatonin content in the pineal gland was determined by high-performance liquid chromatography with electrochemical detection. During tumour development the amount of melatonin secreted increased from 310.9 ng/mg of protein per day from control animals, to 918.1 ng/mg of protein per day 14 days after tumour implantation, and there were changes in the pineal production profile of melatonin. Cultured pineal glands obtained from tumour-bearing rats turned out to be less responsive to noradrenaline, suggesting the existence, in vivo, of putative factor(s) modulating pineal melatonin production. The results demonstrated that during tumour development there is a modification of pineal melatonin production daily profile, possibly contributing to cachexia, associated to changes in pineal gland response to noradrenaline stimulation.

  14. Spectral and lifetime domain measurements of rat brain tumours

    NASA Astrophysics Data System (ADS)

    Abi Haidar, D.; Leh, B.; Allaoua, K.; Genoux, A.; Siebert, R.; Steffenhagen, M.; Peyrot, D.; Sandeau, N.; Vever-Bizet, C.; Bourg-Heckly, G.; Chebbi, I.; Collado-Hilly, M.

    2012-02-01

    During glioblastoma surgery, delineation of the brain tumour margins remains difficult especially since infiltrated and normal tissues have the same visual appearance. This problematic constitutes our research interest. We developed a fibre-optical fluorescence probe for spectroscopic and time domain measurements. First measurements of endogenous tissue fluorescence were performed on fresh and fixed rat tumour brain slices. Spectral characteristics, fluorescence redox ratios and fluorescence lifetime measurements were analysed. Fluorescence information collected from both, lifetime and spectroscopic experiments, appeared promising for tumour tissue discrimination. Two photon measurements were performed on the same fixed tissue. Different wavelengths are used to acquire two-photon excitation-fluorescence of tumorous and healthy sites.

  15. HDR intraluminal brachytherapy for lung tumours--a case report.

    PubMed

    Wee, J T; Yang, E T; Lim, Y C

    1994-06-01

    The lung is a common site for cancer to occur, for both primary as well as metastases. The presence of such tumours can give rise to symptoms such as haemoptysis, cough, breathlessness and pneumonia. In most cases, treatment is strictly for palliation. We present a case report of a patient with an endobronchial metastasis from a primary hypernephroma which recurred following external beam radiotherapy. He was treated with a single fraction of intraluminal brachytherapy to a dose of 10Gy at 1 cm from the axis on a High Dose Rate Ir192 Remote Afterloading Machine. There were no adverse effects following treatment. On follow-up 7 months later, the patient did not have any further recurrence of breathlessness although his disease had progressed at other sites.

  16. Endogenous pacemaker activity of rat tumour somatotrophs

    PubMed Central

    Kwiecien, Renata; Robert, Christophe; Cannon, Robert; Vigues, Stephan; Arnoux, Annie; Kordon, Claude; Hammond, Constance

    1998-01-01

    Cells derived from a rat pituitary tumour (GC cell line) that continuously release growth hormone behave as endogenous pacemakers. In simultaneous patch clamp recordings and cytosolic Ca2+ concentration ([Ca2+]i) imaging, they displayed rhythmic action potentials (44.7 ± 2.7 mV, 178 ± 40 ms, 0.30 ± 0.04 Hz) and concomitant [Ca2+]i transients (374 ± 57 nM, 1.0 ± 0.2 s, 0.27 ± 0.03 Hz). Action potentials and [Ca2+]i transients were reversibly blocked by removal of external Ca2+, addition of nifedipine (1 μM) or Ni2+ (40 μM), but were insensitive to TTX (1 μM). An L-type Ca2+ current activated at -33.6 ± 0.4 mV (holding potential (Vh), −40 mV), peaked at -1.8 ± 1.3 mV, was reduced by nifedipine and enhanced by S-(+)-SDZ 202 791. A T/R-type Ca2+ current activated at -41.7 ± 2.7 mV (Vh, -80 or -60 mV), peaked at -9.2 ± 3.0 mV, was reduced by low concentrations of Ni2+ (40 μM) or Cd2+ (10 μM) and was toxin resistant. Parallel experiments revealed the expression of the class E calcium channel α1-subunit mRNA. The K+ channel blockers TEA (25 mM) and charybdotoxin (10–100 nM) enhanced spike amplitude and/or duration. Apamin (100 nM) also strongly reduced the after-spike hyperpolarization. The outward K+ tail current evoked by a depolarizing step that mimicked an action potential reversed at −69.8 ± 0.3 mV, presented two components, lasted 2–3 s and was totally blocked by Cd2+ (400 μM). The slow pacemaker depolarization (3.5 ± 0.4 s) that separated consecutive spikes corresponded to a 2- to 3-fold increase in membrane resistance, was strongly Na+ sensitive but TTX insensitive. Computer simulations showed that pacemaker activity can be reproduced by a minimum of six currents: an L-type Ca2+ current underlies the rising phase of action potentials that are repolarized by a delayed rectifier and Ca2+-activated K+ currents. In between spikes, the decay of Ca2+-activated K+ currents and a persistent inward cationic current depolarize the membrane

  17. Endobronchial brachytherapy in the treatment of malignant lung tumours.

    PubMed

    Escobar-Sacristán, J A; Granda-Orive, J I; Gutiérrez Jiménez, T; Delgado, J M; Rodero Baños, A; Saez Valls, R

    2004-09-01

    A prospective study was made to assess the short-term clinical and endoscopic response to high-dose-rate endobronchial brachytherapy (HDREB) in patients with malignant endobronchial tumours. From July 1995 to May 2000, 288 HDREB sessions were carried out on 81 patients. The mean patient age was 61.57 yrs (range 34-82); males were predominant (87.65%). Tumours were primary in 76 patients (93.82%) and metastatic in five patients (6.18%). The inclusion criteria were malignant endobronchial tumour and either palliative treatment for incurable disease or intent-to-cure treatment for residual malignancy on the bronchial resection surface after surgery or an inoperable tumour. The exclusion criteria were as follows: impediments to catheter placement, expected survival <2 months, Karnofsky index <60, or absence of informed consent. The clinical response of a symptom was categorised as complete (disappearance of the symptom), partial (less than complete) or absent. The endoscopic response was considered to be complete if lesions disappeared and biopsy findings remained negative 1 month after the last radiation session; partial if lesions improved to some extent, but the biopsy findings were positive; and absent if there was no change in relation to baseline. The technique consisted of delivering high-dose irradiation from an Ir192 source to a target volume using one or two endobronchial catheters inserted under optical or video bronchoscopic guidance. Four sessions were scheduled at weekly intervals and 500 cGy was applied per session over a length of 1-9 cm, measured 0.5-1 cm from the centre of the source. In total, 85% of the symptoms analysed (haemoptysis, cough, dyspnoea, expectoration, and stridor) disappeared with HDREB, which was categorised as a complete response. The endoscopic response was complete in 56.79% of patients, partial or less than complete in 40.74% and absent in 2.46%. One major complication occurred (bronchial fistula 1.2%), but no lethal haemoptysis

  18. TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is a potential prognostic biomarker in lung cancer.

    PubMed

    Liu, Wen-bin; Han, Fei; Jiang, Xiao; Chen, Hong-qiang; Zhao, Huan; Liu, Yong; Li, Yong-hong; Huang, Chuanshu; Cao, Jia; Liu, Jin-yi

    2015-08-28

    Epigenetic silencing of tumour suppressors contributes to the development and progression of lung cancer. We recently found that TMEM196 was hypermethylated in lung cancer. This study aimed to clarify its epigenetic regulation, possible roles and clinical significance. TMEM196 methylation correlated with loss of protein expression in chemical-induced rat lung pathologic lesions and human lung cancer tissues and cell lines. 5-aza-2'-deoxycytidine restored TMEM196 expression. Moreover, TMEM196 hypermethylation was detected in 61.2% of primary lung tumours and found to be associated with poor differentiation and pathological stage of lung cancer. Functional studies showed that ectopic re-expression of TMEM196 in lung cancer cells inhibited cell proliferation, clonogenicity, cell motility and tumour formation. However, TMEM196 knockdown increased cell proliferation and inhibited apoptosis and cell-cycle arrest. These effects were associated with upregulation of p21 and Bax, and downregulation of cyclin D1, c-myc, CD44 and β-catenin. Kaplan-Meier survival curves showed that TMEM196 downregulation was significantly associated with shortened survival in lung cancer patients. Multivariate analysis showed that patients with TMEM196 expression had a better overall survival. Our results revealed for the first time that TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.

  19. Radiofrequency versus microwave ablation for treatment of the lung tumours: LUMIRA (lung microwave radiofrequency) randomized trial.

    PubMed

    Macchi, M; Belfiore, M P; Floridi, C; Serra, N; Belfiore, G; Carmignani, L; Grasso, R F; Mazza, E; Pusceddu, C; Brunese, L; Carrafiello, G

    2017-05-01

    The LUMIRA trial evaluated the effectiveness of radiofrequency (RFA) and microwave ablation (MWA) in lung tumours ablation and defining more precisely their fields of application. It is a controlled prospective multi-centre random trial with 1:1 randomization. Fifty-two patients in stage IV disease (15 females and 37 males, mean age 69 y.o., range 40-87) were included. We randomized the patients in two different subgroups: MWA group and RFA group. For each group, we evaluated the technical and clinical success, the overall survival and complication rate. Inter-group difference was compared using Chi-square test or Fisher's exact test for categorical variables and one-way ANOVA test for continuous variables. For RFA group, there was a significant reduction in tumour size only between 6 and 12 months (p value = 0.0014). For MWA group, there was a significant reduction in tumour size between 6 and 12 months (p value = 0.0003) and between pre-therapy and 12 months (p value = 0.0215). There were not significant differences between the two groups in terms of survival time (p value = 0.883), while the pain level in MWA group was significantly less than in RFA group (1.79 < 3.25, p value = 0.0043). In conclusion, our trial confirms RFA and MWA are both excellent choices in terms of efficacy and safety in lung tumour treatments. However, when compared to RFA therapy, MWA produced a less intraprocedural pain and a significant reduction in tumour mass.

  20. Stereotactic ablative body radiotherapy (SABR) for primary and secondary lung tumours

    PubMed Central

    Gaya, Andrew

    2012-01-01

    Abstract Stereotactic ablative body radiotherapy (SABR) represents a technological breakthrough in radiotherapy technique, with proven benefits to patients in terms of improved tumour control and overall survival. The key components of SABR are described. The current evidence base for SABR for the treatment of primary and secondary lung tumours is appraised, and key ongoing trials are identified. PMID:23023165

  1. Fluoroscopy as a surrogate for lung tumour motion.

    PubMed

    McNair, H A; Kavanagh, A; Powell, C; Symonds-Tayler, J R N; Brada, M; Evans, P M

    2012-02-01

    The aim of this article was to test a simple approach of using pixel density values from fluoroscopy images to enable gated radiotherapy. Anterior and lateral (LAT) from images were acquired from 18 patients referred for radical radiotherapy for non-small cell lung cancer for a period of 30-45 s. The amplitude of movement and the number of breathing cycles were determined in the right-left (RL) and superoinferior (SI) directions on the anterior images and the anteroposterior (AP) and SI directions on the lateral images. The breathing pattern was created by analysing the variation in a summation of pixel values within a defined area. The greatest and lowest 30% of pixel values were set as the duty cycle to represent inhale and exhale amplitude-based gating. A median of eight breathing cycles was captured for each patient with a duration of 2.2-11.8 s per cycle. The mean (range) motion was 4.7 mm (2.4-5.8 mm), 7.2 mm (2.3-17.6 mm), 6.2 mm (1.9-13.8 mm) and 4.8 mm (2.4-11.3 mm) in the RL, SI (AP), SI (LAT) and AP directions, respectively. A total of 10/14 anterior videos and 7/11 LAT videos had correlations between motion and breathing of >0.6. Margins of 5.5 mm, 6.8 mm and 6.6 mm in the RL, SI and AP directions, respectively, were determined to gate in exhale. The benefit of gating was greater when motion was >5 mm. The simple approach of using pixel density values from fluoroscopy images to distinguish inhale from exhale and enable gating was successfully applied in all patients. This technique may potentially provide an accurate surrogate for tumour position.

  2. Fluoroscopy as a surrogate for lung tumour motion

    PubMed Central

    Mcnair, H A; Kavanagh, A; Powell, C; Symonds-Tayler, J R N; Brada, M; Evans, P M

    2012-01-01

    Objectives The aim of this article was to test a simple approach of using pixel density values from fluoroscopy images to enable gated radiotherapy. Methods Anterior and lateral (LAT) from images were acquired from 18 patients referred for radical radiotherapy for non-small cell lung cancer for a period of 30–45 s. The amplitude of movement and the number of breathing cycles were determined in the right–left (RL) and superoinferior (SI) directions on the anterior images and the anteroposterior (AP) and SI directions on the lateral images. The breathing pattern was created by analysing the variation in a summation of pixel values within a defined area. The greatest and lowest 30% of pixel values were set as the duty cycle to represent inhale and exhale amplitude-based gating. Results A median of eight breathing cycles was captured for each patient with a duration of 2.2–11.8 s per cycle. The mean (range) motion was 4.7 mm (2.4–5.8 mm), 7.2 mm (2.3–17.6 mm), 6.2 mm (1.9–13.8 mm) and 4.8 mm (2.4–11.3 mm) in the RL, SI (AP), SI (LAT) and AP directions, respectively. A total of 10/14 anterior videos and 7/11 LAT videos had correlations between motion and breathing of >0.6. Margins of 5.5 mm, 6.8 mm and 6.6 mm in the RL, SI and AP directions, respectively, were determined to gate in exhale. The benefit of gating was greater when motion was >5 mm. Conclusion The simple approach of using pixel density values from fluoroscopy images to distinguish inhale from exhale and enable gating was successfully applied in all patients. This technique may potentially provide an accurate surrogate for tumour position. PMID:21828146

  3. Effect of lung flooding and high-intensity focused ultrasound on lung tumours: an experimental study in an ex vivo human cancer model and simulated in vivo tumours in pigs

    PubMed Central

    2014-01-01

    Background High-intensity focused ultrasound is a valuable tool for minimally invasive tumour ablation. However, due to the air content in ventilated lungs, lung tumours have never been treated with high-intensity focused ultrasound. Lung flooding enables efficient lung sonography and tumour imaging in ex vivo human and in vivo porcine lung cancer models. The current study evaluates the effectiveness of lung flooding and sonography-guided high-intensity focused ultrasound for lung tumour ablation in ex vivo human and in vivo animal models. Methods Lung flooding was performed in four human lung lobes which were resected from non-small cell lung cancers. B-mode imaging and temperature measurements were simultaneously obtained during high-intensity focused ultrasonography of centrally located lung cancers. The tumour was removed immediately following insonation and processed for nicotinamide adenine dinucleotide phosphate-diaphorase and H&E staining. In addition, the left lungs of three pigs were flooded. Purified BSA in glutaraldehyde was injected centrally into the left lower lung lobe to simulate a lung tumour. The ultrasound was focused transthoracically through the flooded lung into the simulated tumour with the guidance of sonography. The temperature of the tumour was simultaneously measured. The vital signs of the animal were monitored during the procedure. Results A well-demarcated lesion of coagulation necrosis was produced in four of four human lung tumours. There did not appear to be any damage to the surrounding lung parenchyma. After high-intensity focused ultrasound insonation, the mean temperature increase was 7.5-fold higher in the ex vivo human tumour than in the flooded lung tissue (52.1 K ± 8.77 K versus 7.1 K ± 2.5 K). The transthoracic high-intensity focused ultrasound of simulated tumours in the in vivo model resulted in a mean peak temperature increase up to 53.7°C (±4.5). All of the animals survived the procedure without

  4. Intra- and interfractional variations in geometric arrangement between lung tumours and implanted markers.

    PubMed

    Ueki, Nami; Matsuo, Yukinori; Nakamura, Mitsuhiro; Mukumoto, Nobutaka; Iizuka, Yusuke; Miyabe, Yuki; Sawada, Akira; Mizowaki, Takashi; Kokubo, Masaki; Hiraoka, Masahiro

    2014-03-01

    To quantify the intra- and interfractional variations between lung tumours and implanted markers. Gold markers were implanted transbronchially around a lung tumour in fifteen patients. They underwent four-dimensional computed tomography scans twice, and the centroids of the tumour and markers were determined. Intrafractional variations were defined as the residual tumour motions relative to the markers due to respiration from the end-exhale phase. Interfractional variations were defined as the residual setup errors after correction for the position of the implanted markers in end-exhale phase images. The intrafractional variations differed between patients. The root mean squares of standard deviations for each phase were 0.6, 0.9, and 1.5mm in the right-left, anterior-posterior, and superior-inferior directions, respectively. The maximum difference in intrafractional variation among 10 phases was correlated with the amplitude of tumour motion in all directions and the tumour-marker distance in the anterior-posterior and superior-inferior directions. The interfractional variations were within 2.5mm. The intrafractional variations differed according to the amount of tumour motion and the tumour-marker distance. Additionally, interfractional variations of up to 2.5mm were observed. Thus, a corresponding margin should be considered during implanted marker-based beam delivery to account for these variations. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Inter-tester reproducibility of tumour change in small cell lung cancer patients undergoing chemoradiotherapy.

    PubMed

    Ellegaard, Mai-Britt Bjørklund; Knap, Marianne Marquard; Hoffmann, Lone

    2013-10-01

    Tumour volume change during delivery of chemoradiotherapy is observed in small cell lung cancer (SCLC) patients. In this study, we have compared tumour volume and anatomical changes, e.g. atelectasis or pleural effusions determined by three different methods. A total of 37 SCLC patients undergoing thoracic radiotherapy during 2010-2011 were included. The patients were treated based on a daily three-dimensional (3D) cone beam computed tomography (CBCT) bony anatomy registration. The CBCT scans were retrospectively reviewed visually by a radiation therapist (Visual-RTT) in order to register tumour volume changes. Furthermore, the tumour volume changes were obtained by either deformable image registration (DIR) or delineation by a radiation oncologist (RO). Kappa (κ) statistics and paired t-tests were used for evaluation of the inter-tester agreement. The tumour volume change between the Visual-RTT, the DIR and the RO assessments obtained 84-97% agreement (κ = 0.68-0.95). Furthermore, there was no statistically significant difference between the tumour change assessment of the RO (mean 13.6 ml) and the DIR (mean 14.5 ml), p = 0.59. Tumour shrinkage was observed in 15 (41%) patients and anatomical changes in seven (19%) patients. The inter-tester reproducibility of tumour volume change between the three methods is excellent. Visual-RTT on-line inspection may be used to determine tumour shrinkage and anatomical changes as atelectasis or pleural effusions during the radiotherapy course by use of daily CBCT scans.

  6. Inflammatory myofibroblastic tumour of the lung: a reactive lesion or a true neoplasm?

    PubMed Central

    Panagiotopoulos, Nikolaos; Gvinianidze, Lasha; Woo, Wen Ling; Borg, Elaine; Lawrence, David

    2015-01-01

    Inflammatory myofibroblastic tumour (IMT) of the lung represents an extremely rare type of inflammatory pseudo tumor that appears most commonly in children and young individuals. There has been an ongoing controversy whether an IMT is a reactive lesion or a true neoplasm making the further management extremely challenging. Purpose of the paper is through a literature review to highlight the existence of this rare tumour along with its key features and the management options available. PMID:26101648

  7. Radiofrequency Ablation of Lung Tumours with the Patient Under Thoracic Epidural Anaesthesia

    SciTech Connect

    Pouliquen, Cassiopee; Kabbani, Youssef Saignac, Pierre; Gekiere, Jean-Pierre; Palussiere, Jean

    2011-02-15

    Radiofrequency ablation of lung tumours is a curative technique that is newly considered being offered to nonsurgical patients. It is of major interest because it enables local destruction of the tumour without surgery and spares healthy parenchyma. However, some patients have previous serious respiratory failure, thus ruling out mechanical ventilation. To operate with the patient under thoracic epidural is an answer to this problem. Our experience shows that the procedure is able to be performed completely without converting to general anaesthesia.

  8. IL-1/IL-3 gene therapy of non-small cell lung cancer (NSCLC) in rats using 'cracked' adenoproducer cells.

    PubMed

    Esandi, M C; van Someren, G D; Bout, A; Mulder, A H; van Bekkum, D W; Valerio, D; Noteboom, J L

    1998-06-01

    Cytokine gene therapy was studied in established L42 tumours in syngeneic rats. L42 is a transplantable non-immunogenic non-small cell lung cancer (NSCLC). Genes coding for human interleukin-1 alpha and for rat interleukin-3 beta were transferred by injecting producer cells of recombinant adenovirus vectors into the tumour in attempts to achieve high concentrations of the cytokines inside the tumor without systemic toxicity. Limited tumour growth delay was obtained with viable producer cells. For logistic reasons stocks of pooled frozen producer cells allowed intensive treatment of groups of tumour bearing rats. The cells were lysed by thawing before administration. Ten daily injections of such 'cracked' producer cells induced reproducible tumour responses. These were due to local release of cytokines, not to systemic effects. Growth retardation also occurred in contralateral tumours which were not injected. When rats carrying established tumours were vaccinated with lysates of tumours collected during treatment with 'cracked' producer cells, significant tumour growth retardation was obtained. We speculate that both cytokines, if produced at sufficiently high concentrations in tumours, induce inflammation which in turn initiates an immune response against tumours growing at a distant site. These findings seem to justify further exploration of IL-1 and IL-3 gene transfer for the treatment of cancers.

  9. Thyroid transcription factor-1 immunohistochemistry: diagnostic tool and malignancy marker in canine malignant lung tumours.

    PubMed

    Bettini, G; Marconato, L; Morini, M; Ferrari, F

    2009-03-01

    Distinguishing primary lung carcinomas (PLCs) from metastases is a challenging task. The diagnostic and prognostic relevance of thyroid transcription factor-1 (TTF-1), a nuclear protein expressed in follicular cells of the thyroid gland and pneumocytes, was tested in 34 primary and 27 nonprimary canine lung tumours. Normal pneumocytes stained negatively in 14 PLCs because of overfixation or prolonged storage of paraffin blocks and were excluded from the study. Among the 20 immunoreactive PLCs, 17 showed strong nuclear positivity. The three tumours that scored negative were two squamous cell and one papillary carcinoma. Metastatic tumours were always negative. TTF-1 was 100% specific and 85% sensitive for PLCs. There was no significant relationship among the percentage of labelled tumour cells (TTF-1 index) and the considered clinicopathological parameters (age, gender, histological type, tumour grade, TNM stage, node status and MIB-1 index). TTF-1 immunohistochemistry may give useful additional information regarding the origin of canine lung tumours, whereas its prognostic use still needs to be determined.

  10. Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer.

    PubMed

    Cooper, W N; Dickinson, R E; Dallol, A; Grigorieva, E V; Pavlova, T V; Hesson, L B; Bieche, I; Broggini, M; Maher, E R; Zabarovsky, E R; Clark, G J; Latif, F

    2008-03-13

    RASSF2 is a recently identified member of a class of novel tumour suppressor genes, all containing a ras-association domain. RASSF2 resides at 20p13, a region frequently lost in human cancers. In this report we investigated methylation status of the RASSF2 promoter CpG island in a series of breast, ovarian and non-small cell lung cancers (NSCLC). RASSF2 was frequently methylated in breast tumour cell lines (65%, 13/20) and in primary breast tumours (38%, 15/40). RASSF2 expression could be switched back on in methylated breast tumour cell lines after treatment with 5'-aza-2'deoxycytidine. RASSF2 was also frequently methylated in NSCLC tumours (44%, (22/50). The small number of corresponding normal breast and lung tissue DNA samples analysed were unmethylated. We also did not detect RASSF2 methylation in ovarian tumours (0/17). Furthermore no mutations were found in the coding region of RASSF2 in these ovarian tumours. We identified a highly conserved putative bipartite nuclear localization signal (NLS) and demonstrated that endogenous RASSF2 localized to the nucleus. Mutation of the putative NLS abolished the nuclear localization. RASSF2 suppressed breast tumour cell growth in vitro and in vivo, while the ability of NLS-mutant RASSF2 to suppress growth was much diminished. Hence we demonstrate that RASSF2 has a functional NLS that is important for its tumour suppressor gene function. Our data from this and a previous report indicate that RASSF2 is frequently methylated in colorectal, breast and NSCLC tumours. We have identified RASSF2 as a novel methylation marker for multiple malignancies and it has the potential to be developed into a valuable marker for screening several cancers in parallel using promoter hypermethylation profiles.

  11. Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

    PubMed Central

    Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

    2015-01-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

  12. Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

    PubMed

    Banerji, Christopher R S; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E

    2015-03-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers.

  13. Refractive index of carcinogen-induced rat mammary tumours

    NASA Astrophysics Data System (ADS)

    Zysk, Adam M.; Chaney, Eric J.; Boppart, Stephen A.

    2006-05-01

    Near-infrared optical techniques for clinical breast cancer screening in humans are rapidly advancing. Based on the computational inversion of the photon diffusion process through the breast, these techniques rely on optical tissue models for accurate image reconstruction. Recent interest has surfaced regarding the effect of refractive index variations on these reconstructions. Although many data exist regarding the scattering and absorption properties of normal and diseased tissue, no measurements of refractive index appear in the literature. In this paper, we present near-infrared refractive index data acquired from N-methyl-N-nitrosourea-induced rat mammary tumours, which are similar in pathology and disease progression to human ductal carcinoma. Eight animals, including one control, were employed in this study, yielding data from 32 tumours as well as adjacent adipose and connective tissues.

  14. Percutaneous computed tomography-guided radiofrequency thermal ablation of small unresectable lung tumours.

    PubMed

    Rossi, S; Dore, R; Cascina, A; Vespro, V; Garbagnati, F; Rosa, L; Ravetta, V; Azzaretti, A; Di Tolla, P; Orlandoni, G; Pozzi, E

    2006-03-01

    The aim of the current study was to evaluate the safety and the efficacy of radiofrequency thermal ablation (RFTA) for the treatment of nonsmall cell lung cancer (NSCLC) and isolated pulmonary metastases (METs) from colorectal cancer (CRC). A total of 31 patients (15 with NSCLCs and 16 with CRC lung METs), with 36 lung tumour nodules (mean+/-sd diameter: 22+/-8 mm, range: 10-35 mm) underwent computed tomography (CT)-guided RFTA using expandable electrodes. Contrast-enhanced CT was performed before and after (immediately and 30+/-5 days) each RFTA session to assess immediate results and complications and repeated 3 and 6 months post-RFTA, as well as every 6 months thereafter, to evaluate long-term results. Complete radiological necrosis was defined as a nonenhancing area at the tumour site that was equal to or larger than the treated tumour; persistence of enhancement at the tumour site indicated incomplete treatment. Local recurrence was defined as an increase in tumour size and/or enhancing tissue at the tumour site. Complete radiological necrosis of the 36 tumours was achieved with 39 RFTA sessions and 42 electrode insertions. No major complications or deaths were observed. Six patients experienced mild-to-moderate pain during the procedure. There were five cases of pneumothorax, none requiring drainage and four cases of pneumonia, which were successfully treated with antibiotics. After a mean follow-up of 11.4+/-7.7 months (range of 3-36 months), the overall local recurrence rate was 13.9% (20 and 9.5% for NSCLC and CRC-METs patients, respectively). Nineteen of the 31 (61.3%) patients were alive (15 apparently disease free) and 12 (38.7%) had died (three from causes unrelated to their cancer). Radiofrequency thermal ablation seems to be a safe, effective method for producing complete ablation of small nonsmall cell lung cancers and pulmonary colorectal cancer metastases.

  15. Induction of tumour necrosis factor, interleukin-1beta and matrix metalloproteinases in pulmonary fibrosis of rats infected with Angiostrongylus cantonensis.

    PubMed

    Tu, W C; Lai, S C

    2006-09-01

    In angiostrongyliasis, chronic parasite-induced granuloma formation can lead to tissue destruction and fibrosis. Here, the histomorphology of granulomatous fibrosis and proteinase production in the lungs of Angiostrongylus cantonensis-infected Sprague-Dawley rats were investigated. The relationship between metalloproteinases and granulomatous fibrosis was investigated following infection of each rat with 60 infective larvae. Granulomata and fibrosis were marked in the lungs of rats on day 180 post-inoculation. Reverse transcriptase polymerase chain reaction of lung mRNA showed an up-expression of proinflammatory cytokine including tumour necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). According to Western blot analysis, matrix metalloproteinase-2 (MMP-2) proenzyme was presented in the lungs of uninfected and infected rats, and partial conversion of 72 kDa proenzyme to the 64 kDa active form occurred in infected rats. In addition, increased protein levels of MMP-9 and MMP-13 were detected in infected lungs, but were undetectable in controls. The results suggest that TNF-alpha, IL-1beta, MMP-2, -9, and -13 may be associated with the granulomatous fibrosis.

  16. Does perfusion CT play a role in the evaluation of percutaneous microwave-ablated lung tumours?

    PubMed

    Parvizi, N; Chung, D; Little, M W; Gleeson, F V; Anderson, E M

    2016-11-01

    To assess the clinical utility of perfusion computed tomography (pCT) parameters in microwave ablation (MWA) of lung tumours. Patients were included who had primary or metastatic lung tumours and underwent pCT studies immediately pre- and post-MWA. Perfusion maps of the tumours were constructed using CT perfusion software (GE, Milwaukee, WI, USA). Regions of interest were drawn on sequential axial sections to extract the pCT parameters, blood volume (BV), average blood flow (BF), and mean transit time (MTT) from the entire tumour volume. Direct visualisation of perfusion maps were performed by two experienced readers blinded to outcome. Data were analysed using the Mann-Whitney test. Thirty-one patients with 34 lung tumours had follow-up data at 12 months. The median tumour diameter was 19 mm (10-52 mm). Seven patients developed local tumour progression (LTP) at 12 months. There was no statistical difference between patients with LTP and complete treatment based on quantitative pCT parameters. Using radiologist visualisation of perfusion maps, there was moderate agreement between the two readers (kappa coefficient 0.53) with a combined 96% sensitivity, 62% specificity, 91% positive predictive value, and 80% negative predictive value. Quantitative pCT parameters do not help differentiate between LTP and complete treatment, but subjective analysis of perfusion maps may be a useful assessment tool for identifying treatment adequacy potentially enabling identification of areas requiring further treatment at the time of the procedure. Copyright © 2016 The Royal College of Radiologists. All rights reserved.

  17. The science behind the 7th edition Tumour, Node, Metastasis staging system for lung cancer.

    PubMed

    Marshall, Henry M; Leong, Steven C; Bowman, Rayleen V; Yang, Ian A; Fong, Kwun M

    2012-02-01

    The Tumour, Node, Metastasis (TNM) system for classifying lung cancer is the cornerstone of modern lung cancer treatment and underpins comparative research; yet is continuously evolving through updated revisions. The recently published Union for International Cancer Control 7th Edition TNM Classification for lung cancer addresses many of its predecessor's shortcomings and has been subject to rigorous evidence-based methodology. It is based on a retrospective analysis of over 80 000 lung cancer patients treated between 1990 and 2000 carried out by the International Association for the Study of Lung Cancer. The dataset was truly international and included patients treated by all modalities. Extensive internal and external validation of the findings has ensured that the recommendations are robust and generalizable. For the first time, a single classification system has been shown to be applicable not only to non-small cell lung cancer, but also to be of prognostic significance in small cell lung cancer and bronchopulmonary carcinoid tumours. We review the history of the Union for International Cancer Control TNM staging system, the changes in the most recent 7th edition and the strength of the scientific basis motivating these changes. Limitations of the current staging edition are explored, post-publication independent validation studies are reviewed, and the future of TNM staging for lung cancer is discussed.

  18. Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung.

    PubMed Central

    Urban, T.; Ricci, S.; Lacave, R.; Antoine, M.; Kambouchner, M.; Capron, F.; Bernaudin, J. F.

    1996-01-01

    Ki-ras activation by point mutation on codon 12 has been reported in non-small-cell lung carcinomas and in various models of experimental lung tumours induced by chemical carcinogens. The cellular targets for carcinogenic compounds of tobacco smoke are usually considered to be the cells of the bronchial mucosa or alveolar epithelium. However, little is known about preneoplastic events in bronchopulmonary carcinogenesis. The hypothesis of the presence of widespread target cells containing Ki-ras mutation was investigated by evaluating concurrent neoplastic and non-neoplastic bronchial and alveolar samples from 51 patients with non-small-cell lung carcinomas. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method used can detect one cell with a mutation on codon 12 among 10(2) normal cells. In tumour samples, a mutation was detected in 20% of adenocarcinomas, but in none of the adenosquamous or squamous cell carcinomas. No mutation was detected in the non-neoplastic bronchial or parenchymal samples. When using an enriched PCR-RFLP method detecting one mutated allele among 10(3) normal alleles a mutation was detected in 23% of adenocarcinomas. In conclusion, Ki-ras activation by mutation on codon 12 was not observed in non-neoplastic bronchial or parenchymal tissues in patients with bronchopulmonary cancers and does not appear to be a genetic event present in non-malignant epithelial target cells exposed to tobacco smoke. Images Figure 1 Figure 2 Figure 3 PMID:8855973

  19. Beneficial role of overexpression of TFPI-2 on tumour progression in human small cell lung cancer☆

    PubMed Central

    Lavergne, Marion; Jourdan, Marie-Lise; Blechet, Claire; Guyetant, Serge; Pape, Alain Le; Heuze-Vourc’h, Nathalie; Courty, Yves; Lerondel, Stephanie; Sobilo, Julien; Iochmann, Sophie; Reverdiau, Pascale

    2013-01-01

    Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin, a protease which is involved in tumour progression by activating (MMPs). This therefore makes TFPI-2 a potential inhibitor of invasiveness and the development of metastases. In this study, low levels of TFPI-2 expression were found in 65% of patients with small cell lung cancer (SCLC), the most aggressive type of lung cancer. To study the impact of TFPI-2 in tumour progression, TFPI-2 was overexpressed in NCI-H209 SCLC cells which were orthotopically implanted in nude mice. Investigations showed that TFPI-2 inhibited lung tumour growth. Such inhibition could be explained in vitro by a decrease in tumour cell viability, blockade of G1/S phase cell cycle transition and an increase in apoptosis shown in NCI-H209 cells expressing TFPI-2. We also demonstrated that TFPI-2 upregulation in NCI-H209 cells decreased MMP expression, particularly by downregulating MMP-1 and MMP-3. Moreover, TFPI-2 inhibited phosphorylation of the MAPK signalling pathway proteins involved in the induction of MMP transcripts, among which MMP-1 was predominant in SCLC tissues and was inversely expressed with TFPI-2 in 35% of cases. These results suggest that downregulation of TFPI-2 expression could favour the development of SCLC. PMID:23905012

  20. MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

    PubMed Central

    Smida, Michal; Fece de la Cruz, Ferran; Kerzendorfer, Claudia; Uras, Iris Z.; Mair, Barbara; Mazouzi, Abdelghani; Suchankova, Tereza; Konopka, Tomasz; Katz, Amanda M.; Paz, Keren; Nagy-Bojarszky, Katalin; Muellner, Markus K.; Bago-Horvath, Zsuzsanna; Haura, Eric B.; Loizou, Joanna I.; Nijman, Sebastian M. B.

    2016-01-01

    Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. PMID:27922010

  1. Telomerase activity (TMA) in tumour and peritumoural tissues in a rat liver cancer model.

    PubMed

    Zhang, Huo-Jun; Yang, Ji-Jin; Tian, Jian-Ming; Wang, Pei-Jun; Shao, Cheng-Wei; Zuo, Chang-Jing; Zhang, Shun-Min; Gupta, Sanjay

    2009-02-01

    To study the levels of telomerase activity (TMA) in tumour and peritumoural tissues in a liver cancer model in rats, and to study the change in TMA expression over time. Using the telomeric repeated amplification protocol (TRAP), TMA was measured in tumour tissue, peritumoural tissue and normal liver tissue of Walker-256 tumour-bearing rats at 4, 6 and 8 days after tumour implantation. TMA at day 4, 6 and 8 was 0.767+/-0.117, 0.768+/-0.118 and 0.774+/-0.111 in tumour tissue, 0.389+/-0.263, 0.492+/-0.253 and 0.584+/-0.239 in peritumoural tissue, and 0.231+/-0.022, 0.229+/-0.022 and 0.233+/-0.021 in normal liver tissue, respectively. TMA in tumour tissue was higher than that in peri-tumour and normal liver tissues at all time points of measurement (P < 0.05). The TMA levels in tumour tissue and normal liver tissue did not show any change over time. TMA level in the peritumoural tissue increased with time; TMA level in animals sacrificed at day 8 was higher than that seen in animals sacrificed at day 4 (P < 0.05). TMA in walker-256 tumour-bearing rats was higher than that in normal and peritumoural tissues. TMA level in the peritumoural tissue increased with time suggesting that TMA activation in peritumoural tissue may be an important factor promoting tumour growth.

  2. Bronchopleural Fistula After Radiofrequency Ablation of Lung Tumours

    SciTech Connect

    Cannella, Mathieu; Cornelis, Francois; Descat, Edouard; Ferron, Stephane; Carteret, Thibault; Castagnede, Hugues; Palussiere, Jean

    2011-02-15

    The present article describes two cases of bronchopleural fistula (BPF) occurring after radiofrequency ablation of lung tumors. Both procedures were carried out using expandable multitined electrodes, with no coagulation of the needle track. After both ablations, ground-glass opacities encompassed the nodules and abutted the visceral pleura. The first patient had a delayed pneumothorax, and the second had a recurrent pneumothorax. Both cases of BPF were diagnosed on follow-up computed tomography chest scans (i.e., visibility of a distinct channel between the lung or a peripheral bronchus and the pleura) and were successfully treated with chest tubes alone. Our goal is to highlight the fact that BPF can occur without needle-track coagulation and to suggest that minimally invasive treatment is sufficient to cure BPFs of this specific origin.

  3. Circulating tumour cells in patients with lung cancer undergoing endobronchial cryotherapy.

    PubMed

    Chudasama, Dimple; Rice, Alexandra; Soppa, Gopal; Anikin, Vladimir

    2015-08-01

    Early diagnosis of lung cancer still poses a major issue, with a large proportion of patients diagnosed at late stages. Therapeutic options and treatment remain limited in these patients. In most cases only palliative therapies are available to alleviate any severe symptoms. Endobronchial cryotherapy (EC) is one form of palliative treatment offered to patients with obstructive airway tumours. Although successful, the impact on circulating tumour cell (CTCs) spread has not been investigated in detail. This study recruited 20 patients awaiting EC treatment. Baseline and post EC blood samples were analysed for presence of CTCs. Results showed an increase in CTCs following EC in 75% of patients. Significant increases were noticeable in some cases. Although EC is a well-accepted modality of treatment to alleviate symptoms, it may lead to an increase in CTCs, which in turn may have implications for tumour dissemination and metastatic spread.

  4. Combined micro-PET/micro-CT imaging of lung tumours in SPC-raf and SPC-myc transgenic mice.

    PubMed

    Rodt, Thomas; Luepke, Matthias; Boehm, Claudia; Hueper, Katja; Halter, Roman; Glage, Silke; Hoy, Ludwig; Wacker, Frank; Borlak, Juergen; von Falck, Christian

    2012-01-01

    SPC-raf and SPC-myc transgenic mice develop disseminated and circumscribed lung adenocarcinoma respectively, allowing for assessment of carcinogenesis and treatment strategies. The purpose of this study was to investigate the technical feasibility, the correlation of initial findings to histology and the administered radiation dose of combined micro-PET/micro-CT in these animal models. 14 C57BL/6 mice (4 nontransgenic, 4 SPC-raf transgenic, 6 SPC-myc transgenic) were examined using micro-CT and (18)F-Fluoro-deoxyglucose micro-PET in-vivo. Micro-PET data was corrected for random events and scatter prior to reconstruction with a 3D-FORE/2D-OSEM iterative algorithm. Rigid micro-PET/micro-CT registration was performed. Tumour-to-non-tumour ratios were calculated for different lung regions and focal lesions. Diffuse tumour growth was quantified using a semiautomated micro-CT segmentation routine reported earlier. Regional histologic tumour load was assessed using a 4-point rating scale. Gamma radiation dose was determined using thermoluminescence dosimeters. Micro-CT allowed visualisation of diffuse and circumscribed tumours in SPC-raf and SPC-myc transgenic animals along with morphology, while micro-PET provided information on metabolism, but lacked morphologic detail. Mean tumour-to-non-tumour ratio was 2.47 for circumscribed lesions. No significant correlation could be shown between histological tumour load and tumour-to-nontumour ratio for diffuse tumours in SPC-raf transgenic animals. Calculation of the expected dose based on gamma dosimetry yielded approximately 140 mGy/micro-PET examination additional to approximately 200 mGy due to micro-CT. Combined micro-PET/micro-CT imaging allows for in-vivo assessment of lung tumours in SPC-raf and SPC-myc transgenic mice. The technique has potential for the evaluation of carcinogenesis and treatment strategies in circumscribed lung tumours.

  5. [Glomus tumour of the lung: a case report and literature review].

    PubMed

    Baena-Del Valle, Javier Alonso; Murillo-Echeverri, Victoria Eugenia; Gaviria-Velásquez, Alejandro; Celis-Mejía, Diego Miguel; Matute-Turizo, Gustavo

    2015-01-01

    Glomus tumours are neoplasms arising from cells of the neuromyoarterial glomus bodies, which almost always occur in a subungual location. A lung location is extremely rare, with few cases reported in the literature. The case is presented of a 33 year-old male, with non-productive cough, dyspnoea at rest, intermittent fever, and mild pain in rib cage. A chest radiograph showed a consolidation in the left lung, and computed tomography revealed a lesion in the hilum that extended to the bronchus of the lingula obstructing, and causing post-obstructive pneumonia. A biopsy was obtained by rigid bronchoscopy biopsy, which showed a well circumscribed tumour constituted by intermediate-sized cells, and abundant cytoplasm that are arranged in a pattern surrounding numerous thin-walled blood vessels, with no pleomorphism, significant mitotic activity or necrosis. Immunohistochemistry revealed diffuse positivity with smooth muscle actin, vimentin, caldesmon; focal reactivity with desmin and CD117, CD34 highlights the vascular pattern. Ki67 proliferation rate was 1%. Synaptophysin, EMA and cytokeratin cocktail were negative, making the diagnosis of glomus tumour. Glomus tumours are rare neoplasms that usually appear in the dermis and subcutaneous tissue, where it is common to find glomus bodies. Occasionally glomus tumours can occur in extra-cutaneous sites such as the gastrointestinal tract, bone and respiratory system, with this case being a new case of rare lung location. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  6. Accuracy of transthoracic ultrasound for the prediction of chest wall infiltration by lung cancer and of lung infiltration by chest wall tumours.

    PubMed

    Caroli, Guido; Dell'Amore, Andrea; Cassanelli, Nicola; Dolci, Giampiero; Pipitone, Emanuela; Asadi, Nizar; Stella, Franco; Bini, Alessandro

    2015-10-01

    We wanted to determine the accuracy of transthoracic ultrasound in the prediction of chest wall infiltration by lung cancer or lung infiltration by chest wall tumours. Patients having preoperative CT-scan suspect for lung/chest wall infiltration were prospectively enrolled. Inclusion criteria for lung cancer were: obliteration of extrapleural fat, obtuse angle between tumour and chest wall, associated pleural thickening. The criteria for chest wall tumours were: rib destruction and intercostal muscles infiltration with extrapleural fat obliteration and intrathoracic extension. Lung cancer patients with evident chest wall infiltration were excluded. Transthoracic ultrasound was preoperatively performed. Predictions were checked during surgical intervention. Twenty-three patients were preoperatively examined. Sensitivity, specificity, positive and negative predictive values of transthoracic ultrasound were 88.89%, 100%, 100% and 93.3%, respectively. Youden index was used to determine the best cut-off for tumour size in predicting lung/chest wall infiltration: 4.5cm. At univariate logistic regression, tumour size (<4.5 vs ≥ 4.5cm) (p=0.0072) was significantly associated with infiltration. Transthoracic ultrasound is a useful instrument for predicting neoplastic lung or chest wall infiltration in cases of suspect CT-scans and could be used as part of the preoperative workup to assess tumour staging and to plan the best surgical approach. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  7. Multidisciplinary collaborative gross tumour volume definition for lung cancer radiotherapy: a prospective study.

    PubMed

    Hollingdale, Abigail E; Roques, Tom W; Curtin, John; Martin, W M Craig; Horan, Gail; Barrett, Ann

    2011-12-07

    Variability in gross tumour volume (GTV) definition is a major source of systematic error in conformal radiotherapy. This prospective study assesses the role of multidisciplinary collaboration between oncologists and radiologists in defining lung cancer volumes. Twenty patients with non-small cell lung cancer due to receive three-dimensional conformal radiotherapy formed the study population. GTVs were defined by a radiologist (GTVrad) and an oncologist (GTVonc) using available clinical information and imaging. A collaborative meeting was then held to agree on a final, common GTV (GTVfin) to be used for treatment planning, and differences analysed. The collaboration changed the GTV in 19/20 patients with a total of 50 regions being edited. Changes made were categorized as (a) differentiation of tumour from atelectasis or ground glass shadowing, (b) separation of tumour from vasculature, and (c) defining mediastinal extent of tumour. Oncologists were more confident in the GTVfin than the GTVonc. The radiologist took longer to define the GTV than the oncologist. Real-time collaborative GTV definition by a radiologist and oncologist is practical and feasible. This approach allows specific areas of uncertainty to be categorized and focussed on, reducing systematic error in GTV definition. The physician's approach to risk and decision making for each patient may also play a role.

  8. Bioluminescent Orthotopic Mouse Models of Human Localized Non-Small Cell Lung Cancer: Feasibility and Identification of Circulating Tumour Cells

    PubMed Central

    Lahon, Benoit; Castier, Yves; Lesèche, Guy; Soria, Jean-Charles; Vozenin, Marie-Catherine; Decraene, Charles; Deutsch, Eric

    2011-01-01

    Background Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. Methods Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. Results Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. Conclusions Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model. PMID:22022511

  9. LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective

    PubMed Central

    Adebahr, S; Collette, S; Shash, E; Lambrecht, M; Le Pechoux, C; Faivre-Finn, C; De Ruysscher, D; Peulen, H; Belderbos, J; Dziadziuszko, R; Fink, C; Guckenberger, M; Hurkmans, C

    2015-01-01

    Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113—LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided. PMID:25873481

  10. First surgical tumour reduction of peritoneal surface malignancy in a rat's model.

    PubMed

    Hartmann, Jens; Kilian, Maik; Atanassov, Vladimir; Braumann, Chris; Ordemann, Juergen; Jacobi, Christoph A

    2008-01-01

    Surgical therapy of peritoneal surface malignancy from colorectal origin in combination with Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) has now become an established treatment approach in very few specialised centres. A peritonectomy procedure is possible to perform with additional HIPEC in patients. An experimental model to simulate peritonectomy procedure and HIPEC does not exist so far in rats. Nevertheless, animal models seem to be very important for evaluation of new therapeutic opportunities and toxicity of different multimodal therapies. In a first step we analysed the surgical tumour debulking of peritoneal surface malignancy in rats. A peritoneal surface malignancy from colonic origin was induced in 75 male BD IX rats. Twenty one days after induction of peritoneal surface malignancy rats were randomised and animals intend to create an operation with surgical tumour debulking. There was no tumour growth in two animals. The aim of the peritonectomy procedure was the complete tumour reduction. In this study the results of the surgical approach will be described. A complete tumour reduction (R0) was achieved in 34 animals. In 39 rats a macroscopic tumour deposit was left behind (R2). The intraoperative experimental Peritoneal Cancer Index (ePCI) was used to describe tumour weight and number of tumour inoculations. Both parameters were found to be dependent factors of complete tumour reduction. Six animals died due to therapeutical interventions. Surgical tumour debulking in rats with peritoneal surface malignancy is possible with high reliability and a low mortality rate. This animal model could be an important step for investigation of multimodal treatment options and toxicity in treatment regimens of peritoneal surface malignancy.

  11. Investigation of the potential carcinogenicity of a range of chromium containing materials on rat lung.

    PubMed Central

    Levy, L S; Martin, P A; Bidstrup, P L

    1986-01-01

    Twenty one chromium containing materials were examined for carcinogenic activity in a two year study using an intrabronchial pellet implantation system whereby pellets loaded with test material were surgically implanted into the lower left bronchus of rats. The principal aim of the study was to extend our knowledge of the carcinogenic potential of chromium compounds and, in particular, chromates (Cr6+). A statistically significant incidence of treatment related lung tumours was found with some sparingly soluble chromate materials. All tumours were large keratinizing squamous carcinomas of the left lung, except for a single left lung adenocarcinoma and two left lung anaplastic carcinomas. No bronchial carcinomas (0/100) were seen in the negative control group (blank pellet loaded with cholesterol), whereas bronchial carcinomas (22/48 and 25/100) occurred in the two positive control groups which received pellets loaded with 20-methylcholanthrene and calcium chromate respectively. Among the 20 test materials, only three groups gave statistically significant numbers of bronchial carcinomas. Two of these were groups receiving different samples of strontium chromate which gave 43/99 and 62/99 tumours. The third group, zinc chromate (low solubility), gave 5/100 bronchial carcinomas. A further zinc chromate group (Norge composition) produced 3/100 bronchial carcinomas which was not statistically significant. A few lung tumours were observed in other test groups. Images PMID:3964573

  12. Treatment of lung tumours with high-energy microwave ablation: a single-centre experience.

    PubMed

    Ierardi, Anna Maria; Coppola, Andrea; Lucchina, Natalie; Carrafiello, Gianpaolo

    2017-01-01

    The purpose of our study is to report safety, technical success, effectiveness, local progression-free survival (LPFS) and overall survival of percutaneous microwave ablation (MWA) to treat lung tumours unsuitable for surgery. Nineteen patients with thirty-one tumours (mean diameter 2.4 cm) underwent percutaneous MWA in 28 sessions. Microwave ablation was carried out using a 2450-MHz generator (Emprint/Covidien, Boulder, CO, USA). Procedures were performed under cone-beam CT (CBCT) and under fluoro-CT (one session) guidance. Safety, technical success, effectiveness, LPFS and overall survival (OS) were evaluated. Safety was defined as the frequency of major and minor complications. The efficacy was evaluated on the basis of imaging characteristics, using RECIST criteria. CT follow-up was performed at 1, 3 and 6 months and yearly. LPFS was defined as the interval between MWA treatment and evidence of local recurrence, if there was any. OS was defined as the percentage of patients who were still alive. We registered one major complication (purulent hydro-pneumothorax). Minor complications were spontaneously resolved (pneumothorax and perilesional haemorrhagic effusion). Technical success was 100%. Residual disease was registered in two cases, one of whom was retreated. Complete ablation was obtained in the remaining cases (90.3%). During available follow-up (mean 9.6 months), 9/31 tumours demonstrated local recurrence. Five tumours were retreated, and none of them presented residual disease during follow-up (LPFS 22.6%). Overall survival was 93.8%. Percutaneous high-energy MWA is a safe, effective and confident technique to treat lung tumours not suitable for surgery.

  13. The human NANOS3 gene contributes to lung tumour invasion by inducing epithelial-mesenchymal transition.

    PubMed

    Grelet, Simon; Andries, Vanessa; Polette, Myriam; Gilles, Christine; Staes, Katrien; Martin, Anne-Pascaline; Kileztky, Claire; Terryn, Christine; Dalstein, Véronique; Cheng, Chun-Wen; Shen, Chen-Yang; Birembaut, Philippe; Van Roy, Frans; Nawrocki-Raby, Béatrice

    2015-09-01

    We have explored the role of the human NANOS3 gene in lung tumour progression. We show that NANOS3 is over-expressed by invasive lung cancer cells and is a prognostic marker for non-small cell lung carcinomas (NSCLCs). NANOS3 gene expression is restricted in testis and brain and is regulated by epigenetic events. It is up-regulated in cultured cells undergoing epithelial - mesenchymal transition (EMT). NANOS3 over-expression in human NSCLC cell lines enhances their invasiveness by up-regulating EMT, whereas its silencing induces mesenchymal - epithelial transition. NANOS3 represses E-cadherin at the transcriptional level and up-regulates vimentin post-transcriptionally. Also, we show that NANOS3 binds mRNAs encoding vimentin and regulates the length of their poly(A) tail. Finally, NANOS3 can also protect vimentin mRNA from microRNA-mediated repression. We thus demonstrate a role for NANOS3 in the acquisition of invasiveness by human lung tumour cells and propose a new mechanism of post-transcriptional regulation of EMT. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  14. Factors Controlling the Growth of the Yoshida Ascites Tumour in the Uterus of the Rat

    PubMed Central

    Lions, Jennifer

    1970-01-01

    The growth of the Yoshida ascites sarcoma following transplantation into the uterine lumen of the rat is influenced by the reproductive state of the animal. The uterus of a rat showing normal oestrous cycles is resistant to the growth of the tumour, although viable tumour cells survive for as long as 5 days within the uterine lumen. The tumour grows readily within the uteri of animals inoculated in early pseudopregnancy. The uterine epithelium is important in determining the resistance of the uterus to tumour growth, since damage to the endometrium, or inoculation directly into the endometrial stroma permits tumour growth within the uterus of the cycling animal. ImagesFigs. 1a-1dFigs. 2a-2b PMID:5531062

  15. Histochemical and histoenzymatic liver changes in Guérin tumour-grafted rats.

    PubMed

    Bădescu, A; Cotuţiu, C; Mârza, D

    1981-01-01

    In order to follow up the morphological changes of the rat liver as a reaction to the tumour graft, three groups of Guérin tumour-grafted animals were used: a first control group, a second one treated with leucotrophine (LT) and a third one treated with LT and thiamine diphosphate (TDP). The tumour-grafted rats showed hepatic changes affecting mainly the organelles involved in cellular respiration and synthesis, as well as some morphological changes of Kupffer cells expressing an increased endocytosis. The protection by immunostimuli determined the diminution of histochemical and histoenzymatic changes both in hepatocytes and Kupffer cells.

  16. Small-cell carcinoma of the lung resembling a brachial plexus tumour.

    PubMed

    Ferreira, A J A; Peleteiro, M C; Correia, J H D; Jesus, S O; Goulão, A

    2005-06-01

    A small-cell carcinoma of the lung was identified in a six-year-old female German shepherd dog with a history of chronic lameness of the left forelimb, Horner's syndrome and sensory deficits on the caudal portion of the left forelimb below the elbow. A mass, the exact location of which was difficult to ascertain, was identified during radiographic examination of the thorax. It was easily identified, using magnetic resonance imaging, as an apical tumour of the left lung with dorsal extension and involvement of paraspinal structures, such as spinal nerve roots C8 to T1 and the sympathetic trunk. Postmortem examination confirmed a mass in the left apical lobe of the lung, compatible with a diagnosis of small-cell carcinoma by histopathology and immunohistochemistry. This clinical presentation is similar to Pancoast syndrome described in humans.

  17. Relevance of density, size and DNA content of tumour cells to the lung colony assay.

    PubMed Central

    Grdina, D. J.; Hittelman, W. N.; White, R. A.; Meistrich, M. L.

    1977-01-01

    Mouse fibrosarcoma tumours were dissociated and divided into subpopulations of viable cells by centrifugation in linear density gradients of Renografin. Two of these subpopulations, designated Band 2 and Band 4, differed in their clonogenic ability in lung colony assay. The less dense Band 2 cells were significantly more clonogenic than the Band 4 cells (2.9 percent vs 1.4 percent respectively). Each band was further separated on the basis of cell size by centrifugal elutriation. Each size class of cells comprising Band 2 showed higher clonogenic ability than the corresponding size class in Band 4. Thus cell size differences were not responsible for the clonogenic differences between these bands. To determine whether cell-cycle distribution of the tumour cells was responsible for differences in cloning efficiency, flow microfluorometric and premature chromosome condensation methods were utilized. The unseparated and Band 4 populations showed a higher percentage of cells in S and G2 than did the Band 2 populations, but many of the S and G2 tumour cells showed extensive chromosome damage. From this study we conclude that the increased clonogenic ability of the lighter tumour cells is not due to differences in cell size or cell-cycle parameters. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:563726

  18. Chronic Glibenclamide Treatment Attenuates Walker-256 Tumour Growth in Prediabetic Obese Rats.

    PubMed

    da Silva Franco, Claudinéia Conationi; Previate, Carina; de Barros Machado, Kátia Gama; Piovan, Silvano; Miranda, Rosiane Aparecida; Prates, Kelly Valério; Moreira, Veridiana Mota; de Oliveira, Júlio Cezar; Barella, Luiz Felipe; Gomes, Rodrigo Mello; Francisco, Flávio Andrade; Martins, Isabela Peixoto; Pavanello, Audrei; Ribeiro, Tatiane Aparecida; Tófolo, Laize Peron; Malta, Ananda; de Souza, Aline Amenencia; Alves, Vander Silva; da Silva Silveira, Sandra; Marçal Natali, Maria Raquel; Fernando Besson, Jean Carlos; de Morais, Hely; de Souza, Helenir Medri; de Sant Anna, Juliane Rocha; Alves de Castro Prado, Marialba Avezum; de Freitas Mathias, Paulo Cezar

    2017-01-01

    The sulphonylurea glibenclamide (Gli) is widely used in the treatment of type 2 diabetes. In addition to its antidiabetic effects, low incidences of certain types of cancer have been observed in Gli-treated diabetic patients. However, the mechanisms underlying this observation remain unclear. The aim of the present work was to evaluate whether obese adult rats that were chronically treated with an antidiabetic drug, glibenclamide, exhibit resistance to rodent breast carcinoma growth. Neonatal rats were treated with monosodium L-glutamate (MSG) to induce prediabetes. Control and MSG groups were treated with Gli (2 mg/kg body weight/day) from weaning to 100 days old. After Gli treatment, the control and MSG rats were grafted with Walker-256 tumour cells. After 14 days, grafted rats were euthanized, and tumour weight as well as glucose homeostasis were evaluated. Treatment with Gli normalized tissue insulin sensitivity and glucose tolerance, suppressed fasting hyperinsulinaemia, reduced fat tissue accretion in MSG rats, and attenuated tumour growth by 27% in control and MSG rats. Gli treatment also resulted in a large reduction in the number of PCNA-positive tumour cells. Although treatment did improve the metabolism of pre-diabetic MSG-rats, tumour growth inhibition may be a more direct effect of glibenclamide. © 2017 The Author(s). Published by S. Karger AG, Basel.

  19. Motion compensation for robotic lung tumour radiotherapy in remote locations: A personalised medicine approach

    NASA Astrophysics Data System (ADS)

    Ionescu, Clara M.; Copot, Cosmin; Verellen, Dirk

    2017-03-01

    The purpose of this work is to integrate the concept of patient-in-the-closed-loop application with tumour treatment of cancer-diagnosed patients in remote areas. The generic closed loop control objective is effective synchronisation of the radiation focus to the movement of a lung tissue tumour during actual breathing of the patient. This is facilitated by accurate repositioning of a robotic arm manipulator, i.e. we emulate the Cyberknife Robotic Radiosurgery system. Predictive control with disturbance filter is used in this application in a minimalistic model design. Performance of the control structure is validated by means of simulation using real recorded breathing patterns from patients measured in 3D space. Latency in communication protocol is taken into account, given telerobotics involve autonomous operation of a robot interacting with a human being in different location. Our results suggest that the proposed closed loop control structure has practical potential to individualise the treatment and improves accuracy by at least 15%.

  20. Enzastaurin has anti-tumour effects in lung cancers with overexpressed JAK pathway molecules

    PubMed Central

    Shimokawa, T; Seike, M; Soeno, C; Uesaka, H; Miyanaga, A; Mizutani, H; Kitamura, K; Minegishi, Y; Noro, R; Okano, T; Yoshimura, A; Gemma, A

    2012-01-01

    Background: Enzastaurin, an oral serine–threonine kinase inhibitor, was initially developed as an ATP-competitive selective inhibitor against protein kinase Cβ. However, the mechanism by which enzastaurin contributes to tumourigenesis remains unclear. Methods: We analysed the anti-tumour effects of enzastaurin in 22 lung cancer cell lines to ascertain the potential for enzastaurin-based treatment of lung cancer. To identify molecules or signalling pathways associated with this sensitivity, we conducted a gene, receptor tyrosine kinases phosphorylation and microRNA expression profiling study on the same set of cell lines. Results: We identified eight genes by pathway analysis of molecules having gene-drug sensitivity correlation, and used them to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. Pathway analysis revealed that the JAK/STAT signalling pathway was one of the main ones involved in sensitivity to enzastaurin. Overexpression of JAK1 was observed in the sensitive cells by western blotting. Simultaneous administration of enzastaurin and JAK inhibitor inhibited enzastaurin-induced cell growth-inhibitory effect. Furthermore, lentiviral-mediated JAK1-overexpressing cells were more sensitive to enzastaurin than control cells. Conclusion: Our results suggested that the JAK1 pathway may be used as a single predictive biomarker for enzastaurin treatment. The anti-tumour effect of enzastaurin should be evaluated in lung cancer with overexpressed JAK pathway molecules. PMID:22333600

  1. Previous tumour as a prognostic factor in stage I non‐small cell lung cancer

    PubMed Central

    López‐Encuentra, Angel; de la Cámara, Agustín Gómez; Rami‐Porta, Ramón; Duque‐Medina, José Luis; de Nicolás, José Luis Martín; Sayas, Javier

    2007-01-01

    Objective To evaluate the effect of comorbidity as an independent prognostic factor in lung cancer. Method Data on 2991 consecutive cases of lung cancer were collected prospectively from 19 Spanish hospitals between 1993 and 1997 by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB‐S). To evaluate the effect of comorbidity on survival, 1121 patients with non‐small cell lung cancer (NSCLC) in pathological stage I who underwent complete resection were selected, excluding operative mortality. The presence of specific comorbidities at the time of thoracotomy was registered prospectively. Results Cox regression analysis showed that tumour size (0–2, 2–4, 4–7, >7 cm) (HR 1.45 95% CI 1.08 to 1.95), 1.86 (95% CI 1.38 to 2.51), 2.84 (95% CI 1.98 to 4.08)), the presence of a previous tumour (HR 1.45 (95% CI 1.17 to 1.79)) and age (HR 1.02 (95% CI 1.01 to 1.03)) had a significant prognostic association with survival. This study excluded the presence of visceral pleural involvement or other comorbidities as independent variables. Conclusion The presence of a previous tumour is an independent prognostic factor in pathological stage I NSCLC with complete resection, increasing the probability of death by 1.5 times at 5 years. It is independent of other comorbidities, TNM classification and age. PMID:16449263

  2. Transient dehydration of lungs in tail-suspended rats

    NASA Technical Reports Server (NTRS)

    Hargens, A. R.; Steskal, J.; Morey-Holton, E. R.

    1985-01-01

    The fluid balance in the lungs of rats exposed to head-down tilt is examined. Six Munich-Wister rats were suspended for 7 days and 10 Sprague-Dawley rats for 14 days using the technique of Morey (1979). The water contents of the lungs of the suspended and a control group are calculated and compared. The data reveal that the two-days suspended rats had dehydrated lungs; however, the lungs of the 14-day suspended and control group rats were similar. It is noted that the dehydration in the 2-day suspended rats is caused by general dehydration not the head-tilt position.

  3. Differential expression of immunohistochemical markers in primary lung and breast cancers enriched for triple-negative tumours.

    PubMed

    Provenzano, Elena; Byrne, David J; Russell, Prudence A; Wright, Gavin M; Generali, Daniele; Fox, Stephen B

    2016-02-01

    In breast cancer patients presenting with a lung lesion, the distinction between lung and breast origin is clinically important. Lung and breast cancers are both CK7(+) /CK20(-) , so additional immunohistochemical markers are needed. We examined the expression of oestrogen receptor (ER), progesterone receptor (PR), thyroid transcription factor-1 (TTF-1), gross cystic disease fluid protein-15 (GCDFP-15), p63 and Wilms' tumour 1 (WT1) in a series of tissue microarrays comprising 266 non-small-cell lung cancers and 837 primary breast cancers enriched for triple-negative tumours (TNBC). Staining for ER, PR, TTF-1 and GCDFP-15 was present in 63%, 49%, 0% and 25% of breast and 6%, 9%, 59% and 1% of lung cancers, respectively. Strong staining for p63 was present in 63 (97%) lung squamous cell carcinomas and only eight (9%) TNBC. WT1 nuclear staining was rare; however, cytoplasmic staining was identified in 49 (40%) TNBC and 10 (5%) lung cancers. Cluster analysis segregated TNBC from lung cancers with TTF-1 and/or p63 staining favouring lung origin, and GCDFP-15 or WT1 staining favouring breast origin. Cancers negative for all four markers (17%) were 60% breast and 40% lung origin. An immunohistochemical panel incorporating ER, TTF-1, GCDFP-15, p63 and WT1 can help to distinguish lung cancer from metastatic breast cancer, including TNBC. © 2015 John Wiley & Sons Ltd.

  4. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

    PubMed

    Chabon, Jacob J; Simmons, Andrew D; Lovejoy, Alexander F; Esfahani, Mohammad S; Newman, Aaron M; Haringsma, Henry J; Kurtz, David M; Stehr, Henning; Scherer, Florian; Karlovich, Chris A; Harding, Thomas C; Durkin, Kathleen A; Otterson, Gregory A; Purcell, W Thomas; Camidge, D Ross; Goldman, Jonathan W; Sequist, Lecia V; Piotrowska, Zofia; Wakelee, Heather A; Neal, Joel W; Alizadeh, Ash A; Diehn, Maximilian

    2016-06-10

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

  5. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

    PubMed Central

    Chabon, Jacob J.; Simmons, Andrew D.; Lovejoy, Alexander F.; Esfahani, Mohammad S.; Newman, Aaron M.; Haringsma, Henry J.; Kurtz, David M.; Stehr, Henning; Scherer, Florian; Karlovich, Chris A.; Harding, Thomas C.; Durkin, Kathleen A.; Otterson, Gregory A.; Purcell, W. Thomas; Camidge, D. Ross; Goldman, Jonathan W.; Sequist, Lecia V.; Piotrowska, Zofia; Wakelee, Heather A.; Neal, Joel W.; Alizadeh, Ash A.; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  6. Investigation of lung tumour induction in C3H/HeH mice, with and without tumour promotion with urethane, following paternal X-irradiation.

    PubMed

    Cattanach, B M; Papworth, D; Patrick, G; Goodhead, D T; Hacker, T; Cobb, L; Whitehill, E

    1998-07-17

    In series of papers Nomura has reported that parental irradiation can lead to an enhanced incidence of lung and other tumours. However, in a recent study with BALB/cJ mice, using optimum conditions as defined by Nomura, we were unable to confirm this. We have now repeated the investigation using a different inbred strain, C3H/HeH, with and without tumour promotion in the F1 by urethane, again using protocols defined by Nomura. In a series of replicate studies spanning over 2 years, males were exposed to single, acute doses of 0, 250 and 500 cGy X-rays and thereafter placed with two females each in each of two consecutive weeks. Half the offspring from each treatment group and each week of mating were given 5 mmol/kg body weight of the urethane, while the remainder remained untreated. Most of the offspring produced were killed and scored for lung tumours at 6 months of age, while the rest were examined at 12 months of age. The proportion of fertile females and litter size provided evidence of a dose-dependent mutational response to the paternal irradiation, but no trace of a radiation-enhanced lung tumour incidence was detected among the progeny, whether in the urethane or non-urethane groups at 6 or 12 months of age, and whether assessed by numbers of mice with tumours, clusters of tumours, or cluster size. As seen in the BALB/cJ study, significant differences among different replicates were found, again suggesting a cyclical or seasonal variation in tumour incidence, but the variations seen with the two strains were not the same. The need for concurrent controls for tumour work was, nevertheless, again indicated. The overall findings do not therefore accord with those of Nomura. Furthermore, they do not support the causal association between the raised incidence of childhood leukaemia and non-Hodgkins lymphoma near Sellafield and the father's recorded radiation exposure during employment in the nuclear industry, as suggested by the Gardner report.

  7. Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

    PubMed

    Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

    2016-09-01

    Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

  8. Cancer cachexia: physical activity and muscle force in tumour-bearing rats.

    PubMed

    Toledo, Míriam; Busquets, Sílvia; Sirisi, Sònia; Serpe, Roberto; Orpí, Marcel; Coutinho, Joana; Martínez, Raquel; López-Soriano, Francisco J; Argilés, Josep M

    2011-01-01

    Rats bearing the Yoshida AH-130 ascites hepatoma are subjected to substantial weight loss, which is accompanied by anorexia at the end of the tumour cycle. Total physical activity (measured using the IR Actimeter system and Actitrack software) was determined during 11 days in control and tumour-bearing animals, skeletal muscle strength being also by the grip-strength test. The results presented clearly show that the presence of the tumour induces an earlier decrease in physical performance, which affects both skeletal muscle force and physical activity (both locomotor movements and stereotyped movements and distance travelled, among others parameters).

  9. Diminution in adenine nucleotide hydrolysis by platelets and serum from rats submitted to Walker 256 tumour.

    PubMed

    Buffon, Andréia; Ribeiro, Vanessa B; Schanoski, Alessandra S; Sarkis, João J F

    2006-01-01

    Extracellular adenine nucleotide hydrolysis in the circulation is mediated by the action of an NTPDase (CD39, apyrase) and of a 5'-nucleotidase (CD73), presenting as a final product, adenosine. Among other properties described for adenine nucleotides, an anti-cancer activity is suggested, since ATP is considered a cytotoxic molecule in several tumour cell systems. Conversely, some studies demonstrate that adenosine presents a tumour-promoting activity. In this study, we evaluated the pattern of adenine nucleotide hydrolysis by serum and platelets from rats submitted to the Walker 256 tumour model. Extracellular adenine nucleotide hydrolysis by blood serum and platelets obtained from rats at, 6, 10 and 15 days after the subcutaneous Walker 256 tumour inoculation, was evaluated. Our results demonstrate a significant reduction in ATP, ADP and AMP hydrolysis in blood serum at 6, 10 and 15 days after tumour induction. In platelets, a significant reduction in ATP and AMP hydrolysis was observed at 10 and 15 days after tumour induction, while an inhibition of ADP hydrolysis was observed at all times studied. Based on these results, it is possible to suggest a physiologic protection mechanism against the tumoral process in circulation. The inhibition in nucleotide hydrolysis observed probably maintains ATP levels elevated (cytotoxic compound) and, at the same time, reduces the adenosine production (tumour-promoting molecule) in the circulation.

  10. Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

    PubMed Central

    Mohan, Sumitra; Chemi, Francesca

    2017-01-01

    Since blood borne circulating tumour cells (CTCs) initially shed from the primary tumour can seed and initiate metastasis at distant sites a better understanding of the biology of CTCs and their dissemination could provide valuable information that could guide therapeutic intervention and real time monitoring of disease progression. Although CTC enumeration has provided a reliable prognostic readout for a number of cancers, including lung cancer, the precise clinical utility of CTCs remains to be established. The rarity of CTCs together with the vanishingly small amounts of nucleic acids present in a single cell as well as cell to cell heterogeneity has stimulated the development of a wide range of powerful cellular and molecular methodologies applied to CTCs. These technical developments are now enabling researchers to focus on understanding the biology of CTCs and their clinical utility as a predictive and pharmacodynamics markers. This review summarises recent advances in the field of CTC research with focus on technical and biological challenges as well the progress made towards clinical utility of characterisation of CTCs with emphasis on studies in lung cancer. PMID:28904889

  11. Increased oxidative stress in the placenta tissue and cell culture of tumour-bearing pregnant rats.

    PubMed

    Toledo, M T; Ventrucci, G; Gomes-Marcondes, M C C

    2011-11-01

    Placental dysfunction leads to foetal damage, which jeopardises the exchange between the maternal and foetal systems. We evaluated the effects of tumour growth on the activity of antioxidant enzymes and oxidative stress in placental tissue and cell culture from tumour-bearing pregnant rats compared to non-tumour-bearing pregnant rats that were ascitic fluid injected. Ascitic fluid is obtained from Walker tumour-bearing rats and contains a cytokine called Walker factor (WF), which is a molecule similar to proteolysis-inducing factor (PIF), and induces changes in protein metabolism and oxidative stress. Pregnant Wistar rats were distributed into control (C), tumour-bearing (W) and ascitic fluid injected (A) groups and were sacrificed on days 16, 19 and 21 of pregnancy to analyse the profile of enzyme activities (glutathione-S-transferase (GST), catalase (CAT), alkaline phosphatase (AP)) and malondialdehyde (MDA) content in placental tissue. Meanwhile, placenta samples from all groups were obtained on day 21, placed in primary culture and treated with WF for 72 h. The presence of tumour or ascitic fluid reduced the protein content of the placental tissue. On day 16 there was a significant reduction in AP activity in W rats, and on day 19, CAT activity and MDA content significantly increased. These results indicate that the presence of cancer decreased antioxidant enzyme capacity in the placenta, increasing the amount of oxidation in these cells, which may contribute to irreversible placental damage and compromisefoetal development. WF treatment induces similar changes in placental cells in primary culture, resulting in less cell viability and increased oxidative stress. These results indicate that WF, provided by the tumour or inoculation of ascitic fluid, has negative effects on placental homeostasis, which impairs foetal health.

  12. Neutron computed tomography of rat lungs.

    PubMed

    Metzke, R W; Runck, H; Stahl, C A; Schillinger, B; Calzada, E; Mühlbauer, M; Schulz, M; Schneider, M; Priebe, H-J; Wall, W A; Guttmann, J

    2011-01-07

    Using conventional methods, three-dimensional imaging of the lung is challenging because of the low contrast between air and tissue and the large differences in dimensions between various pulmonary structures. The small distal airway structures and the high air-to-tissue ratio of lung tissue require an imaging technique which reliably discriminates between air and water. The objective of this study was to assess whether neutron computed tomography would satisfy such a requirement. This method utilizes the unique characteristic of neutrons of directly interacting with the atomic nucleus rather than being scattered by the atomic shell. Neutron computed tomography was tested in rats and allowed differentiation of larger lung structures (e.g., lobes) and distal airways. Airways could be identified reliably down to the sixth bronchial generation, in some cases even down to the tenth generation. The lung could be stabilized for sufficiently long exposure times to achieve an image resolution of 50-60 µm, which is the current physical resolution limit of the neutron computed tomography facility. Neutron computed tomography allowed excellent lung imaging without the need for additional tissue preparation or contrast media. The enhanced structural resolution obtained by applying this new research technique may improve understanding of lung physiology and respiratory therapy.

  13. Radiofrequency ablation suppresses distant tumour growth in a novel rat model of multifocal hepatocellular carcinoma.

    PubMed

    Erös de Bethlenfalva-Hora, Caroline; Mertens, Joachim C; Piguet, Anne-Christine; Kettenbach, Joachim; Schmitt, Johannes; Terracciano, Luigi; Weimann, Rosemarie; Dufour, Jean-François; Geier, Andreas

    2014-02-01

    RFA (radiofrequency ablation) is an established therapy for HCC (hepatocellular carcinoma). The multikinase inhibitor sorafenib prolongs survival in advanced HCC. We examined the effects of RFA alone and in combination with sorafenib on a bystanding tumour in a two-tumour rat model of HCC. A total of 80 rats were implanted with two liver tumours and randomized to four treatment groups: vehicle and sham operation (control), sorafenib and sham operation (Sora/Sham), vehicle and RFA (Vh/RFA), and sorafenib and RFA (Sora/RFA) (n=10/group per time point). RFA or sham-operation was performed on the left lobe tumour on day 15. Animals were killed at day 18 and day 30. Non-RFA-targeted right lobe tumours were analysed for angiogenesis, growth factors [HGF (hepatocyte growth factor), EGF (epidermal growth factor) and VEGF (vascular endothelial growth factor)] and infiltrating immune cells (CD3 and CD68). At day 30, the non-RFA-targeted tumours were significantly smaller in all three treatment groups compared with control (Sora/Sham P≤0.0001, Vh/RFA P=0.005 and Sora/RFA P≤0.0001). The smallest tumours were observed in animals treated with a combination of sorafenib and RFA, whereas the size reduction seen in the RFA-only group indicated an RFA-mediated distant suppression of tumour growth. Growth factor measurement revealed transiently decreased EGF levels after RFA (P=0.008), whereas sorafenib treatment decreased HGF levels (P=0.001). MVD (microvessel density) was reduced by sorafenib (P=0.002) despite increased VEGF levels (P≤0.0001). The immune parameters revealed augmented T-cells and IL-10 (interleukin 10) levels in all three treatment groups; sorafenib additionally increased macrophage numbers (P≤0.0001). RFA and sorafenib alone resulted in significant volume reduction of the non-RFA-targeted tumour; this effect was enhanced when both modalities were combined.

  14. Accuracy of CT parameters for assessment of tumour size and aggressiveness in lung adenocarcinoma with bronchoalveolar elements.

    PubMed

    Bhure, U N; Lardinois, D; Kalff, V; Hany, T F; Soltermann, A; Seifert, B; Steinert, H C

    2010-10-01

    Accurate determination of tumour size in lung adenocarcinoma with bronchoalveolar features (BAC) is important for the determination of TNM (tumour, nodes, metastasis) scores used in staging, prognosis and therapy response assessment. However, tumour sizes derived using lung window (LW) CT or soft-tissue/mediastinal window (MW) CT often give different results. This study examines which measurement correlates best with actual tumour size and which best identifies advanced disease. This retrospective study included 43 BAC patients who underwent surgical resection with mediastinal lymphadenectomy <4 weeks post CT scan. The largest unidimensional tumour diameter on each CT window was compared with actual histopathological tumour size (HP). LW, MW and HP size measurements and a recently described CT parameter - the modified tumour shadow disappearance rate (mTDR) = (1 - [MW/LW]) - were then used to determine which parameter best discriminated between the presence or absence of advanced disease. There was no difference between HP and LW sizes, but MW significantly underestimated HP size (p<0.0001). Unlike MW (p = 0.01) and mTDR (p = 0.001), neither HP (p = 0.14) nor LW (p = 0.10) distinguished between patients with or without advanced disease. On receiver operating characteristic (ROC) analysis at a cut-off of ≤0.13, the sensitivity and specificity of mTDR for detecting advanced disease were 69% and 89%, respectively. In patients with tumours ≤3 cm, only mTDR remained a significant predictor of advanced disease (p = 0.017), with best cut-off at ≤0.20, giving a sensitivity and specificity of 71% and 94%, respectively. MW better predicts advanced disease than LW and might also need to be recorded for RECIST (response evaluation criteria in solid tumours) assessment for T staging of BAC; however, mTDR appears to be an even better predictor and should also be used.

  15. Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk.

    PubMed

    De Luca, Giacomo; Bosello, Silvia L; Berardi, Giorgia; Rucco, Manuela; Canestrari, Giovanni; Correra, Miriam; Mirone, Luisa; Forni, Franca; Di Mario, Clara; Danza, Francesco M; Pirronti, Tommaso; Ferraccioli, Gianfranco

    2015-11-01

    To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P < 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow-up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Immunochemistry of Rat Lung Tumorigenesis

    DTIC Science & Technology

    1983-01-01

    Memorial Institute 1640 (RPMI) tissue culture medium. The extra tissue surrounding the organs is dissected free and discarded; this procedure is done in a...concentration of 0.5 x 106 cells/ml in a total volume of 3 ml/culture using the following medium: Roswell Park Memorial Institute 1640 (RPMI 1640...test tubes containing sterile Roswel] Park Memorial Institute (RPMI) tissue culture medium 1640. Lymphocytes from rat spleens were isolated, counted and

  17. Incidental renal tumours on low-dose CT lung cancer screening exams.

    PubMed

    Pinsky, Paul F; Dunn, Barbara; Gierada, David; Nath, P Hrudaya; Munden, Reginald; Berland, Lincoln; Kramer, Barnett S

    2017-06-01

    Introduction Renal cancer incidence has increased markedly in the United States in recent decades, largely due to incidentally detected tumours from computed tomography imaging. Here, we analyze the potential for low-dose computed tomography lung cancer screening to detect renal cancer. Methods The National Lung Screening Trial randomized subjects to three annual screens with either low-dose computed tomography or chest X-ray. Eligibility criteria included 30 + pack-years, current smoking or quit within 15 years, and age 55-74. Subjects were followed for seven years. Low-dose computed tomography screening forms collected information on lung cancer and non-lung cancer abnormalities, including abnormalities below the diaphragm. A reader study was performed on a sample of National Lung Screening Trial low-dose computed tomography images assessing presence of abnormalities below the diaphragms and abnormalities suspicious for renal cancer. Results There were 26,722 and 26,732 subjects enrolled in the low-dose computed tomography and chest X-ray arms, respectively, and there were 104 and 85 renal cancer cases diagnosed, respectively (relative risk = 1.22, 95% CI: 0.9-1.5). From 75,126 low-dose computed tomography screens, there were 46 renal cancer diagnoses within one year. Abnormalities below the diaphragm rates were 39.1% in screens with renal cancer versus 4.1% in screens without (P < 0.001). Cases with abnormalities below the diaphragms had shorter median time to diagnosis than those without (71 vs. 160 days, P = 0.004). In the reader study, 64% of renal cancer cases versus 13% of non-cases had abnormalities below the diaphragms; 55% of cases and 0.8% of non-cases had a finding suspicious for renal cancer (P < 0.001). Conclusion Low-dose computed tomography screens can potentially detect renal cancers. The benefits to harms tradeoff of incidental detection of renal tumours on low-dose computed tomography is unknown.

  18. Significance of tumour vessel invasion in determining the morphology of isolated tumour cells in the pulmonary vein in non-small-cell lung cancer.

    PubMed

    Funaki, Soichiro; Sawabata, Noriyoshi; Abulaiti, Abulimiti; Nakagiri, Tomoyuki; Shintani, Yasushi; Inoue, Masayoshi; Minami, Masato; Okumura, Meinoshin

    2013-06-01

    The existence of clustered isolated tumour cells (ITCs) in the pulmonary vein (PV) of the lungs of patients with lung cancer has been reported to be a prognostic factor. However, the clinical-pathological characteristics related to their presence in the PV remain unclear. We analysed the surgical results and clinical-pathological findings of 130 patients who underwent surgery for non-small-cell lung cancer in regard to blood vessel invasion (BVI), serum carcinoembryonic antigen (CEA) level, maximum standardized uptake value (SUV-max), size of the solid region in computed tomography findings and pathological stage according to an ITC type, i.e. no tumour (N), singular tumour cells (S) and clustered tumour cells (C). ITCs were detected in 96 (74%) of the patients, with C observed in 43, S in 53 and N in 34. Recurrence was seen in 33 (26%) cases, 21 of which were classified as C, 9 as S and 3 as N. The disease-free survival rate was significantly worse in C cases when compared with the others (P < 0.01). The rate of C was high in cases with high serum CEA, advanced p-staging and positive BVI ratio. Furthermore, BVI positive and ITC morphology were strongly related (BVI positive; 79 in C, 40 in S, 9% in N; P < 0.01). Clustered ITCs were shown to be a prognostic indicator and strongly related to BVI. Our results suggest that determination of BVI has prognostic value, as clustered ITCs with metastatic potential are disseminated from the invaded vein.

  19. Automated lung segmentation of low resolution CT scans of rats

    NASA Astrophysics Data System (ADS)

    Rizzo, Benjamin M.; Haworth, Steven T.; Clough, Anne V.

    2014-03-01

    Dual modality micro-CT and SPECT imaging can play an important role in preclinical studies designed to investigate mechanisms, progression, and therapies for acute lung injury in rats. SPECT imaging involves examining the uptake of radiopharmaceuticals within the lung, with the hypothesis that uptake is sensitive to the health or disease status of the lung tissue. Methods of quantifying lung uptake and comparison of right and left lung uptake generally begin with identifying and segmenting the lung region within the 3D reconstructed SPECT volume. However, identification of the lung boundaries and the fissure between the left and right lung is not always possible from the SPECT images directly since the radiopharmaceutical may be taken up by other surrounding tissues. Thus, our SPECT protocol begins with a fast CT scan, the lung boundaries are identified from the CT volume, and the CT region is coregistered with the SPECT volume to obtain the SPECT lung region. Segmenting rat lungs within the CT volume is particularly challenging due to the relatively low resolution of the images and the rat's unique anatomy. Thus, we have developed an automated segmentation algorithm for low resolution micro-CT scans that utilizes depth maps to detect fissures on the surface of the lung volume. The fissure's surface location is in turn used to interpolate the fissure throughout the lung volume. Results indicate that the segmentation method results in left and right lung regions consistent with rat lung anatomy.

  20. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability.

    PubMed

    Lindblom, Emely; Antonovic, Laura; Dasu, Alexandru; Lax, Ingmar; Wersäll, Peter; Toma-Dasu, Iuliana

    2014-06-30

    Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation.

  1. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

    PubMed Central

    2014-01-01

    Background Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. Methods A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. Results For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Conclusions Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation. PMID:24974778

  2. Carbogen-induced changes in rat mammary tumour oxygenation reported by near infrared spectroscopy

    PubMed Central

    Hull, E L; Conover, D L; Foster, T H

    1999-01-01

    We have evaluated the ability of steady-state, radially-resolved, broad-band near infrared diffuse reflectance spectroscopy to measure carbogen-induced changes in haemoglobin oxygen saturation (SO2) and total haemoglobin concentration in a rat R3230 mammary adenocarcinoma model in vivo. Detectable shifts toward higher saturations were evident in all tumours (n = 16) immediately after the onset of carbogen breathing. The SO2 reached a new equilibrium within 1 min and remained approximately constant during 200–300 s of administration. The return to baseline saturation was more gradual when carbogen delivery was stopped. The degree to which carbogen increased SO2 was variable among tumours, with a tendency for tumours with lower initial SO2 to exhibit larger changes. Tumour haemoglobin concentrations at the time of peak enhancement were also variable. In the majority of cases, haemoglobin concentration decreased in response to carbogen, indicating that increased tumour blood volume was not responsible for the observed elevation in SO2. We observed no apparent relationship between the extent of the change in tumour haemoglobin concentration and the magnitude of the change in the saturation. Near infrared diffuse reflectance spectroscopy provides a rapid, non-invasive means of monitoring spatially averaged changes in tumour haemoglobin oxygen saturation induced by oxygen modifiers. © 1999 Cancer Research Campaign PMID:10206281

  3. Tumour necrosis factor-α expression and cell recruitment in Sephadex particle-induced lung inflammation: effects of dexamethasone and cyclosporin A

    PubMed Central

    Williams, Cara M M; Smith, Lance; Flanagan, Brian F; Steve Clegg, L; Coleman, John W

    1997-01-01

    Tumour necrosis factor-α (TNF-α) is a cytokine with diverse properties consistent with a possible role in inflammatory disease. We investigated whether TNF-α is induced during the progression of lung inflammation elicited by a particulate non-antigenic stimulus, and whether pharmacological control of TNF-α expression influences recruitment of specific inflammatory cell types. A single intravenous injection of Sephadex particles into rats led to extensive granulomatous inflammation in lung alveolar and bronchial tissue that peaked in intensity after 24–72 h. Mononuclear cells were the principal component of granulomas, but neutrophils and eosinophils were also abundant. Numbers of mononuclear cells, neutrophils and eosinophils recovered by bronchoalveolar lavage (BAL) peaked at 72 h, 48 h and 72 h, respectively. Messenger RNA encoding TNF-α was induced in lung epithelial cells, lung granulomas and BAL cells 6 h after Sephadex administration and remained elevated for 72 h before declining to baseline by 7 days. In BAL cell populations TNF-α protein was localized to mononuclear cells at all times points pre- and post-Sephadex administration. Treatment of rats with dexamethasone significantly reduced the Sephadex-induced recruitment of mononuclear cells, neutrophils and eosinophils into the bronchoalveolar cavity, and significantly reduced TNF-α mRNA expression by BAL cells. Treatment of rats with cyclosporin A was without effect on Sephadex-induced elevations of mononuclear cell numbers and expression of TNF-α, but did reduce significantly recruitment of neutrophils and eosinophils to BAL cell populations. These results show that a sequential asthma-like recruitment of neutrophils, eosinophils and mononuclear cells into lung tissue can be induced by single exposure to a non-antigenic stimulus. Pharmacological and histological studies reveal that mononuclear cell mobilization relates closely to induced TNF-α expression, whereas mobilization of

  4. Tumour induction in rats following exposure to short-term high dose aristolochic acid I.

    PubMed

    Cui, Min; Liu, Zhi-Hong; Qiu, Qi; Li, Heng; Li, Lei-Shi

    2005-01-01

    The purpose of this study was to assess the carcinogenic activity of aristolochic acid I (AAI) in short-term high doses. Forty-four female Sprague-Dawley rats were randomly assigned to two groups. A dose of 50 mg/kg/day AAI was administrated to rats in the experimental group by gavage consecutively for 3 days, while the control group received only distilled water, after which renal function and pathological changes were assessed. At day 8 post-treatment AAI had induced elevations of both plasma urea and creatinine, coupled with increased urine production, urinary proteins, glucose and N-acetyl-beta-glucosaminidase. At 1, 3 and 6 months post-treatment renal function and urinary parameters for the experimental group approached baseline values. However, tumours and preneoplastic proliferation were both observed at 6 months for the experimental group. The rate of occurrence of preneoplastic proliferation in the kidneys was 100% (14/14); the rate of occurrence of renal tumours was 28.6% (4/14), which included three mesenchymal tumours and one case of renal oncocytoma; the rate of occurrence of extrarenal tumours was 7.1% (1/14), which was a case of mammary duct carcinoma. Renal preneoplastic proliferation and renal tumours, as well as extrarenal tumours, were not observed in control rats during the 6 months. These results differ from previous reports in that tumours originating from both epithelial and mesenchymal tissues were found, which may be attributed to the duration of treatment and the dosage of the drug. These data indicate that AAI administered in an acute manner at high doses does in fact have carcinogenic properties.

  5. Cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography in tumours other than lung cancer: A systematic review

    PubMed Central

    Annunziata, Salvatore; Caldarella, Carmelo; Treglia, Giorgio

    2014-01-01

    AIM: To systematically review published data on the cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT) in tumours other than lung cancer. METHODS: A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through the 10th of October in 2013 was carried out. A search algorithm based on a combination of the terms: (1) “PET” or “ PET/computed tomography (PET/CT)” or “positron emission tomography”; and (2) “cost-effectiveness” or “cost-utility” or “cost-efficacy” or “technology assessment” or “health technology assessment” was used. Only cost-effectiveness or cost-utility analyses in English language were included. Exclusion criteria were: (1) articles not within the field of interest of this review; (2) review articles, editorials or letters, conference proceedings; and (3) outcome evaluation studies, cost studies or health technology assessment reports. For each included study, information was collected concerning basic study, type of tumours evaluated, perspective/type of study, results, unit and comparison alternatives. RESULTS: Sixteen studies were included. Head and neck tumours were evaluated in 4 articles, lymphoma in 4, colon-rectum tumours in 3 and breast tumours in 2. Only one article was retrieved for melanoma, oesophagus and ovary tumours. Cost-effectiveness results of FDG-PET or PET/CT ranged from dominated to dominant. CONCLUSION: Literature evidence about the cost-effectiveness of FDG-PET or PET/CT in tumours other than lung cancer is still limited. Nevertheless, FDG-PET or PET/CT seems to be cost-effective in selective indications in oncology (staging and restaging of head and neck tumours, staging and treatment evaluation in lymphoma). PMID:24765240

  6. Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk.

    PubMed Central

    Mauderly, J L

    1997-01-01

    Rats and other rodents are exposed by inhalation to identify agents that might present hazards for lung cancer in humans exposed by inhalation. In some cases, the results are used in attempts to develop quantitative estimates of human lung cancer risk. This report reviews evidence for the usefulness of the rat for evaluation of lung cancer hazards from inhaled particles. With the exception of nickel sulfate, particulate agents thought to be human lung carcinogens cause lung tumors in rats exposed by inhalation. The rat is more sensitive to carcinogenesis from nonfibrous particles than mice or Syrian hamsters, which have both produced false negatives. However, rats differ from mice and nonhuman primates in both the pattern of particle retention in the lung and alveolar epithelial hyperplastic responses to chronic particle exposure. Present evidence warrants caution in extrapolation from the lung tumor response of rats to inhaled particles to human lung cancer hazard, and there is considerable uncertainty in estimating unit risks for humans from rat data. It seems appropriate to continue using rats in inhalation carcinogenesis assays of inhaled particles, but the upper limit of exposure concentrations must be set carefully to avoid false-positive results. A positive finding in both rats and mice would give greater confidence that an agent presents a carcinogenic hazard to man, and both rats and mice should be used if the agent is a gas or vapor. There is little justification for including Syrian hamsters in assays of the intrapulmonary carcinogenicity of inhaled agents. PMID:9400748

  7. Radioisotope scanning of brain, liver, lung and bone with a note on tumour localizing agents

    PubMed Central

    Lavender, J. P.

    1973-01-01

    Radioisotopic scanning of brain, liver, lungs and the skeleton is briefly reviewed with a survey of recent developments of clinical significance. In brain scanning neoplasm detection rates of greater than 90% are claimed. The true figure is probably 70-80%. Autopsy data shows a number of false negatives, particularly with vascular lesions. Attempts to make scanning more specific in differentiating neoplasm from vascular lesions by rapid sequence blood flow studies are reviewed. In liver scanning by means of colloids again high success rate is claimed but small metastases are frequently missed and the false negative scan rate is probably quite high. Lung scanning still has its main place in investigating pulmonary embolic disease. Ventilation studies using Xenon 133 are useful, particularly combined with perfusion studies. The various radiopharmaceuticals for use in bone scanning are reviewed. The appearance of technetium labelled phosphate compounds will probably allow much wider use of total skeletal scanning. Research into tumour localizing agents continues, the most recent and interesting being Gallium citrate and labelled bleomycin. Neither agent is predictable however although Gallium may have a place in Hodgkins disease and bronchogenic neoplasm and both may have a place in the detection of cerebral tumours. ImagesFig. 1Fig. 2Fig. 3p452-bFig. 3bFig. 4Fig. 5Fig. 5bFig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 12c & 12dFig. 13Fig. 13 b,c,dFig. 14Fig. 14bFig. 15Fig. 15bFig. 16Fig. 17Fig. 18 PMID:4602127

  8. Inertia based microfluidic capture and characterisation of circulating tumour cells for the diagnosis of lung cancer

    PubMed Central

    Chudasama, Dimple Y.; Freydina, Daria V.; Freidin, Maxim B.; Leung, Maria; Montero Fernandez, Angeles; Rice, Alexandra; Nicholson, Andrew G.; Karteris, Emmanouil; Anikin, Vladimir

    2016-01-01

    Background Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery. Methods Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX systemTM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens. Results Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41–76%) and 41% (95% CI, 24–59%), with a specificity of 53% for both. Conclusions The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer. PMID:28149842

  9. Dendritic cell-based immunotherapy induces transient clinical response in advanced rat fibrosarcoma - comparison with preventive anti-tumour vaccination.

    PubMed

    Kucera, A; Pýcha, K; Pajer, P; Spísek, R; Skába, R

    2009-01-01

    In this study we present the models of preventive and therapeutic vaccination of sarcoma-bearing rats with dendritic cells that present tumour antigens from killed tumour cells. We present the characteristics of dendritic cell-based vaccine and its capacity to induce anti-tumour immune response both in vitro and in vivo. We show that preventive vaccination efficiently prevents tumour growth. On the other hand, vaccination of rats with established tumours did not lead to eradication of the tumours. Despite the induction of a vigorous immune response after administration of dendritic cell-based vaccine and transient decrease in tumour progression, tumours eventually resumed their growth and animals vaccinated with dendritic cells succumbed to cancer. In both settings, preventive and therapeutic, dendritic cell-based vaccination induced a vigorous tumour-specific T-cell response. These results argue for the timing of cancer immunotherapy to the stages of low tumour load. Immunotherapy initiated at the stage of minimal residual disease, after reduction of tumour load by other modalities, will have much better chance to offer a clinical benefit to cancer patients than the immunotherapy at the stage of metastatic disease.

  10. Multiplicative effect of inhaled plutonium oxide and benzo (a) pyrene on lung carcinogenesis in rats.

    PubMed Central

    Métivier, H.; Wahrendorf, J.; Masse, R.

    1984-01-01

    This study describes the effect of intratracheal instillations (2 X 5 mg) of benzo(a)pyrene (B(a)P) on lung carcinogenesis in rats which had previously inhaled different levels of 239 plutonium oxide (220, 630, 6300 Bq, initial lung burden). Survival decreased with increasing PuO2 exposure and additional B(a)P exposure. The incidence of malignant lung tumours, adjusted for differences in survival, increased in a dose-related fashion with PuO2 dose and was elevated in the presence of additional B(a)P exposure. A multiplicative relative risk model was found to describe reasonably well the observed joint effect. The practical implications of these findings are discussed. PMID:6087866

  11. Suppressed rate of carcinogenesis and decreases in tumour volume and lung metastasis in CXCL14/BRAK transgenic mice.

    PubMed

    Hata, Ryu-Ichiro; Izukuri, Kazuhito; Kato, Yasumasa; Sasaki, Soichiro; Mukaida, Naofumi; Maehata, Yojiro; Miyamoto, Chihiro; Akasaka, Tetsu; Yang, Xiaoyan; Nagashima, Yoji; Takeda, Kazuyoshi; Kiyono, Tohru; Taniguchi, Masaru

    2015-03-13

    Cancer progression involves carcinogenesis, an increase in tumour size, and metastasis. Here, we investigated the effect of overexpressed CXC chemokine ligand 14 (CXCL14) on these processes by using CXCL14/BRAK (CXCL14) transgenic (Tg) mice. The rate of AOM/DSS-induced colorectal carcinogenesis in these mice was significantly lower compared with that for isogenic wild type C57BL/6 (Wt) mice. When tumour cells were injected into these mice, the size of the tumours that developed and the number of metastatic nodules in the lungs of the animals were always significantly lower in the Tg mice than in the Wt ones. Injection of anti-asialo-GM1 antibodies to the mice before and after injection of tumour cells attenuated the suppressing effects of CXCL14 on the tumor growth and metastasis, suggesting that NK cell activity played an important role during CXCL14-mediated suppression of tumour growth and metastasis. The importance of NK cells on the metastasis was also supported when CXCL14 was expressed in B16 melanoma cells. Further, the survival rates after tumour cell injection were significantly increased for the Tg mice. As these Tg mice showed no obvious abnormality, we propose that CXCL14 to be a promising molecular target for cancer suppression/prevention.

  12. Inactivation of surfactant in rat lungs.

    PubMed

    Bruni, R; Fan, B R; David-Cu, R; Taeusch, H W; Walther, F J

    1996-02-01

    Although surfactant replacement therapy has dramatically improved the outcome of premature infants with respiratory distress syndrome, approximately 30% of treated infants show a transient or no response. Nonresponse to surfactant replacement therapy may be due to extreme lung immaturity and possibly surfactant inactivation. Surfactant inactivation involves aspecific biophysical events, such as interference with the formation or activity of an alveolar monolayer, and specific interactions with serum proteins, including antibodies, leaking into the alveolar space. As formulations containing surfactant proteins appear to better tolerate serum inactivation, we used an excised rat lung model to compare the susceptibility to serum inactivation of a mixture of synthetic phospholipids selected from surfactant lipid constituents, Exosurf (a protein-free synthetic surfactant), Survanta [containing surfactant proteins B and C (SP-B and -C)], and a porcine surfactant (containing SP-A, -B, and -C). For each of these preparations, we used pressure/volume determinations as an in situ measure of surfactant activity and retested the same preparations after mixing with human serum, a nonspecific surfactant inactivator. Human serum inactivated porcine surfactant to a lesser extent than Survanta, Exosurf, or synthetic phospholipids. Temperature exerted a significant effect on deflation stability, as shown by a greater lung compliance in untreated, normal lungs and a larger improvement in compliance after treating lavaged lungs with synthetic phospholipids at 37 degrees C than at 22 degrees C. We conclude that surfactant containing SP-A, -B, and -C is only moderately susceptible to inactivation with whole serum and may therefore exert a greater clinical response than protein-free surfactants or those containing only SP-B and -C.

  13. Improving accuracy of markerless tracking of lung tumours in fluoroscopic video by incorporating diaphragm motion

    NASA Astrophysics Data System (ADS)

    Schwarz, M.; Teske, H.; Stoll, M.; Bendl, Rolf

    2014-03-01

    Purpose: Conformal radiation of moving tumours is a challenging task in radiotherapy. Tumour motion induced by respiration can be visualized in fluoroscopic images recorded during patients breathing. Markerless methods making use of registration techniques can be used to estimate tumour motion. However, registration methods might fail when the tumour is hidden by ribs. Using motion of anatomical surrogates, like the diaphragm, is promising to model tumour motion. Methods: A sequence of 116 fluoroscopic images was analyzed and the tumour positions were manually defined by three experts. A block matching (BM) technique is used to calculate the displacement vector relatively to a selected reference image of the first breathing cycle. An enhanced method was developed: Positions, when the tumour is not located behind a rib, are taken as valid estimations of the tumour position. Furthermore, these valid estimations are used to establish a linear model of tumour position and diaphragm motion. For invalid estimations the calculated tumour positions are not taken into consideration, and instead the model is used to determine tumour motion. Results: Enhancing BM with a model of tumour motion from diaphragm motion improves the tracking accuracy when the tumour moves behind a rib. The error (mean ± SD) in longitudinal dimension was 2.0 ± 1.5mm using only BM and 1.0 ± 1.1mm when the enhanced approach was used. Conclusion: The enhanced tracking technique is capable to improve tracking accuracy compared to BM in the case that the tumour is occluded by ribs.

  14. Monoclonal antibody Po66 uptake by human lung tumours implanted in nude mice: effect of co-administration with doxorubicin.

    PubMed Central

    Desrues, B.; Léna, H.; Brichory, F.; Ramée, M. P.; Toujas, L.; Delaval, P.; Dazord, L.

    1995-01-01

    The efficacy of radioimmunotherapy of tumours with radiolabelled monoclonal antibodies (MAbs) depends on the amount of antibody taken up by the tumour and on its intratumoral distribution. In the case of MAbs directed against intracellular antigens, increasing the permeability of the cytoplasmic membrane may augment the bioavailability of the antigen for the antibody. This raises the question whether the induction of tumour necrosis by chemotherapy can enhance the tumour uptake of radiolabelled monoclonal antibodies. In this work, the effect of doxorubicin on the biodistribution of Po66, an MAb directed against an intracellular antigen, was studied in nude mice grafted with the human non-small-cell lung carcinoma cell line SK-MES-1. After injection on day 0 of 125I-labelled Po66, tumour radioactivity increased up to days 3-5, and then remained unchanged to day 14. The combined administration of 125I-labelled Po66 with 8 mg kg-1 doxorubicin, in two doses separated by 7 days, doubled the radioactivity retained by the tumour. Histological and historadiographic analysis showed, however, that the drug induced cellular damage. In the absence of doxorubicin, the accumulation of Po66 was restricted to some necrotic areas, whereas with doxorubicin the necrosis was more extensive and the antibody more evenly distributed. These results suggest that chemotherapy and immunoradiotherapy combined would enhance tumour uptake of radioisotope and promote more homogenous distribution of the radiolabelled MAb. This would promote eradication of the remaining drug-resistant cells in tumours. Images Figure 2 Figure 5 PMID:7577450

  15. [Carcinoid tumours of the lung and definition of the medico-legal term "lung cancer" used in the list of occupational disease in Germany--results of the German Mesothelioma Register].

    PubMed

    Neumann, V; Fischer, M; Tannapfel, A

    2008-09-01

    Carcinoid tumours are considered to be malignant epithelial tumours according to the recent WHO classification. This study is based on the examinations of tissue from 108 patients with carcinoid tumours. Our data agree with those of other studies: carcinoid tumours developed mainly in the right lung (40 %) and the lower lobe (30 %), mean age was 56 years, typical carcinoid tumours (74 %) predominated, comparatively high proportion of females (32 %), the mean latency period after asbestos exposure - assuming asbestos as one causal factor - was 35 years. A higher incidence of carcinoid tumours (1.3 %) in the collective of the mesothelioma register compared to the incidence in the collective of all lung carcinomas (1 - 2 %) was not observed. The increased pulmonary asbestos burden analysed in 26 % of patients is explained by the exposure-dependent selection of patients in the register. So far, no association between smoking habits or exposure to other, i. e., occupational pollutions and the development of carcinoid tumours could be established. In the list of occupational diseases (No. 4104) the term "lung cancer" is used without further specification. Thus the following question remains open for discussion: does the term "lung cancer" include carcinoid tumours such as malignant epithelial lung tumours, or is it restricted to the common subtypes such as small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma with regard to occupational disease and compensation?

  16. Tumour growth results in changes in placental amino acid transport in the rat: a tumour necrosis factor alpha-mediated effect.

    PubMed Central

    Carbó, N; López-Soriano, F J; Fiers, W; Argilés, J M

    1996-01-01

    The implantation of a fast growing tumour (Yoshida AH-130 ascites hepatoma) to late pregnant rats resulted in no changes in fetal growth, this possibly being associated with an important increase in the fetal uptake of maternal-derived amino acids [Carbó, López-Soriano and Argilés (1995) Endocrinology 136, 3579-3584]. The present investigation was undertaken to see whether the presence of the tumour induced changes in placental transport systems. For alanine transport, although no changes in affinity (Km) were observed, tumour growth resulted in a 192% increase in Vmax in the Na(+)-independent component. Kinetic analysis of the Na(+)-dependent component resulted in two clearly different components: while the low-affinity and high-capacity component was unaffected by tumour growth, the high-affinity, low-capacity component of the tumour-bearing rats showed an important increase in Vmax. (78%). With regard to leucine transport, tumour burden induced important increases in the Na(+)-independent component, not only in Km (262%) but also in Vmax. (189%). Since elevated tumour necrosis factor-alpha (TNF) concentrations have been reported in this kind of tumour model, we performed the same type of transport experiments in rats chronically treated with TNF, the results obtained showing great similarities with those observed with tumour growth. The Vmax. of Na(+)-independent alanine transport was also increased by the cytokine (104%) while no changes were observed in affinity. TNF treatment also induced an increase in the Vmax. (67%) of the Na(+)-dependent (high-affinity, low-capacity) component while no changes in affinity were observed. Concerning leucine kinetics, TNF treatment, as in the case of tumour growth, also increased Km (155%) and Vmax. (72%) associated with Na(+)-independent transport. Interestingly, treatment with the cytokine increased both the Km (43%) and Vmax. (64%) of the Na(+)-dependent component. The inhibition patterns suggest the existence of more

  17. Growth studies of subcutaneous rat tumours: comparison of 31P-NMR spectroscopy, acid extracts and histology.

    PubMed

    Stubbs, M; Rodrigues, L M; Griffiths, J R

    1989-11-01

    31P-NMP, surface coil spectra of three subcutaneously implanted rat tumours (Morris hepatoma 7777, GH3 prolactinoma, Walker carcinosarcoma) and an N-methyl-N-nitrosourea induced rat mammary adenocarcinoma at different stages of growth were obtained and compared with histological sections taken immediately after NMR acquisitions. Metabolite ratios (phosphocreatine (PCr)/beta nucleoside triphosphate (beta NTP), PCr/Pi, beta NTP/Pi) calculated from the NMR spectra were compared with ratios obtained from acid extracts of tumours of similar size. Measurements of creatine and ADP were also made. Three of the tumours showed positive correlations between increasing tumour size and decreasing metabolite ratios measured both by NMR and in extracts, whereas the Walker carcinosarcoma showed no correlation between size and any parameters measured. Phosphorus metabolite ratios, measured in extracts of skin overlying the tumours, indicated a fall in high energy phosphate when there was histological evidence of skin invasion by the tumour. Surface coil 31P-NMR spectra of subcutaneously grown or induced tumours in the rat represent a slowly changing steady state as the tumour increases in size. We conclude that increasing numbers of hypoxic tumour cells, rather than large areas of necrotic tissue, contribute largely to the NMR spectrum.

  18. Mathematical modelling of tumour volume dynamics in response to stereotactic ablative radiotherapy for non-small cell lung cancer

    NASA Astrophysics Data System (ADS)

    Tariq, Imran; Humbert-Vidan, Laia; Chen, Tao; South, Christopher P.; Ezhil, Veni; Kirkby, Norman F.; Jena, Rajesh; Nisbet, Andrew

    2015-05-01

    This paper reports a modelling study of tumour volume dynamics in response to stereotactic ablative radiotherapy (SABR). The main objective was to develop a model that is adequate to describe tumour volume change measured during SABR, and at the same time is not excessively complex as lacking support from clinical data. To this end, various modelling options were explored, and a rigorous statistical method, the Akaike information criterion, was used to help determine a trade-off between model accuracy and complexity. The models were calibrated to the data from 11 non-small cell lung cancer patients treated with SABR. The results showed that it is feasible to model the tumour volume dynamics during SABR, opening up the potential for using such models in a clinical environment in the future.

  19. Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats.

    PubMed

    Lira, F S; Tavares, F L; Yamashita, A S; Koyama, C H; Alves, M J; Caperuto, E C; Batista, M L; Seelaender, M

    2008-08-01

    The syndrome of cancer cachexia is accompanied by several alterations in lipid metabolism, and the liver is markedly affected. Previous studies showed that moderate exercise training may prevent liver fat accumulation through diminished delivery of lipids to the liver, increased hepatic oxidation and increased incorporation of triacylglycerol (TAG) into very low density lipoprotein (VLDL). Our aim was to examine the influence of moderate intensity training (8 weeks) upon TAG content, VLDL assembly and secretion, apolipoprotein B (apoB) and microsomal transfer protein (MTP) gene expression in the liver of cachectic tumour-bearing rats. Animals were randomly assigned to a sedentary control (SC), sedentary tumour-bearing (ST) or exercise-trained control (EC) or to an exercise trained tumour-bearing (ET) group. Trained rats ran on a treadmill (60% VO(2max)) for 60 min day(-1), 5 day week(-1), for 8 weeks. TAG content and the rate of VLDL secretion (followed for 3 h), as well as mRNA expression of apoB and MTP, and total cholesterol, VLDL-TAG, VLDL-cholesterol, high density lipoprotein cholesterol (HDL-cholesterol) and tumour weight were evaluated. VLDL-cholesterol showed a decrease in ST (p < 0.05) in relation to SC. Serum TAG, VLDL-TAG and tissue TAG content were all increased in ST (p < 0.01), when compared with SC. ST showed a lower rate of VLDL secretion (p < 0.05) and reduced expression of apoB (p < 0.001) and MTP (p < 0.001), when compared with SC. These parameters were restored to control values (p < 0.05) when the animals were submitted to the exercise training protocol. Tumour weight decreased 10-fold after training (p < 0.001). It is possible to affirm, therefore, that endurance training promoted the re-establishment of lipid metabolism in cachectic tumour-bearing animals, especially in relation to VLDL secretion and assembly.

  20. Effect of β-carotene on immunity function and tumour growth in hepatocellular carcinoma rats.

    PubMed

    Cui, Bokang; Liu, Su; Wang, Qibo; Lin, Xiaojun

    2012-07-18

    The aim of the present study was to investigate the anticancer and immunity activity of β-carotene in hepatocellular carcinoma (HCC) rats. Three days after transplantation, forty Wistar rats were randomly divided into four groups, each group consisting of 10 animals. These groups were control group (untreated), low-dose β-carotene-treated group (20 mg/kg), middle-dose group (40 mg/kg) and high-dose (60 mg/kg) group. β-Carotene-treated groups were fed with β-carotene (20, 40, 60 mg/kg b.w.) orally for 30 days. Control group was treated with the same volume of physiological saline. Another ten rats were served as the normal group. Results showed that 30 days of β-carotene treatment could significantly inhibit tumour growth, enhance blood NK, IL-2, TNF-α, WBC, TP, ALB and A/G levels, and decrease blood ALT, AST and ALP activities in HCC rats. Pathological analysis of liver tissue showed that β-carotene treatment may decrease damage of liver tissue in HCC rats. It can be concluded that β-carotene may improve the immunity function and inhibit tumour growth in HCC rats.

  1. NCAPG2 promotes tumour proliferation by regulating G2/M phase and associates with poor prognosis in lung adenocarcinoma.

    PubMed

    Zhan, Ping; Xi, Guang-Min; Zhang, Bin; Wu, Ying; Liu, Hong-Bing; Liu, Ya-Fang; Xu, Wu-Jian; Zhu, Qingqing; Cai, Feng; Zhou, Ze-Jun; Miu, Ying-Ying; Wang, Xiao-Xia; Jin, Jia-Jia; Li, Qian; Lv, Tang-Feng; Song, Yong

    2017-04-01

    NCAPG2 is a component of the condensin II complex and contributes to chromosome segregation via microtubule-kinetochore attachment during mitosis. It is well known that NCAPG2 plays a critical role in cell mitosis; however, the role of altered NCAPG2 expression and its transcriptional regulatory function in cancer development remains mostly unknown. Here, for the first time we reported that NCAPG2 was evidently increased in non-small cell lung cancer tissues compared to adjacent normal lung tissues. Clinicopathological data analysis showed that NCAPG2 overexpression was significantly correlated with lymph node metastasis and pathologic-Tumour Nodes Metastasen stages, and was an independent prognostic factor in lung adenocarcinoma patients. Moreover, siRNA-mediated knockdown of NCAPG2 could inhibit tumour cell growth of lung adenocarcinoma cells (A549 and H1299) in vitro and could significantly lead to cell cycle arrest in the G2 phase. Furthermore, we found that NCAPG2 silencing significantly decreased the expression levels of G2/M phase cell cycle-related protein expressions (Cyclin B1, Cdc2) and increased the expression levels of p27 and p21 through Western blot analysis. Taken together, we demonstrated that increased NCAPG2 expression could regulate cell proliferation and identified as a poor prognostic biomarker in lung adenocarcinoma.

  2. A calcified lung tumour and microcytic anaemia in a young woman: partial expression of the Carney triad.

    PubMed

    Alberto, V O; Kelleher, D; Denholm, R B; Nutt, M; Carney, J A

    2008-08-01

    The Carney triad is the non-familial addociation of gastric stromal tumours (GISTs), pulmonar chondromas and extra-adrenal paragangliomas. Fewer than 100 cases of the disorder have been reported since its description in 1977. The condition has a predeliction for young women. Most patients exhibit only two of the three components. The tumours tend to be multifocal in the affected organ or system. Herein, we describe the case of a 27-year-old woman with multiple gastric GISTs and a pulmonary chondroma, partial expression of the Carney triad. It is important to be aware of the Carney triad when one of its constituent tumours is found, particularly if the patient is a young woman, so that a search can be made for and surveillance instituted for the other components. Treatment for the gastric tumours (sarcomas) and the paragangliomas (potentially malignant) is surgical. The lung chondromas are benign neoplasms and ordinarily not symptomatic. If a diagnosis of the tumour can be established by biopsy, surgical resection may not be necessary.

  3. Identification of Factors for the Preoperative Prediction of Tumour Subtype and Prognosis in Patients with T1 Lung Adenocarcinoma

    PubMed Central

    Zhang, Yong-Kui; Chai, Zhen-da; Hu, Xiao-fei; Tan, Lin-lin; Wang, Zhao-yu; Chen, Zhi-jun

    2016-01-01

    Aims. Identification of factors that can predict the subtypes of lung adenocarcinoma preoperatively is important for selecting the appropriate surgical procedure and for predicting postoperative survival. Methods. We retrospectively evaluated 87 patients with lung adenocarcinomas ≤30 mm. Results. Preoperative radiological findings, serum CEA level, serum microRNA-183 (miR-183) level, and tumour size differed significantly between patients with adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) and those with invasive adenocarcinoma (IAC). Receiver operating characteristic curves and univariate analysis revealed that patients who were older than 57 years or had a pure solid nodule or a tumour with mixed ground-glass opacity (mGGO), a tumour >11 mm, a serum CEA level >2.12 ng/mL, or a serum miR-183 level >1.233 (2−ΔΔCt) were more likely to be diagnosed with IAC than with AIS or MIA. The combination of all five factors had an area under the curve of 0.946, with a sensitivity of 89.13% and a specificity of 95.12%. Moreover, patients with a cut-off value >0.499 for the five-factor combination had poor overall survival. Conclusions. The five-factor combination enables clinicians to distinguish AIS or MIA from IAC, thereby aiding in selecting the appropriate treatment, and to predict the prognosis of lung adenocarcinoma patients. PMID:28115792

  4. A non-surgical method for induction of lung cancer in Wistar rats using a combination of NNK and high dietary fats.

    PubMed

    Bhatnagar, Shilpa; Chaudhary, Naveen; Katare, Deepshikha Pande; Jain, S K

    2013-08-01

    Lung cancer is one of the most common malignant neoplasms all over the world. Smoking and a number of constituents of tobacco are responsible for development of lung tumours; however, the deleterious effects of tobacco-derived carcinogen, nitrosamine 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone (NNK)) remain unmatched. We report the development of a novel rodent model by administering multiple doses of NNK to male Wistar rats and feeding them with high-fat and low-protein diet. Tumour cells in lungs were observed in approximately 98 % rats after 8 months of NNK treatment, as evident by histopathological analysis. This rodent model showed slow progression of lung tumours which has helped us to assess early indicators of oxidative damage in lungs by studying the levels of lipid peroxidation and antioxidant parameters. LPO was elevated by 46.94 %, SOD, CAT, GSH and GR activity was decreased by 48.67 %, 22.04 %, 21.46 % and 20.85 %, respectively in serum of NNK treated rats when compared with control. These findings suggest that increased oxidative stress can represent a risk factor for the development of chronic disease in early future. This new animal model is an attempt to greatly facilitate studies of the pathophysiology, biochemistry and therapy of lung cancer.

  5. Utility of PAX8 mouse monoclonal antibody in the diagnosis of thyroid, thymic, pleural and lung tumours: a comparison with polyclonal PAX8 antibody.

    PubMed

    Toriyama, Akane; Mori, Taisuke; Sekine, Shigeki; Yoshida, Akihiko; Hino, Okio; Tsuta, Koji

    2014-10-01

    The purpose of this study was to compare the immunohistochemical staining profiles of PAX8-polyclonal, PAX8-monoclonal, PAX5-monoclonal and PAX6-monoclonal antibodies in several histological types of primary thoracic and thyroid tumours. In addition, we analysed PAX8 mRNA expression by using in-situ hybridization. We compared polyclonal PAX8 and monoclonal PAX8, PAX5 and PAX6 antibodies in 962 samples (687 lung carcinomas, 40 malignant pleural mesotheliomas, 138 thymic tumours and 97 thyroid tumours) using the tissue microarray technique. Among thyroid tumours, the monoclonal and polyclonal PAX8 antibodies showed a high positive rate (98.0%). Of 167 polyclonal PAX8 antibody-positive tumours, except for thyroid tumours, 54 cases tested positive for PAX5 and/or PAX6 (31 lung carcinomas and 23 thymic tumours). No PAX8 mRNA expression was detected using RNAscope (in-situ hybridization technique) other than in thyroid tumours. A portion of polyclonal PAX8 antibody-positive tumours showed cross-reactivity for PAX5 or PAX6 protein. Monoclonal PAX8 antibody showed high specificity to thyroid tumours and was superior to the polyclonal antibody. © 2014 John Wiley & Sons Ltd.

  6. Reproductive senescence, fertility and reproductive tumour profile in ageing female Han Wistar rats.

    PubMed

    Mitchard, Terri L; Klein, Stephanie

    2016-01-01

    A study using vehicle administration in 104 female rats investigated reproductive aging in Han Wistar rats as a useful tool to interprete carcinogenicity studies where hormonal patterns are perturbated. From 16 weeks of age oestrous cycles were monitored every 6 weeks to investigate reproductive ageing. A subset of 20 females was used to assess fertility at 21 months of age. The animals were necropsied after 106-107 weeks on study and female reproductive organs, mammary glands and pituitary glands were examined for hyperplasias and/or tumours. The majority of rats had regular oestrous cycles up to 6 months of age. After this age, there was a rapid decline in the number of rats with regular oestrous cycles and an increase in irregular cycles and cycles in persistent di-oestrus with an occasional pro-oestrus. By the end of the study, the majority of animals were acyclic and the few remaining cyclic animals had irregular cycles. In the fertility assessment, 19/20 animals mated but only four animals became pregnant. These pregnant animals had normal numbers of corpora lutea of pregnancy but had high pre-implantation losses and could not sustain a viable pregnancy. 65 animals (62.5%) showed adenomas and/or pituitary hyperplasia in the pituitary gland at necropsy. The pituitary tumours were likely to be prolactin secreting that give rise to pseudopregnancy and mammary tumours, demonstrated by the fact that 43/65 (66%) of the affected animals had histopathological signs of these conditions. Multiple corpora lutea were found in 61% of all animals at time of termination. Only one uterine tumour was seen in this study probably due to lack of persistent oestrus seen in these animals.

  7. Histopathology of N-methyl-N-nitrosourea-induced mesenchymal tumours of the rat urinary bladder.

    PubMed Central

    Kunze, E.; Ruschitzka, F.; Schwalbe, K.

    1990-01-01

    The present study reports the induction, histopathology, immunocytochemistry, growth pattern and proliferative behaviour of mesenchymal tumours of the urinary bladder of rats induced by a single intravesical dose (5 mg/kg/body weight) of N-methyl-N-nitrosourea (MNU). In 14 of 283 female Wistar rats (incidence: 4.9%). 16 non-epithelial tumours had developed after an experimental period of 14 months. The most common histological type induced was of fibrohistiocytic origin (eight benign-appearing and three malignant fibrous histiocytomas). Furthermore, two pure histiocytomas (one benign and one malignant) and three capillary and cavernous haemangiomas were produced. Since no metastases occurred and no clear-cut distinction between a merely expansive and a truly invasive growth was possible, the diagnosis of malignancy was based on the degree of cellular atypia and the mitotic activity. The benign-appearing fibrous histiocytomas showed a mean mitotic index of 0.06% and the malignant fibrous histiocytomas of 0.34%. The mitotic activity of the malignant histiocytoma was threefold (0.78%) as high as in the benign-appearing histiocytoma (0.25%). There exist close morphological similarities between the induced mesenchymal tumours in the rat and those occurring in the human bladder. Although the spectrum of histological types of mesenchymal tumours seen in the rat bladder was narrower than that encountered in man, MNU seems suitable for further studying the histogenesis, histopathology and biology of experimentally induced non-epithelial bladder neoplasms to gain information for a better understanding of the pathogenesis of human disease. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 Fig. 17 Fig. 18 Fig. 19 PMID:2164825

  8. The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours

    PubMed Central

    Kamata, Tamihiro; Jin, Hong; Giblett, Susan; Patel, Bipin; Patel, Falguni; Foster, Charles; Pritchard, Catrin

    2015-01-01

    The tumour microenvironment is known to play an integral role in facilitating cancer progression at advanced stages, but its function in some pre-cancerous lesions remains elusive. We have used the V600EBRAF-driven mouse lung model that develop premalignant lesions to understand stroma–tumour interactions during pre-cancerous development. In this model, we have found that immature macrophage-lineage cells (IMCs) producing PDGFA, TGFβ and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 (CCR1)-dependent mechanisms. Stromal IMCs promote proliferation and transcriptional alterations suggestive of epithelial–mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for the maintenance of early-stage lung tumours in vivo. Furthermore, we have found that IMC recruitment to the microenvironment is restrained by the cholesterol-binding protein, Niemann-Pick type C2 (NPC2). Studies on isolated cells ex vivo confirm that NPC2 is secreted from tumour cells and is taken up by IMCs wherein it suppresses secretion of the CCR1 ligand CC chemokine 6 (CCL6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for the development of chemopreventive strategies in lung cancer. PMID:26183450

  9. Atrial natriuretic polypeptide-like material in rat lung

    SciTech Connect

    Chang, J.K.; Chang, D.; Xie, C.W.; Song, D.L.; Li, X.R.; Zhang, S.X.; Wang, T.L.; Tang, J.

    1986-03-05

    Atrial natriuretic polypeptide-like immunoreactive material (ANP-IR) was found in rat lung by radioimmunoassay, with the concentration ranging from 0.6-1.2 pmol/g of tissue in each lobe. PAP-immunohistochemical study demonstrated that specific staining of granules for ..cap alpha..-human ANP are mainly located in the muscular layer of the pulmonary vein. Fractionation of lung extract by gel filtration and reserve phase HPLC revealed the presence of multiple forms of ANP-IR, which possibly possessed molecular structure partially different from rat ANP, atriopeptin I and III. Intravenous injection of lung extract induced potent diuresis and natriuresis in rats. These responses could be abolished when the lung extract was preincubated with antiserum for ..cap alpha..-human ANP. Specific binding sites for /sup 125/I-labeled rat ANP were also found in lung membrane preparation by radioreceptor assay. Incubation of synthetic atriopeptin III (10/sup -9/ to 10/sup -6/M) with lung tissue induced 1-28 fold increase in lung cGMP content. The results suggest that ANP-IR and its receptors existing in rat lung may be involved in the regulation of pulmonary function and have a synergic effect with ANP of cardiac origin in the control of water-electrolytes balance.

  10. Deoxyelephantopin, a novel multifunctional agent, suppresses mammary tumour growth and lung metastasis and doubles survival time in mice

    PubMed Central

    Huang, Chi-Chang; Lo, Chiu-Ping; Chiu, Chih-Yang; Shyur, Lie-Fen

    2010-01-01

    Background and purpose: Elephantopus scaber L. (Asteraceae) is a traditional herbal medicine with anti-cancer effects. We evaluated the in vitro and in vivo efficacy of a major sesquiterpene lactone constituent of E. scaber, deoxyelephantopin (DET), against mammary adenocarcinoma and the underlying molecular mechanism. Experimental approach: A variety of cellular assays, immunoblotting and immunohistochemistry, as well as both orthotopic and metastatic TS/A tumour models in BALB/c mice, were used. Test mice were pretreated and post-treated with DET or paclitaxel and mammary tumour growth evaluated. Key results: DET (≤2 µg·mL−1) significantly inhibited colony formation, cell proliferation, migration and invasion of TS/A cells and induced G2/M arrest and apoptosis in TS/A cells. c-Jun N-terminal kinase-mediated p21Waf1/Cip1 expression and caspase activation cascades were up-regulated by DET, effects suppressed by N-acetyl-L-cysteine. Moreover, tumour necrosis factor α-induced matrix metalloproteinase-9 enzyme activity and expression and nuclear factor-kappa B activation were abolished by DET. Pretreatment with DET was more effective than paclitaxel, for profound suppression of orthotopic tumour growth (99% vs. 68% reduction in tumour size) and lung metastasis of TS/A cells (82% vs. 63% reduction in metastatic pulmonary foci) and prolonged median survival time (56 vs. 37 days, P < 0.01) in mice. The levels of cyclooxygenase-2 and vascular endothelial growth factor in metastatic lung tissues of TS/A-bearing mice were attenuated by DET. Conclusions and implications: Our data provide evidence for the suppression of mammary adenocarcinoma by DET with several mechanisms and suggest that DET has potential as a chemopreventive agent for breast cancer. PMID:20105176

  11. Evaluation of a template-based algorithm for markerless lung tumour localization on single- and dual-energy kilovoltage images.

    PubMed

    Block, Alec M; Patel, Rakesh; Surucu, Murat; Harkenrider, Matthew M; Roeske, John C

    2016-12-01

    To evaluate a template-based matching algorithm on single-energy (SE) and dual-energy (DE) radiographs for markerless localization of lung tumours. A total of 74 images from 17 patients with Stages IA-IV lung cancer were considered. At the time of radiotherapy treatment, gated end-expiration SE radiographs were obtained at 60 and 120 kVp at different gantry angles (33° anterior and 41° oblique), from which soft-tissue-enhanced DE images were created. A template-based matching algorithm was used to localize individual tumours on both SE and DE radiographs. Tumour centroid co-ordinates obtained from the template-matching software on both SE and DE images were compared with co-ordinates defined by physicians. The template-based matching algorithm was able to successfully localize the gross tumor volume within 5 mm on 70% (52/74) of the SE images vs 91% (66/74) of the DE images (p < 0.01). The mean vector differences between the co-ordinates of the template matched by the algorithm and the co-ordinates of the physician-defined ground truth were 3.2 ± 2.8 mm for SE images vs 2.3 ± 1.7 mm for DE images (p = 0.03). Template-based matching on DE images was more accurate and precise than using SE images. Advances in knowledge: This represents, to the authors' knowledge, the largest study evaluating template matching on clinical SE and DE images, considering not only anterior gantry angles but also oblique angles, suggesting a novel lung tumour matching technique using DE subtraction that is reliable, accurate and precise.

  12. The effect of green tea on oxidative damage and tumour formation in Lobund-Wistar rats.

    PubMed

    O'Sullivan, Jacintha; Sheridan, Juliette; Mulcahy, Hugh; Tenniswood, Martin; Morrissey, Colm

    2008-11-01

    A number of epidemiological studies suggest that the consumption of green tea reduces the incidence of prostate cancer. As the major catechins present in green tea are potent antioxidants, we hypothesized that genetic and cellular damage induced by oxygen free radicals could be significantly reduced by potent antioxidants in green tea, thus reducing the cumulative genetic and cellular damage with age, and slowing or preventing tumour formation. Long-term administration of a decaffeinated green tea extract to Lobund-Wistar rats for periods up to 26 months almost halved the incidence of primary tumours in the genitourinary tract when compared with an age-matched cohort receiving just water. We observed no inhibition of DNA adduct formation or lipid peroxidation in animals consuming green tea compared with animals consuming deionized water. The decrease in tumour formation was associated with an increase in 8-hydroxy-2'deoxyguanosine and 4-hydroxynonenal content (markers of DNA adduct formation and lipid peroxidation, respectively) in the epithelium of the ventral prostate in aging animals. In addition, there was an increase in 8-hydroxy-2'deoxyguanosine expression, but no change in 4-hydroxynonenal expression in the seminal vesicles of older animals. An age-associated increase in expression of the antioxidant enzymes manganese superoxide dismutase and catalase in the epithelium of the ventral prostate of aging animals was observed. Furthermore, there was also an increase in manganese superoxide dismutase expression, but no change in catalase expression in the seminal vesicles of older animals. These data demonstrate that consumption of green tea decreases the incidence of genitourinary tract tumours in the Lobund-Wistar rat, but has no effect on age-associated DNA adduct formation and lipid peroxidation in the ventral prostate and seminal vesicles of the aging rat.

  13. Is volumetric 3-dimensional computed tomography useful to predict histological tumour invasiveness? Analysis of 211 lesions of cT1N0M0 lung adenocarcinoma

    PubMed Central

    Shikuma, Kei; Menju, Toshi; Chen, Fengshi; Kubo, Takeshi; Muro, Shigeo; Sumiyoshi, Shinji; Ohata, Keiji; Sowa, Terumasa; Nakanishi, Takao; Cho, Hiroyuki; Neri, Shinya; Aoyama, Akihiro; Sato, Toshihiko; Sonobe, Makoto; Date, Hiroshi

    2016-01-01

    OBJECTIVES The purpose of this study was to use Hounsfield unit (HU) thresholds of computed tomography (CT) images to predict pathological lymph node metastasis and tumour invasiveness of cT1N0M0 lung adenocarcinoma on 3D evaluations. METHODS Preoperative CT images of 211 lesions of surgically resected cT1N0M0 lung adenocarcinoma were retrospectively examined. The tumour size was calculated in 1D, 2D and 3D views. Tumours with −300 HU and over were defined as ‘solid tumours’, and those between −800 and −301 HU were defined as ‘ground glass opacity tumours’. Tumours with −800 HU and over were assumed to be the whole tumour entity. The proportion of ‘solid tumour’ within the whole tumour entity was also calculated as the ‘solid tumour ratio’. These were compared with pathological information. RESULTS Solid tumour size and ratio were positively correlated with microscopic invasion to pleura, vessels and lymphatics in all dimensional evaluations. Pathological lymph node metastases were also well predicted by solid tumour size and ratio in all dimensional evaluations. The P-values for the receiver operating characteristic (ROC) curves of 1D, 1D ×2, 2D and 3D evaluations were: solid tumour size P = 0.013, 0.014 and 0.032; and solid tumour ratio 0.016, 0.0032 and <0.0001. In comparisons of 1D, 2D and 3D evaluations, ‘solid tumour size’ of the area under the curve (AUC) of ROC to detect pathological lymph node metastases was not significant. However, strikingly, the 3D solid tumour ratio was found to be significantly more accurate for the prediction of pathological lymph node metastases than the 1D and 2D solid tumour ratios on ROC evaluation (AUC: 1D 0.736, 2D 0.803 and 3D 0.882; P-values for the AUC comparisons were P = 0.013 for 3D versus 1D and P = 0.022 for 3D versus 2D). The correlations of subtypes of adenocarcinoma and the 3D solid tumour ratio were also investigated. Subtypes of adenocarcinoma were well correlated with the 3D solid

  14. TU-F-CAMPUS-J-01: A Formulation of 4D Treatment Planning for Tumour Tracking Volumetric Modulated Arc Therapy for Lung Cancer

    SciTech Connect

    Cheung, Michael L M; Chan, Anthony T C; Lee, Louis K Y

    2015-06-15

    Purpose: To develop a formulation for 4D treatment planning for a tumour tracking volumetric modulated arc therapy treatment (VMAT) plan for lung cancer. Methods: A VMAT plan was optimized based on a reference phase of the 4DCT of a lung cancer patient. The PTV was generated from the GTV of the reference phase. The collimator angle was set to 90 degrees such that the MLC travels along superior-inferior direction which is the main component of movement of a lung tumour. Then, each control point of the VMAT plan was assigned to a particular phase of the 4DCT in chronological order. The MLC positions of each control point were shifted according to the position of the tumour centroid of its assigned phase to form a tumour tracking VMAT plan. The control points of the same phase were grouped to form a pseudo VMAT plan for that particular phase. Dose calculation was performed for each pseudo VMAT plan on the corresponding phase of the 4DCT. The CTs of all phases were registered to the reference phase CT according to the displacement of the tumour centroid. The individual dose distributions of the pseudo VMAT plans were summed up and displayed on the reference phase of the 4DCT. A control VMAT plan was optimized based on a PTV generated from the ITV of all phases and compared with the tumour tracking VMAT plan. Results: Both plans achieved >95% volume coverage at the prescription dose level (96% for the tumour tracking plan and 97% for the control plan). But the normal lung volume irradiated at the prescription dose level was 39% less for the tumour tracking plan than the control plan. Conclusion: A formulation of 4D treatment planning for tumour tracking VMAT plans for lung cancer was developed.

  15. Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.

    PubMed

    Miyawaki, Shingo; Kawamura, Yoshimi; Oiwa, Yuki; Shimizu, Atsushi; Hachiya, Tsuyoshi; Bono, Hidemasa; Koya, Ikuko; Okada, Yohei; Kimura, Tokuhiro; Tsuchiya, Yoshihiro; Suzuki, Sadafumi; Onishi, Nobuyuki; Kuzumaki, Naoko; Matsuzaki, Yumi; Narita, Minoru; Ikeda, Eiji; Okanoya, Kazuo; Seino, Ken-Ichiro; Saya, Hideyuki; Okano, Hideyuki; Miura, Kyoko

    2016-05-10

    The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype-ARF suppression-induced senescence (ASIS)-that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR.

  16. Oxidative photodamage induced by photodynamic therapy with methoxyphenyl porphyrin derivatives in tumour-bearing rats.

    PubMed

    Daicoviciu, D; Filip, A; Ion, R M; Clichici, S; Decea, N; Muresan, A

    2011-01-01

    The oxidative effects of photodynamic therapy with 5,10,15,20-tetrakis(4-methoxyphenyl) porphyrin (TMP) and Zn-5,10,15,20-tetrakis(4-methoxyphenyl) porphyrin (ZnTMP) were evaluated in Wistar rats subcutaneously inoculated with Walker 256 carcinoma. The animals were irradiated with red light (λ = 685 nm; D = 50 J/cm2; 15 min) 3 h after intra-peritoneal administration of 10 mg/kg body weight of porphyrins. The presence of free radicals in tumours after photodynamic therapy with TMP and ZnTMP revealed by chemiluminescence of luminol attained the highest level at 18 h after irradiation. Lipid peroxides measured as thiobarbituric-reactive substances and protein carbonyls, which are indices of oxidative effects produced on susceptible biomolecules, were significantly increased in tumour tissues of animals 24 h after photodynamic therapy. The levels of thiol groups and total antioxidant capacity in the tumours were decreased. The activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were also increased in tumour tissues after photodynamic therapy. Increased levels of plasma lipid peroxides as well as changes in the levels of erythrocyte antioxidant enzyme activities suggest possible systemic effects of photodynamic therapy with TMP and ZnTMP.

  17. Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats.

    PubMed

    Hong, G-L; Cai, Q-Q; Tan, J-P; Jiang, X-Z; Zhao, G-J; Wu, B; Li, M-F; Qiu, Q-M; Lu, Z-Q

    2015-01-01

    To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05). RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway. © The Author(s) 2014.

  18. Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology.

    PubMed

    Manegold, Christian

    2014-09-01

    The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxics such as pemetrexed, the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as the anti-angiogenic bevacizumab and the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. Decision making in 2014 is characterized by customizing therapy, by selecting a specific therapeutic regimen based on the histotype and the genotype of the tumour. This refers to first-line induction therapy and maintenance therapy as well, but also to subsequent lines of therapy since anti-neoplastic drugs and regimens used upfront clinically influence the selection of agents/regimes considered for second-/third-line treatment. Consequently, therapy customization through tumour histology and molecular markers has significantly influenced the work of pathologists around the globe and the process of obtaining an extended therapeutically relevant tumour diagnosis. Not only histological sub-typing became standard but molecular information is also considered of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and the diagnostic process should ideally be performed under the guidance of evidence based recommendation. The process of investigating and implementing medical targeting in lung cancer therefore, requires advanced diagnostic techniques and expertise and because of its large dimension is costly and influenced by the limitation of financial and clinical resources. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

  19. 3D thoracoscopic ultrasound volume measurement validation in an ex vivo and in vivo porcine model of lung tumours

    NASA Astrophysics Data System (ADS)

    Hornblower, V. D. M.; Yu, E.; Fenster, A.; Battista, J. J.; Malthaner, R. A.

    2007-01-01

    The purpose of this study was to validate the accuracy and reliability of volume measurements obtained using three-dimensional (3D) thoracoscopic ultrasound (US) imaging. Artificial 'tumours' were created by injecting a liquid agar mixture into spherical moulds of known volume. Once solidified, the 'tumours' were implanted into the lung tissue in both a porcine lung sample ex vivo and a surgical porcine model in vivo. 3D US images were created by mechanically rotating the thoracoscopic ultrasound probe about its long axis while the transducer was maintained in close contact with the tissue. Volume measurements were made by one observer using the ultrasound images and a manual-radial segmentation technique and these were compared with the known volumes of the agar. In vitro measurements had average accuracy and precision of 4.76% and 1.77%, respectively; in vivo measurements had average accuracy and precision of 8.18% and 1.75%, respectively. The 3D thoracoscopic ultrasound can be used to accurately and reproducibly measure 'tumour' volumes both in vivo and ex vivo.

  20. Study of the cytotoxicity of asiaticoside on rats and tumour cells

    PubMed Central

    2014-01-01

    Background Cancer chemoprevention is considered one of the most promising areas in current cancer research, and asiaticoside, which is derived from the plant Centella asiatica, has a relative lack of systemic toxicity. The purpose of this study was to investigate whether asiaticoside is effective against 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenicity in vitro (MCF-7 and other cells) and in vivo (DMBA-induced rat cancer). Methods An MTT assay was performed involving the treatment of MCF-7 cells for 48 h with H2O2 alone and H2O2 + different asiaticoside concentrations. Flow cytometry was performed, and the level of caspase 3, tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) were quantified. Adult female Sprague–Dawley (SD) rats were divided into five groups designated I (control), II (DMBA-induced cancer), III (pre- and post-treatment with asiaticoside (200 μg/animal) in DMBA-induced cancer), IV (post-treatment with asiaticoside in DMBA-induced cancer), and V (treated with asiaticoside alone, drug control). Twelve weeks post-DMBA, rats developed mammary tumours. Rats either were sacrificed or imaged with MIBI. Histological examination of tumour tissues was performed. Tumour MIBI uptake ratios were determined. The data are expressed as the means ± standard deviation. Appropriate t-test and ANOVA statistical methods were used to compare data. Results The IC50 of asiaticoside for MCF-7 cells was determined to be 40 μM. Asiaticoside has potential for hydrogen peroxide cytotoxicity, and the caspase-3 activity increased with increasing asiaticoside dose in MCF-7 cells treated for 48 h. The expression of the cytokines TNF-α and IL-1β was significantly decreased and correlated with MIBI uptake ratios in vitro and in vivo after asiaticoside administration. Conclusion This study demonstrates that asiaticoside is effective in vitro and in vivo in inducing apoptosis and enhancing anti-tumour activity. PMID:24667059

  1. Lung tumour growth kinetics in SPC-c-Raf-1-BB transgenic mice assessed by longitudinal in-vivo micro-CT quantification.

    PubMed

    Rodt, Thomas; von Falck, Christian; Dettmer, Sabine; Hueper, Katja; Halter, Roman; Hoy, Ludwig; Luepke, Matthias; Borlak, Juergen; Wacker, Frank

    2012-02-20

    SPC-c-Raf-1-BxB transgenic mice develop genetically induced disseminated lung adenocarcinoma allowing examination of carcinogenesis and evaluation of novel treatment strategies. We report on assessment of lung tumour growth kinetics using a semiautomated region growing segmentation algorithm. 156 non contrast-enhanced respiratory gated micro-CT of the lungs were obtained in 12 SPC-raf transgenic (n = 9) and normal (n = 3) mice at different time points. Region-growing segmentation of the aerated lung areas was obtained as an inverse surrogate for tumour burden. Time course of segmentation volumes was assessed to demonstrate the potential of the method for follow-up studies. Micro-CT allowed assessment of tumour growth kinetics and semiautomated region growing enabled quantitative analysis. Significant changes of the segmented lung volumes over time could be shown (p = 0.009). Significant group differences could be detected between transgenic and normal animals for time points 8 to 13 months (p = 0.043), when marked tumour progression occurred. The presented region-growing segmentation algorithm allows in-vivo quantification of multifocal lung adenocarcinoma in SPC-raf transgenic mice. This enables the assessment of tumour load and progress for the study of carcinogenesis and the evaluation of novel treatment strategies.

  2. Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.

    PubMed

    Pencavel, Tim D; Wilkinson, Michelle J; Mansfield, David C; Khan, Aadil A; Seth, Rohit; Karapanagiotou, Eleni M; Roulstone, Victoria; Aguilar, Richard J; Chen, Nanhai G; Szalay, Aladar A; Hayes, Andrew J; Harrington, Kevin J

    2015-02-15

    Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.

  3. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

    PubMed

    Mata, M; Ruíz, A; Cerdá, M; Martinez-Losa, M; Cortijo, J; Santangelo, F; Serrano-Mollar, A; Llombart-Bosch, A; Morcillo, E J

    2003-12-01

    Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.

  4. Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorγT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung

    PubMed Central

    Balabko, Ljubov; Andreev, Katerina; Burmann, Nadine; Schubert, Melanie; Mathews, Martina; Trufa, Denis I.; Reppert, Sarah; Rau, Tilmann; Schicht, Martin; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta

    2014-01-01

    Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma. PMID:25491772

  5. Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorγT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung.

    PubMed

    Balabko, Ljubov; Andreev, Katerina; Burmann, Nadine; Schubert, Melanie; Mathews, Martina; Trufa, Denis I; Reppert, Sarah; Rau, Tilmann; Schicht, Martin; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta

    2014-12-10

    Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.

  6. Radiobiological and Magnetic Resonance Studies of Combined Radiation and Cisplatin Therapy in the 9l Rat Brain Tumour Model.

    NASA Astrophysics Data System (ADS)

    Wilkins, David E.

    1993-01-01

    The prognosis for adult patients with primary malignant brain tumours is poor. Radiation therapy is a standard adjutant to surgery in the treatment of these patients, but is rarely curative. The extreme radio-resistance of primary malignant brain tumours is due in part to their enhanced capacity for repair of potentially lethal radiation damage. The chemotherapeutic agent cisplatin has been shown to inhibit repair of radiation damage. Therefore combined cisplatin and radiation therapy could be a key to enhanced therapeutic gain in the treatment of primary malignant brain tumours. In this project, the 9L rat brain tumour model was used to investigate combined radiation and cisplatin treatments. In vitro experiments showed the 9L cell line to be highly radioresistant and, like human malignant brain tumour cells, to have a high capacity for repair of potentially lethal radiation damage. These cells were found to be moderately resistant to the cytotoxic effects of cisplatin. In vitro exposure to cisplatin at clinically relevant concentrations caused inhibition of potentially lethal damage repair, with the amount of inhibition depending on cisplatin dose and treatment sequence. Magnetic resonance imaging (MRI) was used to monitor the effects of combined radiation and cisplatin treatments of implanted intracranial 9L tumours in rats. A new technique for implanting experimental tumours was developed which resulted in more uniform tumour growth, and methods for radiation and cisplatin treatment of experimental intracranial tumours were developed and evaluated. Non-invasive measurements of tumour size using MRI were found to correlate well with measurements made from histological sections. Intraperitoneal administration of gadolinium contrast agent immediately before T1-weighted MRI was shown to be the most accurate and reliable method for MRI measurement of intracranial tumour size. The capability of MRI to provide early indications of radiation injury to normal brain

  7. Enhanced in vivo function of bioartificial lungs in rats.

    PubMed

    Song, Jeremy J; Kim, Sam S; Liu, Zhilin; Madsen, Joren C; Mathisen, Douglas J; Vacanti, Joseph P; Ott, Harald C

    2011-09-01

    More than 11 million Americans live with chronic lung disease; in search for an alternative to donor organs, we attempted to regenerate lungs based on perfusion decellularized lung scaffolds that can be transplanted similar to a donor organ. Cadaveric rat lungs were decellularized by detergent perfusion. Resulting scaffolds were mounted in bioreactors and seeded with endothelial and fetal lung cells. Biomimetic organ culture was maintained for 7 days. Resulting bioartificial left lungs were transplanted in orthotopic position after left pneumonectomy in rats. Cadaveric left lung transplants and pneumonectomies served as controls. Blood gas analyses, compliance testing, and fluoroscopies were performed on postoperative days 1, 7, and 14. Lungs were removed for final analysis on day 14. Perfusion decellularization of cadaveric lungs yielded acellular scaffolds with intact architecture and matrix composition. Alveolar volumes, number, and size were comparable in bioartificial and native lungs, as were gas exchange, vital capacity and compliance in vitro. After using improved graft preservation and postoperative weaning protocols, animals could be fully recovered, and bioartificial lung constructs provided oxygenation as long as 7 days at levels comparable to cadaveric lung transplants. Compliance, gas exchange, and radiographic appearance gradually declined over the subsequent 7 days owing to progressive graft consolidation and inflammation. Perfusion decellularization of cadaveric lungs yields intact scaffolds that can be seeded with cells to generate bioartificial lung grafts. After orthotopic transplantation, grafts are perfused by the recipient's circulation, ventilated through the recipient's airway and provide gas exchange in vivo for 7 days. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  8. No tumour-initiating risk associated with scAAV transduction in newborn rat liver.

    PubMed

    Gauttier, V; Pichard, V; Aubert, D; Kaeppel, C; Schmidt, M; Ferry, N; Conchon, S

    2013-07-01

    Delivery of recombinant adeno-associated virus (rAAV) vectors to the newborn liver is followed by a rapid loss of episomal vector copies because of hepatocyte proliferation. In selected hepatocytes, integration of rAAV genomes can lead to a sustained expression of the transgene. The safety of in vivo gene therapy with single-stranded AAV vectors has been questioned in a study reporting a high incidence of hepatocellular carcinoma, associated with provirus integration events in mice that receive an single-stranded AAV injection at birth. To investigate the tumour-initiating potential of the newly established self-complementary AAV (scAAV) vectors in the liver, groups of newborn rats received intravenous injection of a scAAV vector encoding the green fluorescent protein (GFP), or were injected with phosphate-buffered saline (PBS) or diethylnitrosamine (DEN), a well-known liver tumour initiator. The rats were fed on a diet containing 2-acetylaminofluorene, a potent liver tumour-promoting agent to accelerate the carcinogenic process. After 2 months, the animals were killed and their livers analysed. Preneoplastic nodules were identified by glutathion S-transferase-p (GSTp) staining, and GFP expression was detected by immunohistochemistry. Vector genome integration events were analysed. The numbers of GSTp-positive foci were comparable in the PBS and the scAAV-GFP groups and significantly higher in the DEN group. The proportion of GSTp-positive foci that also expressed GFP was low and in the range expected for random occurrence. No specific integration hot spots were detected by linear amplification-mediated-PCR in transduced liver. In conclusion, scAAV transduction of newborn rat liver does not trigger preneoplastic lesions suggesting an absence of liver tumourigenesis.

  9. Single nucleotide polymorphisms, haplotype association and tumour expression of the vascular endothelial growth factor (VEGF) gene with lung carcinoma.

    PubMed

    Naykoo, Niyaz A; Dil-Afroze; Rasool, Roohi; Shah, Sonaullah; Ahangar, A G; Bhat, Imtiyaz A; Qasim, Iqbal; Siddiqi, Mushtaq A; Shah, Zafar A

    2017-04-15

    VEGF contains several polymorphic sites known to influence its expression. We examined the possible association between+405(-634)C>G,+936C>T,-2578C>A and lung cancer in 199 Kashmiri patients and 401 healthy controls. VEGF+405CG,+936CT+TT and-2578CA genotypes were significantly associated with lung cancer risk compared to VEGF+405CC,+936CC and-2578AA+CC genotypes [OR=0.07 (0.04-0.13), P<0.0001, OR=0.36 (0.25-0.52), P<0.0001 and 0.08 (0.05-0.13), P<0.0001]. Haplotype analysis revealed that CGA and TGA haplotypes of VEGF gene conveys the risk for lung cancer [OR=0.18 (0.10-0.33), P<0.0001 and 0.07 (0.03-0.13), P<0.0001]. VEGF expression revealed non-significant association with the genotypes of the three SNPs. In conclusion, the SNPs examined appear to influence lung cancer susceptibility while as genotypes of the SNPs don't appear to have significant association with VEGF mRNA expression in lung tumours.

  10. Changes in liver gluconeogenesis during the development of Walker-256 tumour in rats.

    PubMed

    Moreira, Carolina Campos Lima; Cassolla, Priscila; Dornellas, Ana Paula Segantini; de Morais, Hely; de Souza, Camila Oliveira; Borba-Murad, Glaucia Regina; Bazotte, Roberto Barbosa; de Souza, Helenir Medri

    2013-02-01

    Few studies have investigated liver gluconeogenesis in cancer and there is no agreement as to whether the activity of this pathway is increased or decreased in this disease. The aim of this study was to evaluate gluconeogenesis from alanine, pyruvate and glycerol, and related metabolic parameters in perfused liver from Walker-256 tumour-bearing rats on days 5 (WK5 group), 8 (WK8 group) and 12 (WK12 group) of tumour development. There was reduction (P < 0.05) of liver glucose production from alanine and pyruvate in WK5, WK8 and WK12 groups, which was accompanied by a decrease (P < 0.05) in oxygen consumption. Moreover, there was higher (P < 0.05) pyruvate and lactate production from alanine in the WK5 group and a marked reduction (P < 0.05) of pyruvate and urea production from alanine in the WK12 group. In addition, liver glucose production and oxygen consumption from glycerol were not reduced in WK5, WK8 and WK12 groups. Thus the, the results show inhibition of hepatic gluconeogenesis from alanine and pyruvate, but not from glycerol, on days 5, 8 and 12 of Walker-256 tumour development, which can be attributed to the metabolic step in which the substrate enters the gluconeogenic pathway.

  11. Leucine-rich diet alters the (1)H-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats.

    PubMed

    Viana, Laís Rosa; Canevarolo, Rafael; Luiz, Anna Caroline Perina; Soares, Raquel Frias; Lubaczeuski, Camila; Zeri, Ana Carolina de Mattos; Gomes-Marcondes, Maria Cristina Cintra

    2016-10-03

    Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia). After 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C - control; W - tumour-bearing groups). We utilised (1)H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway. Among the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance. A leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.

  12. Apigenin protects against bleomycin-induced lung fibrosis in rats.

    PubMed

    Chen, Ling; Zhao, Wei

    2016-01-01

    Apigenin is a non-toxic and non-mutagenic flavone that exists abundantly in numerous herbs and vegetables. Apigenin exerts anti-proliferative and anti-inflammatory properties. The aim of the present study was to investigate the effects of apigenin on bleomycin-induced lung fibrosis in rats. A single intratracheal instillation of bleomycin (5 mg/kg) was administered and rats were sacrificed on 7 and 28 days post bleomycin instillation. The instillation of bleomycin resulted in decreased body weight and an increase in the lung index. In addition, bleomycin administration increased the hydroxyproline content, myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β levels and decreased the superoxide dismutase (SOD) activity in the rat lung tissues. Excessive collagen deposits were detected in the lung tissues in bleomycin-treated rats compared with normal control rats. Notably, the oral administration of apigenin (10, 15 and 20 mg/kg/day) appeared to prevent the fibrotic process. The treatment suppressed the increases in hydroxyproline content, MPO activity, TNF-α and TGF-β levels and attenuated the reduction of SOD activity that were induced by bleomycin. Furthermore, excessive collagen deposition was inhibited by the apigenin treatment. Collectively, these results suggest that apigenin may function as a potent anti-inflammatory and anti-fibrotic agent against bleomycin-induced lung fibrosis.

  13. Efficacy and safety of cryobiopsy versus forceps biopsy for interstitial lung diseases and lung tumours: A systematic review and meta-analysis.

    PubMed

    Ganganah, Oormila; Guo, Shu Liang; Chiniah, Manu; Li, Yi Shi

    2016-07-01

    Forceps biopsy (FB) is the most commonly used diagnostic tool for lung pathologies. FB is associated with a high diagnostic failure rate. Cryobiopsy (CB) is a novel technique providing a larger specimen size, few artefacts, more alveolar parts and superior diagnostic yield. CB, however, has drawbacks such as higher bleeding and pneumothorax rate. We conducted a meta-analysis to investigate the specimen area, diagnostic rate and bleeding severity in CB versus FB in interstitial lung diseases (ILDs) and lung tumours. A systematic literature search of PUBMED, BIOSIS PREVIEW and OVID databases was conducted using specific search terms. Eligible studies including RCTs and non-RCTs comparing cryobiopsy/cryotransbronchial biopsy (CB/CTBB) and forceps biopsy/forceps transbronchial biopsy (FB/FTBB) for specimen area, diagnostic rate and bleeding rate in ILDs and lung tumours were analysed. Two reviewers independently extracted data and evaluated the quality of the studies. Eight studies involving 916 patients were analysed. Specimen area (mm(2) ) was significantly larger in CB/CTBB than FB/FTBB (standard mean difference = 1.21, 95% confidence interval (0.94, 1.48), P < 0.00001). The diagnostic rate was significantly higher in CB/CTBB than FB/FTBB (Risk ratio 1.36, 95% confidence interval (1.16, 1.59), P = 0.0002). Three studies compared the bleeding severity with only one showing significantly more bleeding in CB. Cryobiopsy/cryotransbronchial shows superiority to FB/FTBB for specimen area and diagnostic rate. CB/CTBB has better efficacy over FB/FTBB.

  14. Responses of rat lungs following inhalation of beryllium metal particles to achieve relatively low lung burdens

    SciTech Connect

    Finch, G.L.; Haley, P.J.; Hoover, M.D.; Cuddihy, R.G.

    1991-01-01

    Potential health effects resulting from the accidental exposure of people to beryllium metal are of concern. To investigate the effects of relatively low levels of beryllium metal on lung clearance, we simultaneously exposed rats to beryllium metal and radioactive tracer particles. Exposure to beryllium metal aerosol to achieve estimated lung burdens of 9 or 52 {mu}g significantly retarded clearance up to 365 days after exposure compared to controls, whereas lung burdens of 1.5 or 2 {mu}g had no significant effect on clearance. Groups of rats were sacrificed at 8, 16, 40, 90, 210 and 365 days after exposure for bronchoalveolar lavage. The total numbers of cells, incidence of neutrophils, the levels of total protein, and the enzymes lactate dehydrogenase and {beta}-glucuronidase were generally elevated in lavage fluids from groups of rats that also had impaired lung clearance. This study serves to further define the levels of beryllium metal required to retard lung clearance and induce accompanying pathological responses in the lungs of rats. 11 refs., 5 figs., 1 tab.

  15. A proposed framework for consensus-based lung tumour volume auto-segmentation in 4D computed tomography imaging.

    PubMed

    Martin, Spencer; Brophy, Mark; Palma, David; Louie, Alexander V; Yu, Edward; Yaremko, Brian; Ahmad, Belal; Barron, John L; Beauchemin, Steven S; Rodrigues, George; Gaede, Stewart

    2015-02-21

    This work aims to propose and validate a framework for tumour volume auto-segmentation based on ground-truth estimates derived from multi-physician input contours to expedite 4D-CT based lung tumour volume delineation. 4D-CT datasets of ten non-small cell lung cancer (NSCLC) patients were manually segmented by 6 physicians. Multi-expert ground truth (GT) estimates were constructed using the STAPLE algorithm for the gross tumour volume (GTV) on all respiratory phases. Next, using a deformable model-based method, multi-expert GT on each individual phase of the 4D-CT dataset was propagated to all other phases providing auto-segmented GTVs and motion encompassing internal gross target volumes (IGTVs) based on GT estimates (STAPLE) from each respiratory phase of the 4D-CT dataset. Accuracy assessment of auto-segmentation employed graph cuts for 3D-shape reconstruction and point-set registration-based analysis yielding volumetric and distance-based measures. STAPLE-based auto-segmented GTV accuracy ranged from (81.51  ±  1.92) to (97.27  ±  0.28)% volumetric overlap of the estimated ground truth. IGTV auto-segmentation showed significantly improved accuracies with reduced variance for all patients ranging from 90.87 to 98.57% volumetric overlap of the ground truth volume. Additional metrics supported these observations with statistical significance. Accuracy of auto-segmentation was shown to be largely independent of selection of the initial propagation phase. IGTV construction based on auto-segmented GTVs within the 4D-CT dataset provided accurate and reliable target volumes compared to manual segmentation-based GT estimates. While inter-/intra-observer effects were largely mitigated, the proposed segmentation workflow is more complex than that of current clinical practice and requires further development.

  16. A proposed framework for consensus-based lung tumour volume auto-segmentation in 4D computed tomography imaging

    NASA Astrophysics Data System (ADS)

    Martin, Spencer; Brophy, Mark; Palma, David; Louie, Alexander V.; Yu, Edward; Yaremko, Brian; Ahmad, Belal; Barron, John L.; Beauchemin, Steven S.; Rodrigues, George; Gaede, Stewart

    2015-02-01

    This work aims to propose and validate a framework for tumour volume auto-segmentation based on ground-truth estimates derived from multi-physician input contours to expedite 4D-CT based lung tumour volume delineation. 4D-CT datasets of ten non-small cell lung cancer (NSCLC) patients were manually segmented by 6 physicians. Multi-expert ground truth (GT) estimates were constructed using the STAPLE algorithm for the gross tumour volume (GTV) on all respiratory phases. Next, using a deformable model-based method, multi-expert GT on each individual phase of the 4D-CT dataset was propagated to all other phases providing auto-segmented GTVs and motion encompassing internal gross target volumes (IGTVs) based on GT estimates (STAPLE) from each respiratory phase of the 4D-CT dataset. Accuracy assessment of auto-segmentation employed graph cuts for 3D-shape reconstruction and point-set registration-based analysis yielding volumetric and distance-based measures. STAPLE-based auto-segmented GTV accuracy ranged from (81.51  ±  1.92) to (97.27  ±  0.28)% volumetric overlap of the estimated ground truth. IGTV auto-segmentation showed significantly improved accuracies with reduced variance for all patients ranging from 90.87 to 98.57% volumetric overlap of the ground truth volume. Additional metrics supported these observations with statistical significance. Accuracy of auto-segmentation was shown to be largely independent of selection of the initial propagation phase. IGTV construction based on auto-segmented GTVs within the 4D-CT dataset provided accurate and reliable target volumes compared to manual segmentation-based GT estimates. While inter-/intra-observer effects were largely mitigated, the proposed segmentation workflow is more complex than that of current clinical practice and requires further development.

  17. Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma.

    PubMed

    Becker-Santos, Daiana D; Thu, Kelsie L; English, John C; Pikor, Larissa A; Martinez, Victor D; Zhang, May; Vucic, Emily A; Luk, Margaret Ty; Carraro, Anita; Korbelik, Jagoda; Piga, Daniela; Lhomme, Nicolas M; Tsay, Mike J; Yee, John; MacAulay, Calum E; Lam, Stephen; Lockwood, William W; Robinson, Wendy P; Jurisica, Igor; Lam, Wan L

    2016-10-01

    Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these 'oncofetal' miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40-70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  18. Clearance of inhaled ceramic fibers from rat lungs.

    PubMed Central

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1994-01-01

    Deposition, clearance, retention, and durability of inhaled particles in lung are important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of aluminium silicate ceramic fibers from the lung, male Wistar rats were exposed to ceramic fibers, with a mass median aerodynamic diameter (MMAD) of 3.7 microns, for 6 hr/day, 5 days/week for 2 weeks. The average exposure concentration was 27.2 mg/m3 (SD 9.0). The rats were killed at 1 day, 1 month, 3 months, and 6 months after the end of exposure, and the fiber numbers and dimensions were measured with a scanning electron microscope. No significant difference in length of residual ceramic fibers in the lungs was found among the groups. The geometric mean diameter and number of ceramic fibers, however, decreased according to the clearance period. These findings suggest that the fibers were dissolved at their surface. PMID:7882924

  19. Correlation between molecular analysis, diagnosis according to the 2015 WHO classification of unresected lung tumours and TTF1 expression in small biopsies and cytology specimens from 344 non-small cell lung carcinoma patients.

    PubMed

    Russell, Prudence A; Rogers, Toni-Maree; Solomon, Benjamin; Alam, Naveed; Barnett, Stephen A; Rathi, Vivek; Williams, Richard A; Wright, Gavin M; Conron, Matthew

    2017-08-12

    We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

  20. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-DPhe1, Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours.

    PubMed

    Stolz, B; Weckbecker, G; Smith-Jones, P M; Albert, R; Raulf, F; Bruns, C

    1998-07-01

    Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe1, Tyr3]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst2) (human sst2 IC50=0.9 nM, rat sst2 IC50=0.5 nM). In vivo, 90Y-SMT 487 distributed rapidly to the sst2 expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg 90Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 microg/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of 90Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997.

  1. Trophoblast Deportation to the Lungs of Cotton Rats (Sigmodon hispidus)

    PubMed Central

    Perle, Krista M D La; Green, M Gia; Niewiesk, Stefan

    2014-01-01

    Cotton rats (Sigmodon hispidus) have been used to study a variety of infectious agents, particularly human respiratory viral pathogens. During the course of comprehensive pathologic evaluations of aging breeders from our breeding colony, 6 of 22 (27%) female cotton rats had histologic evidence, limited to the lungs, of embolized cells that were confirmed to be trophoblastic in origin by HSD3B1 immunoreactivity. When pulmonary trophoblast emboli were numerous, they usually were associated with additional histologic findings in the lungs, including pulmonary edema and hemorrhage, endothelial hypertrophy, fibrinoid vascular necrosis, and abundant alveolar macrophages containing fresh fibrin and hemolyzing erythrocytes. Of the 6 cotton rats with pulmonary trophoblast emboli, 5 (83%) were at 8 to 18 d of the 27-d gestation period, with the greatest number of emboli per lung present between days 10 through 14. The remaining cotton rat had a focal pulmonary trophoblast embolus and was not pregnant but had delivered a litter 3 mo previously. Three other cotton rats in either the early or late stages of gestation showed no histologic evidence of pulmonary trophoblast deportation. This report is the first to document pulmonary trophoblast emboli in cotton rats. This finding suggests that cotton rats may be an alternative animal model for the study of normal and aberrant trophoblast deportation in routine pregnancies and gestational pathologic conditions in women. PMID:25527025

  2. Epithelial-myoepithelial tumour of the lung: a case report referring to its molecular histogenesis.

    PubMed

    Muñoz, Guillermo; Felipo, Francesc; Marquina, Isabel; Del Agua, Celia

    2011-07-28

    Tracheobronchial submucous glands can be considered the pulmonary equivalent of minor salivary glands and therefore they can develop most of the tumours originated in these. Nevertheless, in spite of the wide distribution of this kind of glands along the tracheobronchial tree, pulmonary salivary gland-like neoplasms are not very frequent. Among them, the most frequent are mucoepidermoid and adenoid cystic carcinomas. On the contrary, pulmonary neoplasms showing a mixture of epithelial and myoepithelial elements are extraordinary infrequent, with only 11 cases collected from literature.We present the case of a 76 year-old woman with no interesting pathological history, to whom a pulmonary nodule is detected during a study of unknown origin neutropenia. An upper right lobectomy is performed.After macro and microscopic study, the diagnosis of pulmonary epithelial-myoepithelial tumour is made. It is a low malignant potential tumour with capacity to locally recur and less frequently to metastasize. Our case has the peculiarity of not being connected neither to visceral pleura nor to bronchial tree; we have not found this characteristic in any literature reviewed case.These tumours have been named in a lot of different ways, including adenomyoepithelioma, epithelial-myoepithelial tumour, epithelial-myoepithelial carcinoma or epithelial-myoepithelial tumour of uncertain malignant potential.The p27/kip-1 protein plays a fundamental role in the development of these neoplasms. As we have verified in our case, its aberrant cytoplasmic location, besides its proved oncogenic function, would favour the proliferation of stem cells, which would explain both dual phenotype with presence of myoepithelial cells without connection with the bronchial tree, and TTF-1 immunostaining in epithelial cells.

  3. Epithelial-myoepithelial tumour of the lung: a case report referring to its molecular histogenesis

    PubMed Central

    2011-01-01

    Tracheobronchial submucous glands can be considered the pulmonary equivalent of minor salivary glands and therefore they can develop most of the tumours originated in these. Nevertheless, in spite of the wide distribution of this kind of glands along the tracheobronchial tree, pulmonary salivary gland-like neoplasms are not very frequent. Among them, the most frequent are mucoepidermoid and adenoid cystic carcinomas. On the contrary, pulmonary neoplasms showing a mixture of epithelial and myoepithelial elements are extraordinary infrequent, with only 11 cases collected from literature. We present the case of a 76 year-old woman with no interesting pathological history, to whom a pulmonary nodule is detected during a study of unknown origin neutropenia. An upper right lobectomy is performed. After macro and microscopic study, the diagnosis of pulmonary epithelial-myoepithelial tumour is made. It is a low malignant potential tumour with capacity to locally recur and less frequently to metastasize. Our case has the peculiarity of not being connected neither to visceral pleura nor to bronchial tree; we have not found this characteristic in any literature reviewed case. These tumours have been named in a lot of different ways, including adenomyoepithelioma, epithelial-myoepithelial tumour, epithelial-myoepithelial carcinoma or epithelial-myoepithelial tumour of uncertain malignant potential. The p27/kip-1 protein plays a fundamental role in the development of these neoplasms. As we have verified in our case, its aberrant cytoplasmic location, besides its proved oncogenic function, would favour the proliferation of stem cells, which would explain both dual phenotype with presence of myoepithelial cells without connection with the bronchial tree, and TTF-1 immunostaining in epithelial cells. PMID:21798017

  4. EDU pretreatment decreases polymorphonuclear leukocyte migration into rat lung airways.

    PubMed

    Bassett, D J; Elbon, C L; Ishii, Y; Yang, H; Otterbein, L; Boswell, G A; Kerr, J S

    1994-07-01

    Pretreatment with the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has previously been shown to reduce polymorphonuclear leukocyte (PMN) infiltration into the airways of ozone-exposed rats. The present study further examined the effects of 1 and 2 days EDU pretreatment on rat lung inflammatory responses by determining PMN infiltration in response to intratracheal instillation with the chemoattractant formyl-norleucine-leucine-phenylalanine (fNLP). Maximal recovery of PMNs by bronchoalveolar lavage was observed 4 hr after fNLP instillation with no alteration in the numbers of recoverable macrophages and lymphocytes. Although 1-day pretreatment with EDU did not affect PMN recovery from fNLP-instilled rat lungs, 2 days of EDU pretreatment prevented PMN infiltration as indicated by PMN recoveries that were similar to those obtained from saline-instilled lungs. Measurements of lung-marginated and interstitial pools of inflammatory cells using collagenase tissue digestion demonstrated no effect of 2 days EDU pretreatment. Although 2 days EDU pretreatment alone did not alter blood PMN content, lung permeability, and the lavage recoveries of inflammatory cells, blood PMN responses to chemotactic stimuli in vitro were impaired. In addition, EDU was shown to directly inhibit PMN chemotaxis and superoxide anion generation in vitro. These data demonstrated that EDU acts by interfering with PMN activation and migration rather than by decreasing PMN availability. EDU, by modulating the inflammatory response, represents a useful compound for preventing PMN-associated amplification of acute lung injuries.

  5. Effects of employing a 10B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy

    PubMed Central

    Masunaga, S; Sakurai, Y; Tanaka, H; Suzuki, M; Liu, Y; Kondo, N; Maruhashi, A; Kinashi, Y; Ono, K

    2012-01-01

    Objectives To evaluate the effects of employing a 10B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy (BNCT) by measuring the response of intratumour quiescent (Q) cells. Methods B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumours received reactor thermal neutron beam irradiation following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)] in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. Results BPA-BNCT increased the sensitivity of the total tumour cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B–carrier, MTH enhanced the sensitivity of the Q cell population. Without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with nicotinamide treatment, showed the potential to reduce the number of metastases more than BSH-BNCT. Conclusion BSH-BNCT in combination with MTH improves local tumour control, while BPA-BNCT in combination with nicotinamide may reduce the number of lung metastases. PMID:22391496

  6. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Itoh, Takefumi; Obata, Hiroaki; Murakami, Shinsuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi; Nagaya, Noritoshi

    2007-08-01

    Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

  7. Changes in blood metabolic parameters during the development of Walker-256 tumour-induced cachexia in rats are not caused by decreased food intake.

    PubMed

    Cassolla, Priscila; Moreira, Carolina Campos Lima; Liboni, Thaís Fernanda; Zaia, Cássia Thaïs Bussamra Vieira; Borba-Murad, Glaucia Regina; Bazotte, Roberto Barbosa; de Souza, Helenir Medri

    2012-06-01

    Blood metabolic parameters of Walker-256 tumour-bearing rats, on days 5, 8, 11 and 14 after implantation of tumour, were compared with those of rats without tumour fed ad libitum (free-fed control) or with reduced feeding (pair-fed control), similar to the anorexic tumour-bearing rats. Cachexia parameters and tumour mass also were investigated. In general, especially on day 14 after implantation of tumour, there was reduction of body mass, gastrocnemius muscle mass, food intake and glycemia and increase of blood triacylglycerol, free fatty acids, lactate and urea, compared with free-fed controls rats. These changes did not occur in pair-fed control, except a slight reduction of glycemia. Pair-fed control showed no significant changes in blood cholesterol and glycerol in comparison with free-fed control, although there was reduction of cholesterol and increase of blood glycerol on day 14 after tumour implantation compared with pair-fed control. The results demonstrate that, besides the characteristic signs of the cachexia syndrome such as anorexia, weight loss and muscle catabolism, Walker-256 tumour-bearing rats show several blood metabolic alterations, some of which begin as early as day 5 after implantation of tumour, and are accentuated during the development of cachexia. Evidence that the alterations of blood metabolic parameters of tumour-bearing rats were not found in pair-fed control indicate that they were not caused by decreased food intake. These changes were probably mediated by factors produced by tumour or host tissue in response to the presence of tumour.

  8. Vascular endothelial growth factor directly stimulates tumour cell proliferation in non-small cell lung cancer.

    PubMed

    Devery, Aoife M; Wadekar, Rekha; Bokobza, Sivan M; Weber, Anika M; Jiang, Yanyan; Ryan, Anderson J

    2015-09-01

    Vascular endothelial growth factor (VEGF) is a key stimulator of physiological and pathological angiogenesis. VEGF signals primarily through VEGF receptor 2 (VEGFR2), a receptor tyrosine kinase whose expression is found predominantly on endothelial cells. The purpose of this study was to determine the role of VEGFR2 expression in NSCLC cells. NSCLC cells and tissue sections were stained for VEGFR2 expression by immunohistochemistry (IHC). Immunoblotting and ELISA were used to determine the activation and inhibition of VEGFR2 and its downstream signalling pathways. Five-day proliferation assays were carried out in the presence or absence of VEGF. IHC analysis of NSCLC demonstrated tumour cell VEGFR2 expression in 20% of samples. Immunoblot analysis showed expression of VEGFR2 protein in 3/8 NSCLC cell lines that correlated with VEGFR2 mRNA expression levels. VEGF-dependent VEGFR2 activation was apparent in NSCLC cells, and was associated with increased tumor cell proliferation. Cediranib treatment or siRNA against VEGFR2 inhibited VEGF-dependent increases in cell proliferation. Inhibition of VEGFR2 tyrosine kinase activity using cediranib was more effective than inhibition of AKT (MK2206) or MEK (AZD6244) for overcoming VEGFR2-driven cell proliferation. VEGF treatment did not affect cell survival following treatment with radiation, cisplatin, docetaxel or gemcitabine. Our data suggest that a subset of NSCLC tumour cells express functional VEGFR2 which can act to promote VEGF-dependent tumour cell growth. In this tumour subset, therapies targeting VEGFR2 signalling, such as cediranib, have the potential to inhibit both tumour cell proliferation and angiogenesis.

  9. Experimental colonic carcinogenesis: changes in faecal bile acids after promotion of intestinal tumours by small bowel resection in the rat.

    PubMed Central

    Savage, A P; Sian, M S; Matthews, J L; Bloom, S R; Cooke, T

    1988-01-01

    Small bowel resection promotes the development of colonic tumours in azoxymethane treated rats. As high faecal bile acid concentrations are associated with colonic cancer and may be altered by resection, we have studied changes in faecal bile acid concentrations during promotion of colonic carcinogenesis by increasing small bowel resection. Twenty rats in each group underwent either jejunal transection or 20%, 50%, or 80% proximal small bowel resection. Tumours were induced with azoxymethane 10 mg/kg by 12 weekly subcutaneous injections, and faecal bile acid concentrations were measured at six and 16 weeks. Colonic tumour number rose from 0.6 per rat in the transection group to 1.6 per rat in the 50% resection group (p less than 0.01) but were not significantly different to transection values at 0.8 per rat in the 80% resection group. Total daily faecal bile acid excretion and bile acid concentrations fell with increasing resection from 14.2 (1.6) mg/rat/day and 5.8 (0.7) mg/g dry faeces respectively in the transection group to 6.5 (0.5) mg/rat/day and 2.9 (0.2) mg/g respectively in the 80% resection group (p less than 0.001). The greatest reduction was seen in the concentration of deoxycholic acid which has been particularly associated with the aetiology of colonic cancer. The promotion of colonic tumours following small bowel resection in carcinogen treated rats is unlikely to be mediated by changes in faecal bile acid concentration or composition. PMID:3371718

  10. Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion.

    PubMed Central

    Marinelli, A.; van Dierendonck, J. H.; van Brakel, G. M.; Irth, H.; Kuppen, P. J.; Tjaden, U. R.; van de Velde, C. J.

    1991-01-01

    Regional chemotherapy allows further exploitation of the steep dose response curve of most chemotherapeutic agents, while systemic toxicity remains tolerable. We investigated the difference in maximally tolerated dose, pharmacokinetics and antitumour effect comparing administration of melphalan as a bolus in isolated liver perfusion (ILP) or via hepatic artery infusion (HAI). For these in vivo studies an experimental model for liver metastases in male WAG/Ola rats is obtained by subcapsular inoculation of CC531 rat colon carcinoma cells. In this system, ILP allowed administration of a two times higher dose than HAI (12 mg kg-1 vs 6 mg kg-1). In both treatment modalities systemic toxicity (leukopenia) was dose limiting. No hepatic toxicity was observed. Bolus administration of the maximally tolerated doses of melphalan in HAI (6 mg kg-1) and ILP (12 mg kg-1) resulted in four times higher concentrations in both liver and tumour tissue of the ILP treated rats. However, the ratio of mean drug concentration in liver vs tumour tissue appeared to be 1.5 times that found for HAI. In the range of the in tumour tissue measured melphalan concentrations the CC531 cells showed a steep dose response relationship in vitro. Whereas HAI resulted in significant tumour growth delay, complete remissions were observed in 90% of the rats treated with ILP. This study shows that with 12 mg kg-1 melphalan in ILP highly effective drug concentrations are achieved in CC531 tumour tissue; although the melphalan concentration in liver tissue shows an even higher increase than in tumour tissue, hepatic toxicity is negligible in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1764369

  11. Pleuro-pulmonary tumours detected by clinical and chest X-ray analyses in rats transplanted with mesothelioma cells

    PubMed Central

    Pimpec-Barthes, F Le; Bernard, I; Alsamad, I Abd; Renier, A; Kheuang, L; Fleury-Feith, J; Devauchelle, P; Colonna, F Quintin; Riquet, M; Jaurand, M C

    1999-01-01

    New strategies for cancer therapy must be developed, especially in severe neoplasms such as malignant pleural mesothelioma. Animal models of cancer, as close as possible to the human situation, are needed to investigate novel therapeutical approaches. Orthotopic transplantation of cancer cells is then relevant and efforts should be made to follow up tumour evolution in animals. In the present study, we developed a method for the orthotopic growth of mesothelioma cells in the pleural cavity of Fischer 344 and nude rats, along with a procedure for clinical survey. Two mesothelioma cell lines, of rat and human origin, were inoculated by transthoracic puncture. Body weight determination and chest X-ray analyses permitted the follow-up of tumour evolution by identifying different stages. Autopsies showed that tumours localized on the whole pleural cavity (diaphragm, parietal pleura), mediastinum and pericardium. Tumour morphology and antigenic characteristics were consistent with those of the inoculated cells and were similar in both types of rats inoculated with the same cell type. These results demonstrate that mesothelioma formation in rats can be followed up by clinical and radiographic survey after gentle intrathoracic inoculation of mesothelioma cells, thus allowing the definition of stages of interest for further experimental trials. © 1999 Cancer Research Campaign PMID:10604731

  12. [Oxidative damage of gasoline engine exhausts to rat lung tissues].

    PubMed

    Che, Wang-Jun; Wang, Ling; Luo, Qing-Ying; Wu, Mei; Zhang, Zun-Zhen

    2009-01-01

    To study the effects of extracts of condensate, particulates and semivolatile organic compounds from gasoline engine exhaust on DNA damage, 8-oxoguanine DNA glycosylase-1 (OGG1) expression, and changes of ultra-structures in lungs of rats. Organic extracts of gasoline engine exhaust (GEE) was intratrachealy instilled into rat lungs at 0, 5.6, 16.7, and 50.0 L/kg body weight, respectively, once a week for a month. The single DNA strand break was measured by comet assay. The OGG1 was determined using immunohistochemistry method. The ultrastructure of lung cells was observed with electronic microscope. The rates of tailed cells detected by the comet assay increased significantly when the rats were exposed to 16.7 and 50.0 L/kg of GEE compared with those exposed to solvent only (P < 0.05). However, the tail length did not differ significantly between the groups. Similarly, exposure to 16.7 and 50.0 L/kg of GEE led to increased OGG1 significantly. Significant changes of mitochondria in type I and II alveolar cells as well as respiratory bronchiole epithelial cells were observed, which included decrease of numbers, pyknosis and swelling. Gasoline engine exhausts induce single DNA strand break, increase OGG1 expression, decrease numbers of mitochondria, and destroy ultrastructures of mitochondria in various lung cells of rats.

  13. Monitoring therapeutic response to tamoxifen in NMU-induced rat mammary tumours by 31P MRS.

    PubMed Central

    Baluch, S.; Midwood, C. J.; Griffiths, J. R.; Stubbs, M.; Coombes, R. C.

    1991-01-01

    Tamoxifen injections were given once a week for 4 weeks to 19 rats bearing N-methyl-N-nitrosourea (NMU)-induced mammary carcinomas. NMR spectra were collected on days 2, 7, 14, 21 and 28. Only 42% of the tumours responded to the tamoxifen in that they regressed significantly; another 21% did not change in size and 37% grew significantly. In the ones that did subsequently regress there were significant changes in the NTP/Pi ratio as early as 2 days after treatment, before any detectable change in volume was recorded, and continuing up to 21 days. The significance of these findings and the possible mechanisms underlying the changes are discussed. PMID:2069847

  14. Selenium repletion protects neonatal rat lungs from hyperoxia

    SciTech Connect

    Hyeyoung Kim; Wallig, M.A.; Picciano, M.F. Pennsylvania State Univ., University Park )

    1991-03-15

    Previously the authors reported that selenium adequate rat pups were resistant to lung damage due to high O{sub 2} exposure. The present study was designed to assess whether Se-deficient pups repleted during postnatal period could also be protected from lung injury. Female SD rats were bred and fed a Se deficient diet during pregnancy. On day 2 postpartum, dams were divided into two groups and either continued on a Se{sup {minus}} diet or fed a Se supplemented diet. On day 5 postpartum, litters in each group were randomly assigned to either air or high O{sub 2} environments. Matched dams were rotated daily between litters in air and O{sub 2} for 4 days. Double-blinded, histopathologic scoring of lungs from 9 day old pup showed that Se repletion significantly reduced the incidence of septal attenuation and interstitial inflammation. Additionally lung volume of Se repleted pups were significantly enhanced. RNA/DNA ratio and glutathione concentration of lung were increased in response to hyperoxia, but unrelated to Se nutriture. These results show that postnatal Se repletion protects the developing lung from oxygen-induced injury.

  15. Fluorometry of ischemia reperfusion injury in rat lungs in vivo

    NASA Astrophysics Data System (ADS)

    Sepehr, R.; Staniszewski, K.; Jacobs, E. R.; Audi, S.; Ranji, Mahsa

    2013-02-01

    Previously we demonstrated the utility of optical fluorometry to evaluate lung tissue mitochondrial redox state in isolated perfused rats lungs under various chemically-induced respiratory states. The objective of this study was to evaluate the effect of acute ischemia on lung tissue mitochondrial redox state in vivo using optical fluorometry. Under ischemic conditions, insufficient oxygen supply to the mitochondrial chain should reduce the mitochondrial redox state calculated from the ratio of the auto-fluorescent mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavoprotein Adenine Dinucleotide). The chest of anesthetized, and mechanically ventilated Sprague-Dawley rat was opened to induce acute ischemia by clamping the left hilum to block both blood flow and ventilation to one lung for approximately 10 minutes. NADH and FAD fluorescent signals were recorded continuously in a dark room via a fluorometer probe placed on the pleural surface of the left lung. Acute ischemia caused a decrease in FAD and an increase in NADH, which resulted in an increase in the mitochondrial redox ratio (RR=NADH/FAD). Restoration of blood flow and ventilation by unclamping the left hilum returned the RR back to its baseline. These results (increase in RR under ischemia) show promise for the fluorometer to be used in a clinical setting for evaluating the effect of pulmonary ischemia-reperfusion on lung tissue mitochondrial redox state in real time.

  16. Rat bone marrow mesenchymal stem cells undergo malignant transformation via indirect co-cultured with tumour cells.

    PubMed

    Liu, Jianping; Zhang, Yalan; Bai, Lu; Cui, Xiangrong; Zhu, Jing

    2012-12-01

    Mesenchymal stem cells (MSCs) have potential applications in regenerative medicine and tissue engineering as well as being potential carriers for tumour therapy. However, the safety of using MSCs in tumours is unknown. Herein, we analyse malignant transformation of MSCs in the tumour microenvironment. Rat bone marrow MSCs were cultured with malignant rat glioma C6 cells without direct cell-cell contact. After 7 days, the cells were assessed for transformation using flow cytometry, real-time quantitative PCR, immunofluorescence and chromosomal analysis. In addition, wild-type (WT) p53, mutant p53 and mdm2 was determined using Western blotting. Almost all MSCs became phenotypically malignant cells, with significantly decreased WT p53 expression and increased expression of mutant p53 and mdm2, along with an aneuploid karyotype. To evaluate tumorigenesis in vivo, the MSCs indirect co-cultured with C6 cells for 7 days were transplanted subcutaneously into immuno-deficient mice. The cells developed into a large tumour at the injection site within 8 weeks, with systemic symptoms including cachexia and scoliosis. Pathological and cytological analysis revealed poorly differentiated pleomorphic cells with a dense vascular network and aggressive invasion into the adjacent muscle. These data demonstrate that MSCs became malignant cancer cells when exposed to the tumour microenvironment and suggest that factors released from the cancer cells have a critical role in the malignant transformation of MSCs.

  17. Automatic classification of lung tumour heterogeneity according to a visual-based score system in dynamic contrast enhanced CT sequences

    NASA Astrophysics Data System (ADS)

    Bevilacqua, Alessandro; Baiocco, Serena

    2016-03-01

    Computed tomography (CT) technologies have been considered for a long time as one of the most effective medical imaging tools for morphological analysis of body parts. Contrast Enhanced CT (CE-CT) also allows emphasising details of tissue structures whose heterogeneity, inspected through visual analysis, conveys crucial information regarding diagnosis and prognosis in several clinical pathologies. Recently, Dynamic CE-CT (DCE-CT) has emerged as a promising technique to perform also functional hemodynamic studies, with wide applications in the oncologic field. DCE-CT is based on repeated scans over time performed after intravenous administration of contrast agent, in order to study the temporal evolution of the tracer in 3D tumour tissue. DCE-CT pushes towards an intensive use of computers to provide automatically quantitative information to be used directly in clinical practice. This requires that visual analysis, representing the gold-standard for CT image interpretation, gains objectivity. This work presents the first automatic approach to quantify and classify the lung tumour heterogeneities based on DCE-CT image sequences, so as it is performed through visual analysis by experts. The approach developed relies on the spatio-temporal indices we devised, which also allow exploiting temporal data that enrich the knowledge of the tissue heterogeneity by providing information regarding the lesion status.

  18. Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats.

    PubMed

    Lin, Xiaoxi B; Dieleman, Levinus A; Ketabi, Ali; Bibova, Ilona; Sawyer, Michael B; Xue, Hongyu; Field, Catherine J; Baracos, Vickie E; Gänzle, Michael G

    2012-01-01

    Intestinal microbiota mediate toxicity of irinotecan (CPT-11) cancer therapies and cause systemic infection after CPT-11-induced loss of barrier function. The intestinal microbiota and their functions are thus potential targets for treatment to mitigate CPT-11 toxicity. However, microbiota changes during CPT-11 therapy remain poorly described. This study analysed changes in intestinal microbiota induced by CPT-11 chemotherapy. Qualitative and quantitative taxonomic analyses, and functional analyses were combined to characterize intestinal microbiota during CPT-11-based chemotherapy, and in presence or absence of oral glutamine, a treatment known to reduce CPT-11 toxicity. In the first set of experiments tumour-bearing rats received a dose-intensive CPT-11 regimen (125 mg kg(-1)×3 days), with or without oral glutamine bolus (0.75 g kg(-1)). In a subsequent more clinically-oriented chemotherapy regimen, rats received two cycles of CPT-11 (50 mg kg(-1)) followed by 5-flurouracil (50 mg kg(-1)). The analysis of fecal samples over time demonstrated that tumours changed the composition of intestinal microbiota, increasing the abundance of clostrridial clusters I, XI, and Enterobacteriaceae. CPT-11 chemotherapy increased cecal Clostridium cluster XI and Enterobacteriaceae, particularly after the dose-intensive therapy. Glutamine treatment prevented the reduced abundance of major bacterial groups after CPT-11 administration; i.e. total bacteria, Clostridium cluster VI, and the Bacteroides-group. Virulence factor/toxin genes of pathogenic Escherichia coli and Clostridium difficile were not detected in the cecal microbiota. In conclusion, both colon cancer implantation and CPT-11-based chemotherapies disrupted the intestinal microbiota. Oral glutamine partially mitigated CPT-11 toxicity and induced temporary changes of the intestinal microbiota.

  19. Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer

    PubMed Central

    Gu, Fenfen; Hu, Chuling; Tai, Zhongguang; Yao, Chong; Tian, Jing; Zhang, Lijuan; Xia, Qingming; Gong, Chunai; Gao, Yuan; Gao, Shen

    2016-01-01

    In the present study, we developed a novel type of reduction-sensitive nanoparticles (NPs) for docetaxel (DTX) delivery based on cross-linked lipoic acid NPs (LANPs). The physicochemical properties, cellular uptake and in vitro cytotoxicity of DTX loaded LANPs (DTX-LANPs) on A549 cells were investigated. Furthermore, the in vivo distribution and in vivo efficacy of DTX-LANPs was evaluated. The results showed that DTX-LANPs had a particle size of 110 nm and a negative zeta potential of −35 mv with excellent colloidal stability. LANPs efficiently encapsulated DTX with a high drug loading of 4.51% ± 0.49% and showed remarkable reduction-sensitive drug release in vitro. Cellular uptake experiments demonstrated that LANPs significantly increased intracellular DTX uptake by about 10 fold as compared with free DTX. The cytotoxicity of DTX-LANPs showed significantly higher potency in inhibiting A549 cell growth than free DTX, while blank LANPs had a good biocompatibility. In addition, in vivo experiments demonstrated that DTX-LANPs could enhance tumour targeting and anti-tumour efficacy with low systemic toxicity. In conclusion, LANPs may prove to be a potential tumour microenvironment-responsive delivery system for cancer treatment, with the potential for commercialization due to the simple component, controllable synthesis, stability and economy. PMID:27805051

  20. Inhibitory effect of endostatin gene therapy combined with phosphorus-32 colloid on tumour growth in Wistar rats.

    PubMed

    Gao, Huiqi; Zhu, Jing; Li, Yong; Fu, Peng; Shen, Baozhong

    2016-07-01

    Eighty healthy male Wistar rats, aged 5 weeks, weighing 100-120 g, were utilized for establishing tumour-bearing models by immediate Walker-256 cancerous ascites injection and randomly divided to four groups (n=20) treated with 0.2 ml solution containing saline, (32)P-colloid (0.3 mCi), endostatin gene (20 μg), endostatin gene combined with colloid (32)P. The effect of endostatin combined with a small dose of (32)P-colloidal on tumour growth in vivo was evaluated and the potential mechanism underlying the combined therapy was explored. We found that (32)P-colloid combined with endostatin exhibited higher inhibitory effect upon tumour growth compared with application of (32)P-colloid or endostatin alone, although three therapies all significantly inhibited tumour growth compared with saline control group. The higher inhibitory effect of (32)P-colloid combined with endostatin upon tumour growth might be attributed to a synergistic effect of inhibiting angiogenesis by endostatin and inducing apoptosis by (32)P-colloid, as demonstrated by microvessel density (MVD) and apoptotic index (AI) measurement. Combined therapy of (32)P-colloid and endostatin probably serves as a novel and efficacious therapy of tumour growth.

  1. In patients with a tumour invading the phrenic nerve does prophylactic diaphragm plication improve postoperative lung function?

    PubMed

    Beattie, Gwyn W; Dunn, William G; Asif, Mohammed

    2016-09-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In patients with tumours involving the phrenic nerve, does prophylactic diaphragm plication improve lung function following tumour resection?' Using the reported search, 258 papers were found of which 6 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Three case reports and one case series represent 37 patients in the literature along with two relevant animal studies. Patients treated with prophylactic plication at the time of injury or sacrifice of the phrenic nerve had reduced radiological evidence of diaphragm paralysis, lower reported shortness of breath and reduced requirement for ventilatory support. In patients with prophylactic diaphragm plication and a concurrent pulmonary resection, the predicted postoperative lung function correlated closely with the postoperative measured FEV1, FVC and gas transfer. The postoperative measured FEV1 was reported as 86-98%, the FVC 82-89% and gas transfer 97% of the predicted values. Two animal models investigate the mechanics of respiration, spirometry and gas exchange following diaphragmatic plication. A randomized control study in four dogs measured a 50% reduction in tidal volume and respiratory rate, a 40% decrease in arterial PO2 and a 43% increase in arterial CO2 when the phrenic nerve was crushed in animals with a pneumonectomy but without prophylactic diaphragm plication. A further randomized control animal study with 28 dogs found that plicating the diaphragm after unilateral phrenic nerve transection resulted in a significant increase in tidal volume and lung compliance and a significant decrease in respiratory frequency and the work of breathing. Prophylactic diaphragm plication may preserve lung function, reduce the risk of

  2. Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma.

    PubMed

    Kinoshita, Tomonari; Kudo-Saito, Chie; Muramatsu, Reiko; Fujita, Tomonobu; Saito, Miyuki; Nagumo, Haruna; Sakurai, Toshiharu; Noji, Shinobu; Takahata, Emi; Yaguchi, Tomonori; Tsukamoto, Nobuo; Hayashi, Yuichiro; Kaseda, Kaoru; Kamiyama, Ikuo; Ohtsuka, Takashi; Tomizawa, Kenji; Shimoji, Masaki; Mitsudomi, Tetsuya; Asamura, Hisao; Kawakami, Yutaka

    2017-09-23

    We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8(+) T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8(+) T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8(+) T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8(+) T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8(+) T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8(+) FOXP3(+) T cells and immunodysfunctional CD8(+) GATA3(+) T cells were increased in adenocarcinoma of non-smokers. CD4(+) FOXP3(+) regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163(+) M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Inhibition of Lysyl Oxidase and Lysyl Oxidase-Like Enzymes Has Tumour-Promoting and Tumour-Suppressing Roles in Experimental Prostate Cancer.

    PubMed

    Nilsson, Maria; Adamo, Hanibal; Bergh, Anders; Halin Bergström, Sofia

    2016-01-25

    Lysyl oxidase (LOX) and LOX-like (LOXL) enzymes are key players in extracellular matrix deposition and maturation. LOX promote tumour progression and metastasis, but it may also have tumour-inhibitory effects. Here we show that orthotopic implantation of rat prostate AT-1 tumour cells increased LOX and LOXLs mRNA expressions in the tumour and in the surrounding non-malignant prostate tissue. Inhibition of LOX enzymes, using Beta-aminopropionitrile (BAPN), initiated before implantation of AT-1 cells, reduced tumour growth. Conversely, treatment that was started after the tumours were established resulted in unaffected or increased tumour growth. Moreover, treatment with BAPN did not suppress the formation of spontaneous lymph node metastases, or lung tumour burden, when tumour cells were injected intravenously. A temporal decrease in collagen fibre content, which is a target for LOX, was observed in tumours and in the tumour-adjacent prostate tissue. This may explain why early BAPN treatment is more effective in inhibiting tumour growth compared to treatment initiated later. Our data suggest that the enzymatic function of the LOX family is context-dependent, with both tumour-suppressing and tumour-promoting properties in prostate cancer. Further investigations are needed to understand the circumstances under which LOX inhibition may be used as a therapeutic target for cancer patients.

  4. Metabolic fluxes in the liver of rats bearing the Walker-256 tumour: influence of the circulating levels of substrates and fatty acids.

    PubMed

    da Veiga, Renata P; da Silva, Mário H R Alves; Teodoro, Graziele R; Yamamoto, Nair Seiko; Constantin, Jorgete; Bracht, Adelar

    2008-01-01

    Studies on fatty acid and amino acid metabolism in the liver of Walker-256 tumour-bearing rats have revealed several changes. Comparisons, however, have been based on experiments performed with non-physiological, frequently unrealistic, substrate concentrations. The aim of the present work was to examine the influence of physiological substrate concentrations on gluconeogenesis, ketogenesis and related parameters. Isolated livers were perfused and substrates were infused at concentrations that were reported to occur in healthy and tumour-bearing rats. Ketogenesis and the mitochondrial NADH/NAD+ ratio were smaller in the tumour-bearing condition at low (0.2 mM) and high (0.8 mM) oleate concentrations. In the absence of oleate, gluconeogenesis from alanine (0.7 mM) and gluconeogenesis plus the associated changes in oxygen uptake due to lactate/pyruvate (2/0.2 and 6/0.3 mM) were smaller in livers of tumour-bearing rats. However, the response of gluconeogenesis from lactate/pyruvate in livers of tumour-bearing rats to 0.8 mM oleate was more pronounced so that a trend towards normalization was apparent at high substrate and oleate concentrations. Gluconeogenesis from 0.7 mM alanine was not significantly changed by oleate in the tumour-bearing state; in the control condition, stimulation occurred at 0.2 mM oleate and inhibition at 0.8 mM oleate. This diminution almost equalized the hepatic alanine-dependent gluconeogenesis of both control and tumour-bearing rats. Ureogenesis was smaller in the tumour-bearing state and was not affected by oleate. It was concluded that the high concentrations of fatty acids and lactate/pyruvate, which predominate in rats bearing the Walker-256 tumour, could be effective in normalizing the gluconeogenic response of livers from tumour-bearing rats.

  5. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

    SciTech Connect

    El-Agamy, Dina S.

    2011-06-01

    The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells

  6. Asbestos fibres and man made mineral fibres: induction and release of tumour necrosis factor-alpha from rat alveolar macrophages.

    PubMed Central

    Ljungman, A G; Lindahl, M; Tagesson, C

    1994-01-01

    OBJECTIVES--Mounting evidence suggests that asbestos fibres can stimulate alveolar macrophages to generate the potent inflammatory and fibrogenic mediator, tumour necrosis factor-alpha (TNF-alpha), and that this may play an important part in the onset and development of airway inflammation and lung fibrosis due to asbestos fibre inhalation. Little is known, however, about the ability of other mineral fibres to initiate formation and release of TNF-alpha by alveolar macrophages. Therefore the effects of different fibres (crocidolite, chrysotile A, chrysotile B, two man made mineral fibres (MMVF 21 and MMVF 22), a ceramic fibre (RCF 1), and a silicon carbide whisker fibre (SiCwh)) on formation and release of TNF-alpha by rat alveolar macrophages were examined. METHODS--Cells were isolated and incubated at 37 degrees C with the different fibres, or with culture medium alone (controls), and the amounts of TNF-alpha messenger RNA (mRNA) in the cells and TNF-alpha bioactivity released into the culture medium were measured at different time points. RESULTS--Significantly (P < 0.05 v control) increased amounts of TNF-alpha mRNA were found in cells exposed to crocidolite, chrysotile A, chrysotile B, MMVF 21, RCF 1, or SiCwh for 90 minutes, and significantly (P < 0.05 v control) increased activities of TNF-alpha were found in the medium of macrophages exposed to crocidolite, chrysotile A, chrysotile B, or MMVF 21 for four hours. CONCLUSION--These observations suggest that not only natural mineral fibres but also certain man made mineral fibres are able to induce the formation and release of TNF-alpha by alveolar macrophages in vitro. Images Figure 1 Figure 3 PMID:7849857

  7. Treatment outcomes and patterns of radiologic appearance after hypofractionated image-guided radiotherapy delivered with helical tomotherapy (HHT) for lung tumours.

    PubMed

    Arcangeli, Stefano; Falcinelli, Lorenzo; Bracci, Stefano; Greco, Alessandro; Monaco, Alessia; Dognini, Jessica; Chiostrini, Cinzia; Bellavita, Rita; Aristei, Cynthia; Donato, Vittorio

    2017-03-01

    To evaluate treatment outcomes and patterns of CT lung injury after hypofractionated image-guided radiotherapy delivered with helical tomotherapy (HHT) in a series of inoperable lung lesions. 68 patients who were medically inoperable (69 lesions) without evidence of viable extrathoracic disease were included. Dose prescription was driven by tumour location (hilar/pericentral vs peripheral) and/or target volume. 52% of the lesions received a biological equivalent dose (BED10) ≥100 Gy. Assessment of tumour response was based on the Response Evaluation Criteria in Solid Tumours 1.1 criteria coupled with fluorine-18 fludeoxyglucose/positron emission tomography-CT. Toxicity monitoring was focused on treatment-related pulmonary adverse events according to the Common Terminology Criteria for Adverse Events v. 4.0. Acute and late events were classified as radiation pneumonitis (RP) and radiation fibrosis (RF), respectively. Survival curves were calculated using the Kaplan-Meier method. Univariate and multivariate analyses of survival were performed using the Cox proportional hazards model. After a median follow-up of 12 months (range, 3-31 months), no instances of ≥Grade 4 RP was documented, and clinically severe (Grade 3) RP occurred in 5.8% of the patients. 2 (3%) patients developed a late severe (≥Grade 3) symptomatic RF. No specific pattern of CT lung injury was demonstrated, in both acute and late settings. Median overall survival (OS) and progression-free survival (PFS) for the entire population were 30.8 and 14.1 months, respectively. At multivariate analysis (MVA), BED10 ≥ 100 Gy and KPS ≥ 90 emerged as significant prognostic factors for OS (p = 0.01 and p = 0.001, respectively), and BED10 ≥ 100 Gy for PFS (p = 0.02). Our findings show that HHT adjusted for tumour location and/or target volume is an effective treatment with an acceptable toxicity profile in patients who are medically inoperable with lung tumours and is not

  8. Quantitative x ray microanalysis of pulmonary mineral particles in a patient with pneumoconiosis and two primary lung tumours.

    PubMed Central

    Anttila, S; Sutinen, S; Pääkkö, P; Alapieti, T; Peura, R; Sivonen, S J

    1984-01-01

    The right upper lung lobe of a 74 year old man was resected for a central tumour. Two primary cancers were found; a central small cell carcinoma and a peripheral squamous cell carcinoma. In addition, the peripheral lung tissue showed generalised peribronchiolar fibrosis extending from the non-respiratory bronchioles to the level of the alveolar ducts. Abundant asbestos bodies and large amounts of black dust were seen around the bronchioles. Pulmonary mineral particles were studied by quantitative energy dispersive x ray microanalysis (EDS) using scanning transmission electron microscopy (STEM). The x ray spectra for mineral particles were measured in thin sections, and the characteristic peak intensities of the elements were converted to weight fractions (in oxides). The results enabled the minerals present to be identified and their presence confirmed by calculating the mineral formula. These originated from nine natural minerals, anthophyllite and chrysotile asbestos, talc, and quartz, feldspars, and muscovite, which are components of sand, and also from two artificial mullites used in fire clay. The exposure history of the patient explained the most likely origins of the minerals detected. The patient had been a mason for 23 years, repairing and demolishing stoves and fireplaces and using asbestos for insulation work. Images PMID:6093848

  9. Determinant factor for clearance of ceramic fibres from rat lungs.

    PubMed Central

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1992-01-01

    Deposition, clearance, retention, and durability of inhaled particles from lungs are known to be important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of alumina silicate ceramic fibres from the lung, male Wistar rats were exposed to ceramic fibre particles with a mass median aerodynamic diameter (MMAD) of 4.2 micron, for six hours a day, five days a week for two weeks. The average exposure concentration was 20.7 (standard deviation (SD) 4.5) mg/m3. The rats were killed at one day, three months, and six months after the end of exposure, and the fibre numbers and dimensions were measured with a scanning electron microscope. No significant differences in number and geometric mean length of residual ceramic fibres in the lungs were found between the groups. The geometric mean diameter, however, decreased according to the duration of the clearance period. These findings suggest that solubility of fibre contributes most in the clearance of the inhaled ceramic fibres from the lungs. PMID:1554614

  10. Determinant factor for clearance of ceramic fibres from rat lungs.

    PubMed

    Yamato, H; Tanaka, I; Higashi, T; Kido, M

    1992-03-01

    Deposition, clearance, retention, and durability of inhaled particles from lungs are known to be important factors for induction of pulmonary fibrosis or lung cancer. To study the deposition and clearance of alumina silicate ceramic fibres from the lung, male Wistar rats were exposed to ceramic fibre particles with a mass median aerodynamic diameter (MMAD) of 4.2 micron, for six hours a day, five days a week for two weeks. The average exposure concentration was 20.7 (standard deviation (SD) 4.5) mg/m3. The rats were killed at one day, three months, and six months after the end of exposure, and the fibre numbers and dimensions were measured with a scanning electron microscope. No significant differences in number and geometric mean length of residual ceramic fibres in the lungs were found between the groups. The geometric mean diameter, however, decreased according to the duration of the clearance period. These findings suggest that solubility of fibre contributes most in the clearance of the inhaled ceramic fibres from the lungs.

  11. Curcumin protects bleomycin-induced lung injury in rats.

    PubMed

    Venkatesan, N; Punithavathi, V; Chandrakasan, G

    1997-01-01

    The present study was designed to determine the protective effects of curcumin against bleomycin (BLM)-induced inflammatory and oxidant lung injury. The data indicate that BLM-mediated lung injury resulted in increases in lung lavage fluid biomarkers such as total protein, angiotensin-converting enzyme (ACE), lactate dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), lipid peroxidation (LPO) products, superoxide dismutase (SOD) and catalase. Bleomycin administration also resulted in increased levels of malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage (BAL) cells and greater amounts of alveolar macrophage (AM) superoxide dismutase activity. By contrast, lower levels of reduced glutathione (GSH) were observed in lung lavage fluid, BAL cells and AM. Stimulated superoxide anion and hydrogen peroxide release by AM from BLM rats were found to be higher. Curcumin treatment resulted in a significant reduction in lavage fluid biomarkers. In addition, curcumin treatment resulted in the restoration of antioxidant status in BLM rats. These data suggest that curcumin treatment reduces the development of BLM-induced inflammatory and oxidant activity. Therefore, curcumin offers the potential for a novel pharmacological approach in the suppression of drug or chemical-induced lung injury.

  12. A Mechanism for the induction of renal tumours in male Fischer 344 rats by short-chain chlorinated paraffins.

    PubMed

    Warnasuriya, Gayathri D; Elcombe, Barbara M; Foster, John R; Elcombe, Clifford R

    2010-03-01

    Short-chain chlorinated paraffins (SCCPs) cause kidney tumours in male rats, but not in female rats or mice of either sex. Male rat-specific tumours also occur in rats dosed with a range of compounds including 1,4- dichlorobenzene (DCB) and d-limonene (DL). These compounds bind to a male rat-specific hepatic protein, alpha-2-urinary globulin (α2u), and form degradationresistant complexes in the kidney. The resulting accumulation of α2u causes cell death and sustained regenerative cell proliferation, which in turn leads to the formation of renal tumours. To investigate whether the SCCP, Chlorowax 500C (C500C), causes tumours via the accumulation of α2u male rats were orally dosed with either C500C (625 mg/kg of body weight), DCB (300 mg/kg of body weight), or DL (150 mg/kg of body weight) for 28 consecutive days. An increase in renal α2u and cell proliferation was observed in DCB- and DL-treated rats but not in C500C-treated rats. C500C caused peroxisome proliferation and a down-regulation of α2u synthesis in male rat liver. This down-regulation occurred at the transcriptional level. Since less α2u was produced in C500C-treated rats, there was less available for accumulation in the kidney hence a typical α2u nephropathy did not appear. However, the administration of a radiolabelled SCCP, [14C]polychlorotridecane (PCTD), to male rats demonstrated its binding to renal α2u. Thus, it is possible that SCCPs bind to α2u and cause a slow accumulation of the protein in the kidney followed by delayed onset of α2u nephropathy. As a consequence of these findings in the current experiments, while evidence exists implicating α2u-globulin in the molecular mechanism of action of the C500C, the classic profile of a α2u-globulin nephropathy seen with other chemicals such as DCB and DL was not reproduced during this experimental protocol.

  13. Changes in thermogenesis and brown fat activity in response to tumour necrosis factor in the rat.

    PubMed

    Coombes, R C; Rothwell, N J; Shah, P; Stock, M J

    1987-10-01

    A single intravenous injection of recombinant human tumour necrosis factor (TNF) resulted in significant, but transient (24-48 hr) reductions in food intake and body weight, and increases in rectal temperature, resting oxygen consumption (VO2) and brown adipose tissue (BAT) thermogenic activity (mitochondrial GDP-binding). The increased VO2 was inhibited by beta-adrenergic blockade (propranolol), and activation of BAT was prevented by denervation of the tissue. In adult (4-month old) animals, TNF induced greater reductions in food intake and body weight, caused general malaise and some fatalities, but did not significantly alter VO2 or BAT activity. However, the reduction in VO2 following beta-adrenergic blockade was greater in TNF-treated rats and BAT activity was enhanced when compared to pair-fed controls. Injection of adult rats with gamma-interferon induced small changes in body weight and temperature which were slightly potentiated when injected with a low dose of TNF. The results indicate that TNF stimulates sympathetic outflow to BAT. This effect may be partly responsible for the increases in body temperature and metabolic rate associated with TNF treatment and with cancer cachexia.

  14. Primary renal carcinoid tumour with lung metastasis misdiagnosed as renal cell carcinoma.

    PubMed

    Daboul, Nour; Monga, Dulabh; Bunker, Mark

    2016-03-07

    A 58-year-old man with a history of metastatic renal cell carcinoma (RCC) diagnosed 10 years prior, status post right nephrectomy, presented for evaluation of pulmonary nodules. A year after the nephrectomy, he had undergone cutaneous metastasectomy in the right flank area, and a further 2 years later he had had his second cutaneous metastasectomy in the right chest wall. Both cutaneous pathologies had, at the time, shown metastatic neoplasm with histological features compatible with those of the previous renal tumour. He was treated with sorafenib. 3 years later he developed asymptomatic pulmonary nodules, which gradually doubled in size over the next 2.5 years. He underwent bronchoscopy and left lower lobe biopsy. Pathology revealed a metastatic renal carcinoid/neuroendocrine tumour. Second review of the previous renal neoplasm and the cutaneous metastatic pathology showed trabecular architecture, consistent with carcinoid, but mimicking the long parallel arrays that have been described in some cases of papillary RCC. 2016 BMJ Publishing Group Ltd.

  15. Lung cancer in rats exposed to fibrogenic dusts

    SciTech Connect

    Holland, L.M.; Wilson, J.S.; Tillery, M.I.; Smith, D.M.

    1984-01-01

    Fischer-344 rats were exposed to quartz dusts and to quartz-bearing oil shale dusts in long-term inhalation studies. Aerosol concentrations of 12 mg/m/sup 3/ and 152-176 mg/m/sup 3/ for quartz and shale dusts, respectively, were used in exposure regimens lasting up to two years. Pulmonary fibrosis was observed in most animals surviving beyond 400 days. Adenocarcinomas and epidermoid carcinomas of the lung were observed in animals from all exposure groups, including those exposed to quartz alone. The pulmonary tumors were a late effect, with the earliest lung tumor being observed after 651 days. 13 references, 10 figures, 4 tables.

  16. Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats.

    PubMed

    Liu, Rongfang; Fang, Xianhai; Meng, Chao; Xing, Jingchun; Liu, Jinfeng; Yang, Wanchao; Li, Wenzhi; Zhou, Huacheng

    2015-09-01

    Hydrogen has antioxidant and anti-inflammatory effects on lung ischemia-reperfusion injury when it is inhaled by donor or/and recipient. This study examined the effects of lung inflation with 3% hydrogen during the cold ischemia phase on lung graft function in rats. The donor lung was inflated with 3% hydrogen, 40% oxygen, and 57% nitrogen at 5 mL/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. In the control group, the donor lung was inflated with 40% oxygen and 60% nitrogen at 5 mL/kg. The recipient was euthanized 2 h after orthotropic lung transplantation. The hydrogen concentration in the donor lung during the cold ischemia phase was 1.99-3%. The oxygenation indices in the arterial blood and pulmonary vein blood were improved in the hydrogen group. The inflammation response indices, including lung W/D ratio, the myeloperoxidase activity in the grafts, and the levels of IL-8 and TNF-α in serum, were significantly lower in the hydrogen group (5.2 ± 0.8, 0.76 ± 0.32 U/g, 340 ± 84 pg/mL, and 405 ± 115 pg/mL, respectively) than those in the control group (6.5 ± 0.7, 1.1 ± 0.5 U/g, 443 ± 94 pg/mL, and 657 ± 96 pg/mL, respectively (P < 0.05), and the oxidative stress indices, including the superoxide dismutase activity and the level of malonaldehyde in lung grafts were improved after hydrogen application. Furthermore, the lung injury score determined by histopathology, the cell apoptotic index, and the caspase-3 protein expression in lung grafts were decreased after hydrogen treatment, and the static pressure-volume curve of lung graft was improved by hydrogen inflation. In conclusion, lung inflation with 3% hydrogen during the cold ischemia phase alleviated lung graft injury and improved graft function.

  17. Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats

    PubMed Central

    Liu, Rongfang; Fang, Xianhai; Meng, Chao; Xing, Jingchun; Liu, Jinfeng; Yang, Wanchao

    2015-01-01

    Hydrogen has antioxidant and anti-inflammatory effects on lung ischemia–reperfusion injury when it is inhaled by donor or/and recipient. This study examined the effects of lung inflation with 3% hydrogen during the cold ischemia phase on lung graft function in rats. The donor lung was inflated with 3% hydrogen, 40% oxygen, and 57% nitrogen at 5 mL/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. In the control group, the donor lung was inflated with 40% oxygen and 60% nitrogen at 5 mL/kg. The recipient was euthanized 2 h after orthotropic lung transplantation. The hydrogen concentration in the donor lung during the cold ischemia phase was 1.99–3%. The oxygenation indices in the arterial blood and pulmonary vein blood were improved in the hydrogen group. The inflammation response indices, including lung W/D ratio, the myeloperoxidase activity in the grafts, and the levels of IL-8 and TNF-α in serum, were significantly lower in the hydrogen group (5.2 ± 0.8, 0.76 ± 0.32 U/g, 340 ± 84 pg/mL, and 405 ± 115 pg/mL, respectively) than those in the control group (6.5 ± 0.7, 1.1 ± 0.5 U/g, 443 ± 94 pg/mL, and 657 ± 96 pg/mL, respectively (P < 0.05), and the oxidative stress indices, including the superoxide dismutase activity and the level of malonaldehyde in lung grafts were improved after hydrogen application. Furthermore, the lung injury score determined by histopathology, the cell apoptotic index, and the caspase-3 protein expression in lung grafts were decreased after hydrogen treatment, and the static pressure–volume curve of lung graft was improved by hydrogen inflation. In conclusion, lung inflation with 3% hydrogen during the cold ischemia phase alleviated lung graft injury and improved graft function. PMID:25662956

  18. Patient characteristics, treatment and survival in pulmonary carcinoid tumours: an analysis from the UK National Lung Cancer Audit

    PubMed Central

    Hobbins, Stephanie; West, Doug; Peake, Michael; Beckett, Paul; Woolhouse, Ian

    2016-01-01

    Objectives Pulmonary carcinoid (PC) is a rare tumour with good prognosis following surgical resection. However, little is known regarding patient characteristics and use of other treatments modalities. Our objective was to review patient characteristics, treatment and survival for patients with PC and contrast these results with other forms of non-small cell lung cancer (NSCLC). Setting Audit data from UK National Lung Cancer Audit (NLCA) 2008–2013. Participants 184 906 lung cancer cases were submitted to the NLCA. Outcome measures Primary outcome—survival rates between PC and NSCLC. Secondary outcome—differences in performance status, lung function and treatment modality between PC and NSCLC. Results PC histology was recorded in 1341 (0.73%) patients and non-carcinoid NSCLC histology in 162 959 (87.4%) cases. 91% of patients with PC had good performance status (Eastern Cooperative Oncology Group (ECOG) 0–1), compared with only 53% of NSCLC. 66% of PC had localised disease. Of all PC cases, 77% were treated with surgery, 6.2% received chemotherapy and 3.6% received radiotherapy, with the remainder treated with best supportive care. Overall 1-year and 3-year survival rates for PC were 92% and 84.7%, respectively. In contrast, 1-year and 3-year survival rates for NSCLC were 36.2% and 15.6%, However, 3-year survival for PC markedly decreased with worsening performance status and advanced disease to 23.8% for performance status ECOG 3–4 and 33.6% for stage IV disease. Conclusions In contrast to other forms of NSCLC, the majority of patients with PC present with good performance status, preserved lung function and early stage disease amenable to surgical resection. However, 1 in 5 patients with PC has metastatic disease which is associated with poor prognosis, as is poor performance status at presentation. We believe these data will help clinicians provide accurate prognostic predictions stratified according to patient characteristics at presentation, as

  19. Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

    PubMed Central

    Ono, K; Ishihara, M; Ishikawa, K; Ozeki, Y; Deguchi, H; Sato, M; Hashimoto, H; Saito, Y; Yura, H; Kurita, A; Maehara, T

    2002-01-01

    Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2- or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy. British Journal of Cancer (2002) 86, 1803–1812. doi:10.1038/sj.bjc.6600307 www

  20. Tracking lung tumour motion using a dynamically weighted optical flow algorithm and electronic portal imaging device

    NASA Astrophysics Data System (ADS)

    Teo, P. T.; Crow, R.; Van Nest, S.; Sasaki, D.; Pistorius, S.

    2013-07-01

    This paper investigates the feasibility and accuracy of using a computer vision algorithm and electronic portal images to track the motion of a tumour-like target from a breathing phantom. A multi-resolution optical flow algorithm that incorporates weighting based on the differences between frames was used to obtain a set of vectors corresponding to the motion between two frames. A global value representing the average motion was obtained by computing the average weighted mean from the set of vectors. The tracking accuracy of the optical flow algorithm as a function of the breathing rate and target visibility was investigated. Synthetic images with different contrast-to-noise ratios (CNR) were created, and motions were tracked. The accuracy of the proposed algorithm was compared against potentiometer measurements giving average position errors of 0.6 ± 0.2 mm, 0.2 ± 0.2 mm and 0.1 ± 0.1 mm with average velocity errors of 0.2 ± 0.2 mm s-1, 0.4 ± 0.3 mm s-1 and 0.6 ± 0.5 mm s-1 for 6, 12 and 16 breaths min-1 motions, respectively. The cumulative average position error reduces more rapidly with the greater number of breathing cycles present in higher breathing rates. As the CNR increases from 4.27 to 5.6, the average relative error approaches zero and the errors are less dependent on the velocity. When tracking a tumour on a patient's digitally reconstructed radiograph images, a high correlation was obtained between the dynamically weighted optical flow algorithm, a manual delineation process and a centroid tracking algorithm. While the accuracy of our approach is similar to that of other methods, the benefits are that it does not require manual delineation of the target and can therefore provide accurate real-time motion estimation during treatment.

  1. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

    PubMed

    Lin, Chia-Chih; Hsieh, Nan-Kuang; Liou, Huey Ling; Chen, Hsing I

    2012-03-01

    Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial

  2. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

    PubMed Central

    2012-01-01

    Background Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. Methods The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. Results PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Conclusions Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA

  3. Classifying geometric variability by dominant eigenmodes of deformation in regressing tumours during active breath-hold lung cancer radiotherapy.

    PubMed

    Badawi, Ahmed M; Weiss, Elisabeth; Sleeman, William C; Hugo, Geoffrey D

    2012-01-21

    The purpose of this study is to develop and evaluate a lung tumour interfraction geometric variability classification scheme as a means to guide adaptive radiotherapy and improve measurement of treatment response. Principal component analysis (PCA) was used to generate statistical shape models of the gross tumour volume (GTV) for 12 patients with weekly breath hold CT scans. Each eigenmode of the PCA model was classified as 'trending' or 'non-trending' depending on whether its contribution to the overall GTV variability included a time trend over the treatment course. Trending eigenmodes were used to reconstruct the original semi-automatically delineated GTVs into a reduced model containing only time trends. Reduced models were compared to the original GTVs by analyzing the reconstruction error in the GTV and position. Both retrospective (all weekly images) and prospective (only the first four weekly images) were evaluated. The average volume difference from the original GTV was 4.3% ± 2.4% for the trending model. The positional variability of the GTV over the treatment course, as measured by the standard deviation of the GTV centroid, was 1.9 ± 1.4 mm for the original GTVs, which was reduced to 1.2 ± 0.6 mm for the trending-only model. In 3/13 cases, the dominant eigenmode changed class between the prospective and retrospective models. The trending-only model preserved GTV and shape relative to the original GTVs, while reducing spurious positional variability. The classification scheme appears feasible for separating types of geometric variability by time trend.

  4. Endotoxin suppresses surfactant synthesis in cultured rat lung cells

    SciTech Connect

    Li, J.J.; Sanders, R.L.; McAdam, K.P.; Gelfand, J.A.; Burke, J.F.

    1989-02-01

    Pulmonary complications secondary to postburn sepsis are a major cause of death in burned patients. Using an in vitro organotypic culture system, we examined the effect of E. coli endotoxin (LPS) on lung cell surfactant synthesis. Our results showed that E. coli endotoxin (1.0, 2.5, 10 micrograms LPS/ml) was capable of suppressing the incorporation of /sup 3/H-choline into de novo synthesized surfactant, lamellar bodies (LB), and common myelin figures (CMF) at 50%, 68%, and 64%, respectively. In a similar study, we were able to show that LPS also inhibited /sup 3/H-palmitate incorporation by cultured lung cells. LPS-induced suppression of surfactant synthesis was reversed by hydrocortisone. Our results suggest that LPS may play a significant role in reducing surfactant synthesis by rat lung cells, and thus contribute to the pathogenesis of sepsis-related respiratory distress syndrome (RDS) in burn injury.

  5. Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

    PubMed Central

    Singleton, Eric; Tang, Chi; Zuena, Michael; Shukla, Sean; Gupta, Shilpi; Dharani, Sonal; Onyile, Onoyom; Rinaggio, Joseph; Connell, Nancy D.

    2016-01-01

    ABSTRACT Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are predatory bacteria that naturally—and obligately—prey on other Gram-negative bacteria, and their use has been proposed as a potential new approach to control microbial infection. The ability of predatory bacteria to prey on Gram-negative human pathogens in vitro is well documented; however, the in vivo safety and efficacy of predatory bacteria have yet to be fully assessed. In this study, we examined whether predatory bacteria can reduce bacterial burden in the lungs in an in vivo mammalian system. Initial safety studies were performed by intranasal inoculation of rats with predatory bacteria. No adverse effects or lung pathology were observed in rats exposed to high concentrations of predatory bacteria at up to 10 days postinoculation. Enzyme-linked immunosorbent assay (ELISA) of the immune response revealed a slight increase in inflammatory cytokine levels at 1 h postinoculation that was not sustained by 48 h. Additionally, dissemination experiments showed that predators were efficiently cleared from the host by 10 days postinoculation. To measure the ability of predatory bacteria to reduce microbial burden in vivo, we introduced sublethal concentrations of Klebsiella pneumoniae into the lungs of rats via intranasal inoculation and followed with multiple doses of predatory bacteria over 24 h. Predatory bacteria were able to reduce K. pneumoniae bacterial burden, on average, by more than 3.0 log10 in the lungs of most rats as measured by CFU plating. The work presented here provides further support for the idea of developing predatory bacteria as a novel biocontrol agent. PMID:27834203

  6. Biochemical signatures of in vitro radiation response in human lung, breast and prostate tumour cells observed with Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Matthews, Q.; Jirasek, A.; Lum, J. J.; Brolo, A. G.

    2011-11-01

    This work applies noninvasive single-cell Raman spectroscopy (RS) and principal component analysis (PCA) to analyze and correlate radiation-induced biochemical changes in a panel of human tumour cell lines that vary by tissue of origin, p53 status and intrinsic radiosensitivity. Six human tumour cell lines, derived from prostate (DU145, PC3 and LNCaP), breast (MDA-MB-231 and MCF7) and lung (H460), were irradiated in vitro with single fractions (15, 30 or 50 Gy) of 6 MV photons. Remaining live cells were harvested for RS analysis at 0, 24, 48 and 72 h post-irradiation, along with unirradiated controls. Single-cell Raman spectra were acquired from 20 cells per sample utilizing a 785 nm excitation laser. All spectra (200 per cell line) were individually post-processed using established methods and the total data set for each cell line was analyzed with PCA using standard algorithms. One radiation-induced PCA component was detected for each cell line by identification of statistically significant changes in the PCA score distributions for irradiated samples, as compared to unirradiated samples, in the first 24-72 h post-irradiation. These RS response signatures arise from radiation-induced changes in cellular concentrations of aromatic amino acids, conformational protein structures and certain nucleic acid and lipid functional groups. Correlation analysis between the radiation-induced PCA components separates the cell lines into three distinct RS response categories: R1 (H460 and MCF7), R2 (MDA-MB-231 and PC3) and R3 (DU145 and LNCaP). These RS categories partially segregate according to radiosensitivity, as the R1 and R2 cell lines are radioresistant (SF2 > 0.6) and the R3 cell lines are radiosensitive (SF2 < 0.5). The R1 and R2 cell lines further segregate according to p53 gene status, corroborated by cell cycle analysis post-irradiation. Potential radiation-induced biochemical response mechanisms underlying our RS observations are proposed, such as (1) the regulated

  7. Relationship of jute dust to interstitial fibrosis in rat lung.

    PubMed

    Chen, Jie; Wang, Xiaobin; Lou, Jiezhi; Liu, Zhenlin

    2003-03-01

    The relationship between jute dust and lung interstitial fibrosis was studied by instilling groups of rats, via trachea, with jute dust and comparing the results with those for positive (quartz) and negative (saline) controls. The rats were sacrificed at regular intervals and their lungs and hilar lymph nodes were analyzed for collagen content and morphologic changes. The earliest changes consisted of alveolar edema, increased numbers of intraalveolar macrophages, and marked thickening of the interalveolar septa, with mixed cellular infiltrates. Moderate thickening of the alveolar walls and the zones around the peribronchioles was seen in the test groups at 6 mo. After 12 mo, some fibrosis of the alveoli walls and peribronchiole zones occurred. Interstitial cellular nodules were observed occasionally, composed mainly of dust particles, fibroblasts, reticular fibers, and collagen fibers. The collagen content in the lungs of the jute dust groups was significantly higher than for the saline control group for all test periods. The authors conclude that jute dust may induce lung interstitial fibrosis.

  8. Correlation analysis of [(18)F]fluorodeoxyglucose and [(18)F]fluoroazomycin arabinoside uptake distributions in lung tumours during radiation therapy.

    PubMed

    Di Perri, Dario; Lee, John A; Bol, Anne; Hanin, François-Xavier; Janssens, Guillaume; Labar, Daniel; Robert, Annie; Sterpin, Edmond; Geets, Xavier

    2017-09-01

    PET-guided dose painting (DP) aims to target radioresistant tumour regions in order to improve radiotherapy (RT) outcome. Besides the well-known [(18)F]fluorodeoxyglucose (FDG), the hypoxia positron emission tomography (PET) tracer [(18)F]fluoroazomycin arabinoside (FAZA) could provide further useful information to guide the radiation dose prescription. In this study, we compare the spatial distributions of FDG and FAZA PET uptakes in lung tumours. Fourteen patients with unresectable lung cancer underwent FDG and FAZA 4D-PET/CT on consecutive days at three time-points: prior to RT (pre), and during the second (w2), and the third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP). The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax), and the hypoxic volume (HV: FAZA SUV > 1.4) were delineated within the gross tumour volume (GTVCT). FDG and FAZA intratumoral PET uptake distributions were subsequently pairwise compared, using both volume-, and voxel-based analyses. Volume-based analysis showed large overlap between MTV and HV: median overlapping fraction was 0.90, 0.94 and 0.94, at the pre, w2 and w3 time-points, respectively. Voxel-wise analysis between FDG and FAZA intratumoral PET uptake distributions showed high correlation: median Spearman's rank correlation coefficient was 0.76, 0.77 and 0.76, at the pre, w2 and w3 time-points, respectively. Interestingly, tumours with high FAZA uptake tended to show more similarity between FDG and FAZA intratumoral uptake distributions than those with low FAZA uptake. In unresectable lung carcinomas, FDG and FAZA PET uptake distributions displayed unexpectedly strong similarity, despite the distinct pathways targeted by these tracers. Hypoxia PET with FAZA brought very little added value over FDG from the perspective of DP in this population.

  9. Immunotherapy of human tumour xenografts overexpressing the EGF receptor with rat antibodies that block growth factor-receptor interaction.

    PubMed Central

    Modjtahedi, H.; Eccles, S.; Box, G.; Styles, J.; Dean, C.

    1993-01-01

    Athymic mice bearing xenografts of human tumours that overexpress the receptor (EGFR) for EGF and TGF alpha have been used to evaluate the therapeutic potential of three new rat monoclonal antibodies (mAbs) directed against two distinct epitopes on the extracellular domain of the human EGFR. The antibodies, ICR16 (IgG2a), ICR62 (IgG2b) and ICR64 (IgG1), have been shown (Modjtahedi et al., 1993) to be potent inhibitors of the growth in vitro of a number of human squamous cell carcinomas because they block receptor-ligand interaction. When given i.p. at 200 micrograms dose, the three antibodies were found to induce complete regression of xenografts of the HN5 tumour if treatment with antibody commenced at the time of tumour implantation (total doses: ICR16, 3.0 mg; ICR62, 1.2 mg; ICR64, 2.2 mg). More importantly when treatment was delayed until the tumours were established (mean diam. 0.5 cm) both ICR16 and ICR62 induced complete or almost complete regression of the tumours. Furthermore, treatment with a total dose of only 0.44 mg of ICR62 was found to induce complete remission of xenografts of the breast carcinoma MDA-MB 468, but ICR16 was less effective at this dose of antibody and only 4/8 tumours regressed completely. ICR16 and ICR62 were poor inhibitors of the growth in vitro of the vulval carcinoma A431, but both induced a substantial delay in the growth of xenografts of this tumour and 4/8 tumours regressed completely in the mice treated with ICR62 (total dose 2.2 mg). Although ICR16 and ICR64 were more effective than ICR62 as growth inhibitors in vitro, ICR62 was found to be substantially better at inducing regression of the tumour xenografts due perhaps to additional activation of host immune effector functions by the IgG2b antibody. We conclude that these antibodies may be useful therapeutic agents that can be used alone without conjugation to other cytotoxic moieties. PMID:7679281

  10. Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury

    PubMed Central

    Miranda, Luis F.; Rodrigues, Claudia O.; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Klim, Jammie; Hehre, Dorothy; McNiece, Ian; Hare, Joshua M.; Suguihara, Cleide Y.; Young, Karen C.

    2016-01-01

    BACKGROUND Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID:24153399

  11. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    PubMed

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (P<0.05, PQ vs. PQ+OT). Total antioxidant capacity in PQ+OT group was significantly higher than PQ group (P < 0.05, PQ+OT vs. PQ). These findings suggest that outcome in PQ-induced lung injury may be improved by using OT as an adjuvant therapy.

  12. Measurement of the acute metabolic response to hypoxia in rat tumours in vivo using magnetic resonance spectroscopy and hyperpolarised pyruvate

    PubMed Central

    Bluff, Joanne E.; Reynolds, Steven; Metcalf, Stephen; Alizadeh, Tooba; Kazan, Samira M.; Bucur, Adriana; Wholey, Emily G.; Bibby, Becky A.S.; Williams, Leigh; Paley, Martyn N.; Tozer, Gillian M.

    2015-01-01

    Purpose To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised 13C1-pyruvate and magnetic resonance spectroscopy. Methods and materials Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised 13C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised 13C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate (kpl). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO2) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. Results MABP, ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p < 0.01) from 0.029 ± 0.002 s−1 to 0.049 ± 0.006 s−1 (mean ± SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO2 and MABP influenced the estimate of kpl, with a strong negative correlation between kpl and the product of ArtpO2 and MABP under hypoxia. Conclusion The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation. PMID:25824978

  13. [Effects of endogenous beta-adrenoceptor agonist on lung edema in scalded rats].

    PubMed

    Jiang, M; Li, S; Zhang, Y

    1997-07-01

    The effect of endogenous beta-adrenoceptor agonist on lung edema in scalded rats were investigated. The results showed that lung water content, wet/dry lung weight ration, bronchoalveolar lavage (BAL) protein concentration, malondialdehyde (MDA) content and leukocyte count in scalded and PPN treated rats were obviously higher than hose in control rats. The above parameters in scalded rats pretreated with PPN were even much higher than those of control and tended to be higher than burn group. It is suggested that endogenous beta-agonist is effective in the prevention of lung edema and lipid peroxidation, and it acts as an important anti-inflammatory factor in vivo.

  14. Poster — Thur Eve — 65: A dosimetric comparison of isocentric and non-isocentric coplanar SBRT VMAT plans for peripheral lung tumours

    SciTech Connect

    Conroy, L; Liu, HW; Lau, H; Smith, WL

    2014-08-15

    Volumetric modulated arc therapy (VMAT) delivers lung sterotactic body radiotherapy (SBRT) in shorter treatment time and less monitor units with comparable coverage and organ at risk sparing compared to conventional SBRT treatments. Isocentric VMAT treatment of peripheral lung tumours occasionally requires couch shifts that can inhibit 360° gantry rotation, resulting in additional imaging shifts for each treatment session, and increased potential for involuntary in-fraction motion. Here, we investigate whether non-isocentric VMAT plans can achieve comparable plan quality to isocentric plans for peripheral lung tumours. Three patient plans were selected with targets displaced > 8.5 cm (range: 8.8 – 9.9 cm) laterally from patient midline. For each patient, a plan with isocentre placed within the target volume (isocentric plan) was created and optimized. The same optimization parameters were then used to create a plan with the isocentre at patient midline (non-isocentric plan). Plan quality was evaluated and compared based on planning target volume (PTV) coverage, high dose spillage, dose homogeneity, intermediate dose spillage, dose fall-off gradient, and organ at risk contraints. Non-isocentric plans of equivalent plan quality to isocentric plans were achieved for all patients by optimizing collimator rotations. Field isocentres can be placed at patient midline, as opposed to inside the target volume, with no significant degradation in VMAT plan quality for lateral tumour displacements up to 10 cm. Non-isocentric treatment of peripheral lung tumours could result in decreased overall treatment session time and eliminate the need for imaging shifts prior to VMAT treatment.

  15. Gene expression analysis in rat lungs after intratracheal exposure to nanoparticles doped with cadmium

    NASA Astrophysics Data System (ADS)

    Coccini, Teresa; Fabbri, Marco; Roda, Elisa; Grazia Sacco, Maria; Manzo, Luigi; Gribaldo, Laura

    2011-07-01

    Silica nanoparticles (NPs) incorporating cadmium (Cd) have been developed for a range of potential application including drug delivery devices. Occupational Cd inhalation has been associated with emphysema, pulmonary fibrosis and lung tumours. Mechanistically, Cd can induce oxidative stress and mediate cell-signalling pathways that are involved in inflammation.This in vivo study aimed at investigating pulmonary molecular effects of NPs doped with Cd (NP-Cd, 1 mg/animal) compared to soluble CdCl2 (400 μg/animal), in Sprague Dawley rats treated intra-tracheally, 7 and 30 days after administration. NPs of silica containing Cd salt were prepared starting from commercial nano-size silica powder (HiSil™ T700 Degussa) with average pore size of 20 nm and surface area of 240 m2/g. Toxicogenomic analysis was performed by the DNA microarray technology (using Agilent Whole Rat Genome Microarray 4×44K) to evaluate changes in gene expression of the entire genome. These findings indicate that the whole genome analysis may represent a valuable approach to assess the whole spectrum of biological responses to cadmium containing nanomaterials.

  16. Quantitative studies of natural immunity to solid tumours in rats. Persistence of natural immunity throughout reproductive life, and absence of suppressor cells in infant rats.

    PubMed Central

    Brooks, C G; Flannery, G R

    1980-01-01

    Consideration of cell-mediated cytotoxicity as an enzyme-substrate reaction provided a theoretical and practical basis for the quantification of natural immunity to solid tumours. The natural cytotoxic activity of spleen cells from normal rats towards cultured target cells from solid tumours, measured in a 6 h chromium release assay, developed between 2 and 5 weeks after birth and, in contrast to previous reports of natural cytotoxicity against lymphoid tumour cells, showed no sign of decline up till at least 22 months of age. Both virgin and breeder (multiparous) females showed equally good maintenance of natural immunity, and the apparent specificity of this natural immunity on a panel of four target cells did not change between 8 weeks and 18 months of age. The low level of natural immunity in infant spleen, and also in adult lymph nodes and thymus, was not caused by suppressor cells but rather by an absence of appropriate effector cells. PMID:6445867

  17. Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats.

    PubMed

    Venkatesan, N; Punithavathi, D; Chandrakasan, G

    1998-10-01

    The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in

  18. Feasibility of quantitative parameters of dynamically enhanced patterns of spiral computed tomography scanning integrated into tumour progression before targeted treatment of non-small cell lung cancer.

    PubMed

    Qiao, Peng-Gang; Huang, Qiong; Zhou, Juan; Wang, Xiang-Chao; Li, Ming; Ma, Jin-Lin; Tian, Ning; Li, Gong-Jie

    2015-04-01

    The relationship between quantitative parameters of contrast-enhanced computed tomography (CT) and non-small cell lung cancer (NSCLC) progression remains controversial. We aimed to explore the usefulness of contrast-enhanced spiral CT scanning for confirming the time of tumour progression before targeted treatment of NSCLC. Contrast-enhanced spiral CT scanning was performed on 33 NSCLC patients with a biopsy-proven diagnosis of NSCLC. All the patients were divided into three groups according to times of tumour progression (<6 weeks, 6-20 weeks, and >20 weeks). The perfusion CT data were used to calculate quantitative parameters, including enhanced peak values, peak time of tumour enhancement, ratio of tumour mass and enhanced aorta peak value and perfusion value of blood flow. Variance analysis was used for statistical analysis among the three groups using SAS 9.13 statistical software. Tumour perfusion values among the three group with different stage of TTP were significantly different from each other with P = 0.0129 (<6 weeks, perfusion value = 0.35 ± 0.15 mL/(min × mL); 6-20 weeks, perfusion value = 0.41 ± 0.086 mL/(min × mL); > 20 weeks, perfusion value = 0.47 ± 0.087 mL/(min × mL)). However, no significant differences were found in other parameters (enhanced peak values, peak time of tumour enhancement, ratios of tumour mass, and enhanced aorta peak value) among three groups (P > 0.05). The NSCLC patients with high perfusion value before targeted therapy are more sensitive to targeted therapy, and further experiments with larger sample size are needed. © 2015 The Royal Australian and New Zealand College of Radiologists.

  19. Whole-tumour CT-perfusion of unresectable lung cancer for the monitoring of anti-angiogenetic chemotherapy effects.

    PubMed

    Fraioli, F; Anzidei, M; Serra, G; Liberali, S; Fiorelli, A; Zaccagna, F; Longo, F; Anile, M; Catalano, C

    2013-09-01

    To determine whether CT-perfusion (CT-p) can be used to evaluate the effects of chemotherapy and anti-angiogenic treatment in patients with non-small-cell lung carcinoma (NSCLC) and whether CT-p and standard therapeutic response assessment (RECIST) data obtained before and after therapy correlate. 55 patients with unresectable NSCLC underwent CT-p before the beginning of therapy and 50 of them repeated CT-p 90 days after it. Therapeutic protocol included platinum-based doublets plus bevacizumab for non-squamous carcinoma and platinum-based doublets for squamous carcinoma. RECIST measurements and calculations of blood flow (BF), blood volume (BV), time to peak (TTP) and permeability surface (PS) were performed, and baseline and post-treatment measurements were tested for statistically significant differences. Baseline and follow-up perfusion parameters were also compared based on histopathological subclassification (2004 World Health Organization Classification of Tumours) and therapy response assessed by RECIST. Tumour histology was consistent with large cell carcinoma in 14/50 (28%) cases, adenocarcinoma in 22/50 (44%) cases and squamous cell carcinoma in the remaining 14/50 (28%) cases. BF and PS differences for all tumours between baseline and post-therapy measurements were significant (p=0.001); no significant changes were found for BV (p=0.3) and TTP (p=0.1). The highest increase of BV was demonstrated in adenocarcinoma (5.2±34.1%), whereas the highest increase of TTP was shown in large cell carcinoma (6.9±22.4%), and the highest decrease of PS was shown in squamous cell carcinoma (-21.5±18.5%). A significant difference between the three histological subtypes was demonstrated only for BV (p<0.007). On the basis of RECIST criteria, 8 (16%) patients were classified as partial response (PR), 2 (4%) as progressive disease (PD) and the remaining 40 (80%) as stable disease (SD). Among PR, a decrease of both BF (18±9.6%) and BV (12.6±9.2%) were observed; TTP

  20. Whole-tumour CT-perfusion of unresectable lung cancer for the monitoring of anti-angiogenetic chemotherapy effects

    PubMed Central

    Anzidei, M; Serra, G; Liberali, S; Fiorelli, A; Zaccagna, F; Longo, F; Anile, M; Catalano, C

    2013-01-01

    Objective: To determine whether CT-perfusion (CT-p) can be used to evaluate the effects of chemotherapy and anti-angiogenic treatment in patients with non-small-cell lung carcinoma (NSCLC) and whether CT-p and standard therapeutic response assessment (RECIST) data obtained before and after therapy correlate. Methods: 55 patients with unresectable NSCLC underwent CT-p before the beginning of therapy and 50 of them repeated CT-p 90 days after it. Therapeutic protocol included platinum-based doublets plus bevacizumab for non-squamous carcinoma and platinum-based doublets for squamous carcinoma. RECIST measurements and calculations of blood flow (BF), blood volume (BV), time to peak (TTP) and permeability surface (PS) were performed, and baseline and post-treatment measurements were tested for statistically significant differences. Baseline and follow-up perfusion parameters were also compared based on histopathological subclassification (2004 World Health Organization Classification of Tumours) and therapy response assessed by RECIST. Results: Tumour histology was consistent with large cell carcinoma in 14/50 (28%) cases, adenocarcinoma in 22/50 (44%) cases and squamous cell carcinoma in the remaining 14/50 (28%) cases. BF and PS differences for all tumours between baseline and post-therapy measurements were significant (p=0.001); no significant changes were found for BV (p=0.3) and TTP (p=0.1). The highest increase of BV was demonstrated in adenocarcinoma (5.2±34.1%), whereas the highest increase of TTP was shown in large cell carcinoma (6.9±22.4%), and the highest decrease of PS was shown in squamous cell carcinoma (−21.5±18.5%). A significant difference between the three histological subtypes was demonstrated only for BV (p<0.007). On the basis of RECIST criteria, 8 (16%) patients were classified as partial response (PR), 2 (4%) as progressive disease (PD) and the remaining 40 (80%) as stable disease (SD). Among PR, a decrease of both BF (18±9.6%) and BV (12

  1. Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population.

    PubMed

    Uvirova, Magdalena; Simova, Jarmila; Kubova, Barbora; Dvorackova, Nina; Tomaskova, Hana; Sedivcova, Monika; Dite, Petr

    2015-09-01

    A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours. DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method. The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples. Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6

  2. Nuclear magnetic resonance in cancer, XII: Application of NMR malignancy index to human lung tumours.

    PubMed Central

    Goldsmith, M.; Koutcher, J. A.; Damadian, R.

    1977-01-01

    Sixty specimens of human lung tissue from 52 individuals were inspected at 22.5 MHz by proton magnetic resonance techniques. The purpose of the study was to evaluate the diagnostic capabilities of the nuclear magnetic resonance (NMR) technique for the diagnosis of malignancy. The combination of two NMR parameters (spin-lattice (T1) and spin-spin (T2) relaxation times) into a malignancy index yielded 3 cases of overlap between the two populations of tissue. The mean and standard deviations obtained were 1.966 +/- 0.262 for normal tissue, and 2.925 +/- 0.864 for malignant specimens. In addition, analysis of the electrolyte and water content of the tissues confirm that factors other than specimen water content influence the relaxation time. PMID:911662

  3. Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

    PubMed

    da Cunha, Maira J; da Cunha, Aline A; Scherer, Emilene B S; Machado, Fernanda Rossato; Loureiro, Samanta O; Jaenisch, Rodrigo B; Guma, Fátima; Lago, Pedro Dal; Wyse, Angela T S

    2014-04-01

    In the present study we investigated the effects of lung injury on energy metabolism (succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels), respiratory mechanics (dynamic and static compliance, elastance and respiratory system resistance) in the lungs of rats, as well as on phospholipids in bronchoalveolar lavage fluid. The protective effect of physical exercise on the alterations caused by lung injury, including lung edema was also evaluated. Wistar rats were submitted to 2 months of physical exercise. After this period the lung injury was induced by intratracheal instillation of lipopolysaccharide. Adult Wistar rats were submitted to 2 months of physical exercise and after this period the lung injury was induced by intratracheal instillation of lipopolysaccharide in dose 100 μg/100 g body weight. The sham group received isotonic saline instillation. Twelve hours after the injury was performed the respiratory mechanical and after the rats were decapitated and samples were collected. The rats subjected to lung injury presented a decrease in activities of the enzymes of the electron transport chain and ATP levels in lung, as well as the formation of pulmonary edema. A decreased lung dynamic and static compliance, as well as an increase in respiratory system resistance, and a decrease in phospholipids content were observed. Physical exercise was able to totally prevent the decrease in succinate dehydrogenase and complex II activities and the formation of pulmonary edema. It also partially prevented the increase in respiratory system resistance, but did not prevent the decrease in dynamic and static compliance, as well as in phospholipids content. These findings suggest that the mitochondrial dysfunction may be one of the important contributors to lung damage and that physical exercise may be beneficial in this pathology, although it did not prevent all changes present in lung injury.

  4. Tumour growth of colorectal rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation.

    PubMed

    Sperling, Jens; Ziemann, Christian; Gittler, Anika; Benz-Weißer, Anna; Menger, Michael D; Kollmar, Otto

    2015-04-01

    Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5×10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL.

  5. Bitumen fume-induced gene expression profile in rat lung

    SciTech Connect

    Gate, Laurent . E-mail: laurent.gate@inrs.fr; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Herve; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stephane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 {sup o}C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  6. Bitumen fume-induced gene expression profile in rat lung.

    PubMed

    Gate, Laurent; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Hervé; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stéphane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 degrees C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  7. Comparison of Celsior and Perfadex lung preservation solutions in rat lungs subjected to 6 and 12 hours of ischemia using an ex-vivo lung perfusion system.

    PubMed

    Menezes, Arteiro Queiroz; Pêgo-Fernandes, Paulo Manuel; Cardoso, Paulo Francisco Guerreiro; Braga, Karina Andrighetti de Oliveira; Nepomuceno, Natalia Aparecida; Pazetti, Rogerio; Correia, Aristides Tadeu; Canzian, Mauro; Santim, Jacqueline Klarosk; Jatene, Fabio Biscegli

    2012-11-01

    This study evaluated the performance of lungs that were preserved with different solutions (Celsior, Perfadex or saline) in an ex vivo rat lung perfusion system. Sixty Wistar rats were anesthetized, anticoagulated and randomized into three groups (n = 20). The rats were subjected to antegrade perfusion via the pulmonary artery with Perfadex, Celsior, or saline, followed by 6 or 12 hours of ischemia (4ºC, n = 10 in each group). Respiratory mechanics, gas exchange and hemodynamics were measured at 10-minute intervals during the reperfusion of heart-lung blocks in an ex vivo system (IL2-Isolated Perfused Rat or Guinea Pig Lung System, Harvard Apparatus, Holliston, Massachusetts, USA; Hugo Sachs Elektronik, Germany) for 60 minutes. The lungs were prepared for histopathology and evaluated for edema following reperfusion. Group comparisons were performed using ANOVA and the Kruskal-Wallis test with a 5% level of significance. Gas exchange was not significantly different between lungs perfused with either Perfadex or Celsior at the same ischemic times, but it was very low in lungs that were preserved with saline. Airway resistance was greater in the lungs that were preserved for 12 hours. Celsior lungs that were preserved for 6 and 12 hours exhibited lower airway resistance (p = 0.01) compared to Perfadex lungs. Pulmonary artery pressure was not different between the groups, and no significant differences in histopathology and apoptosis were observed between the groups. Lungs that were preserved with Celsior or Perfadex exhibited similar gas exchange and histopathological findings. Airway resistance was slightly lower in the Celsior-preserved lungs compared with the Perfadex-preserved lungs.

  8. The increased gastroprotective effect of pioglitazone in cholestatic rats: role of nitric oxide and tumour necrosis factor alpha.

    PubMed

    Moezi, Leila; Janahmadi, Zeinab; Amirghofran, Zahra; Nekooeian, Ali Akbar; Dehpour, Ahmad R

    2014-02-01

    The prevalence of gastric ulcers is high in cholestatic patients, but the exact mechanism of this increased frequency remains uncertain. It has been shown that pioglitazone accelerates the healing of pre-existing gastric ulcers. The present study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cholestatic rats. Cholestasis was induced by surgical ligation of common bile duct and sham-operated rats served as control. Different groups of sham and cholestatic animals received solvent or pioglitazone (5, 15, 30 mg/kg) for 7 days. On the day eight rats were killed after oral ethanol administration and the area of gastric lesions was measured. The serums of rats were also collected to determine serum levels of tumour necrosis factor alpha (TNF-α), IL-1β and bilirubin. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than sham-operated ones. Pretreatment with pioglitazone dose-dependently attenuated gastric lesions induced by ethanol in both sham and cholestatic rats, but this effect was more prominent in cholestatic ones. The effect of pioglitazone was associated with a significant fall in serum levels of TNF-α in cholestatic rats. L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, and decreased pioglitazone-induced gastroprotective effect in cholestatic rats, while aminoguanidine, a selective inducible NOS inhibitor, potentiated pioglitazone-induced gastroprotective effect in the cholestatic rats. Chronic treatment with pioglitazone exerts an enhanced gastroprotective effect on the stomach ulcers of cholestatic rats compared to sham rats probably due to constitutive NOS induction and/or inducible NOS inhibition and attenuating release of TNF-α.

  9. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

    PubMed Central

    Melosky, B.; Agulnik, J.; Albadine, R.; Banerji, S.; Bebb, D.G.; Bethune, D.; Blais, N.; Butts, C.; Cheema, P.; Cheung, P.; Cohen, V.; Deschenes, J.; Ionescu, D.N.; Juergens, R.; Kamel-Reid, S.; Laurie, S.A.; Liu, G.; Morzycki, W.; Tsao, M.S.; Xu, Z.; Hirsh, V.

    2016-01-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  10. Proteomic analysis of lamellar bodies isolated from rat lungs

    PubMed Central

    Wang, Pengcheng; Chintagari, Narendranath Reddy; Narayanaperumal, Jeyaparthasarathy; Ayalew, Sahlu; Hartson, Steven; Liu, Lin

    2008-01-01

    Background Lamellar bodies are lysosome-related secretory granules and store lung surfactant in alveolar type II cells. To better understand the mechanisms of surfactant secretion, we carried out proteomic analyses of lamellar bodies isolated from rat lungs. Results With peptide mass fingerprinting by Matrix Assisted Laser Desorption/Ionization – Time of Flight mass spectrometry, 44 proteins were identified with high confidence. These proteins fell into diverse functional categories: surfactant-related, membrane trafficking, calcium binding, signal transduction, cell structure, ion channels, protein processing and miscellaneous. Selected proteins were verified by Western blot and immunohistochemistry. Conclusion This proteomic profiling of lamellar bodies provides a basis for further investigations of functional roles of the identified proteins in lamellar body biogenesis and surfactant secretion. PMID:18577212

  11. Biodistribution and clearance of instilled carbon nanotubes in rat lung

    PubMed Central

    Elgrabli, Dan; Floriani, Magali; Abella-Gallart, Steve; Meunier, Laurent; Gamez, Christelle; Delalain, Patrice; Rogerieux, Françoise; Boczkowski, Jorge; Lacroix, Ghislaine

    2008-01-01

    Background Constituted only by carbon atoms, CNT are hydrophobic and hardly detectable in biological tissues. These properties make biokinetics and toxicology studies more complex. Methods We propose here a method to investigate the biopersistence of CNT in organism, based on detection of nickel, a metal present in the MWCNT we investigated. Results and conclusion Our results in rats that received MWCNT by intratracheal instillation, reveal that MWCNT can be eliminated and do not significantly cross the pulmonary barrier but are still present in lungs 6 months after a unique instillation. MWCNT structure was also showed to be chemically modified and cleaved in the lung. These results provide the first data of CNT biopersistence and clearance at 6 months after respiratory administration. PMID:19068117

  12. Synergistic effects of mineral fibres and cigarette smoke on the production of tumour necrosis factor by alveolar macrophages of rats.

    PubMed

    Morimoto, Y; Kido, M; Tanaka, I; Fujino, A; Higashi, T; Yokosaki, Y

    1993-10-01

    The objective of this study was to evaluate the combined effects of mineral fibres and cigarette smoke on the production of tumour necrosis factor (TNF) by alveolar macrophages. Rats were exposed to cigarette smoke in vivo, and production of TNF by alveolar macrophages was measured in the presence of mineral fibres in vitro. For smoke exposure, rats were divided into two groups. Five were exposed to a daily concentration of 10 mg/m3 of cigarette smoke for an eight hour period, and five rats (controls) were not exposed to smoke. Bronchoalveolar lavage was performed after exposure to smoke and the recovered alveolar macrophages were incubated with either chrysotile or ceramic fibres on a microplate for 24 hours. Activity of TNF in the supernatant was determined by the L-929 fibroblast cell bioassay. When alveolar macrophages were not stimulated by mineral fibres, production of TNF by rats exposed to smoke and unexposed rats was essentially the same. When alveolar macrophages were stimulated in vitro by chrysotile or ceramic fibres, production of TNF by alveolar macrophages from rats exposed to smoke was higher than that by alveolar macrophages from unexposed rats. The findings suggest that cigarette smoke and mineral fibres have a synergistic effect on TNF production by alveolar macrophages.

  13. Synergistic effects of mineral fibres and cigarette smoke on the production of tumour necrosis factor by alveolar macrophages of rats.

    PubMed Central

    Morimoto, Y; Kido, M; Tanaka, I; Fujino, A; Higashi, T; Yokosaki, Y

    1993-01-01

    The objective of this study was to evaluate the combined effects of mineral fibres and cigarette smoke on the production of tumour necrosis factor (TNF) by alveolar macrophages. Rats were exposed to cigarette smoke in vivo, and production of TNF by alveolar macrophages was measured in the presence of mineral fibres in vitro. For smoke exposure, rats were divided into two groups. Five were exposed to a daily concentration of 10 mg/m3 of cigarette smoke for an eight hour period, and five rats (controls) were not exposed to smoke. Bronchoalveolar lavage was performed after exposure to smoke and the recovered alveolar macrophages were incubated with either chrysotile or ceramic fibres on a microplate for 24 hours. Activity of TNF in the supernatant was determined by the L-929 fibroblast cell bioassay. When alveolar macrophages were not stimulated by mineral fibres, production of TNF by rats exposed to smoke and unexposed rats was essentially the same. When alveolar macrophages were stimulated in vitro by chrysotile or ceramic fibres, production of TNF by alveolar macrophages from rats exposed to smoke was higher than that by alveolar macrophages from unexposed rats. The findings suggest that cigarette smoke and mineral fibres have a synergistic effect on TNF production by alveolar macrophages. Images PMID:8217857

  14. Recovery from silver-nanoparticle-exposure-induced lung inflammation and lung function changes in Sprague Dawley rats.

    PubMed

    Song, Kyung Seuk; Sung, Jae Hyuck; Ji, Jun Ho; Lee, Ji Hyun; Lee, Jong Seong; Ryu, Hyeon Ryol; Lee, Jin Kyu; Chung, Yong Hyun; Park, Hyun Min; Shin, Beom Soo; Chang, Hee Kyung; Kelman, Bruce; Yu, Il Je

    2013-03-01

    In a previous study, the lung function, as indicated by the tidal volume, minute volume, and peak inspiration flow, decreased during 90 days of exposure to silver nanoparticles and was accompanied by inflammatory lesions in the lung morphology. Therefore, this study investigated the recovery from such lung function changes in rats following the cessation of 12 weeks of nanoparticle exposure. Male and female rats were exposed to silver nanoparticles (14-15 nm diameter) at concentrations of 0.66 × 10(6) particles/cm(3) (49 μg/m(3), low dose), 1.41 × 10(6) particles/cm(3) (117 μg/m(3), middle dose), and 3.24 × 10(6) particles/cm(3) (381 μg/m(3), high dose) for 6 h/day in an inhalation chamber for 12 weeks. The rats were then allowed to recover. The lung function was measured every week during the exposure period and after the cessation of exposure, plus animals were sacrificed after the 12-week exposure period, and 4 weeks and 12 weeks after the exposure cessation. An exposure-related lung function decrease was measured in the male rats after the 12-week exposure period and 12 weeks after the exposure cessation. In contrast, the female rats did not show a consistent lung function decrease either during the exposure period or following the exposure cessation. The histopathology showed a gradual recovery from the lung inflammation in the female rats, whereas the male rats in the high-dose group exhibited persistent inflammation throughout the 12-week recovery period. Therefore, the present results suggest a potential persistence of lung function changes and inflammation induced by silver nanoparticle exposure above the no observed adverse effect level.

  15. Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs.

    PubMed

    Shatzkes, Kenneth; Singleton, Eric; Tang, Chi; Zuena, Michael; Shukla, Sean; Gupta, Shilpi; Dharani, Sonal; Onyile, Onoyom; Rinaggio, Joseph; Connell, Nancy D; Kadouri, Daniel E

    2016-11-08

    Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are predatory bacteria that naturally-and obligately-prey on other Gram-negative bacteria, and their use has been proposed as a potential new approach to control microbial infection. The ability of predatory bacteria to prey on Gram-negative human pathogens in vitro is well documented; however, the in vivo safety and efficacy of predatory bacteria have yet to be fully assessed. In this study, we examined whether predatory bacteria can reduce bacterial burden in the lungs in an in vivo mammalian system. Initial safety studies were performed by intranasal inoculation of rats with predatory bacteria. No adverse effects or lung pathology were observed in rats exposed to high concentrations of predatory bacteria at up to 10 days postinoculation. Enzyme-linked immunosorbent assay (ELISA) of the immune response revealed a slight increase in inflammatory cytokine levels at 1 h postinoculation that was not sustained by 48 h. Additionally, dissemination experiments showed that predators were efficiently cleared from the host by 10 days postinoculation. To measure the ability of predatory bacteria to reduce microbial burden in vivo, we introduced sublethal concentrations of Klebsiella pneumoniae into the lungs of rats via intranasal inoculation and followed with multiple doses of predatory bacteria over 24 h. Predatory bacteria were able to reduce K. pneumoniae bacterial burden, on average, by more than 3.0 log10 in the lungs of most rats as measured by CFU plating. The work presented here provides further support for the idea of developing predatory bacteria as a novel biocontrol agent. A widely held notion is that antibiotics are the greatest medical advance of the last 50 years. However, the rise of multidrug-resistant (MDR) bacterial infections has become a global health crisis over the last decade. As we enter the postantibiotic era, it is crucial that we begin to develop new strategies to combat bacterial

  16. Carcinoid tumours of the lung and the 'PEPPS' approach: evaluation of preoperative bronchoscopic tumour debulking as preparation for subsequent parenchyma-sparing surgery.

    PubMed

    Neuberger, Michael; Hapfelmeier, Alexander; Schmidt, Michael; Gesierich, Wolfgang; Reichenberger, Frank; Morresi-Hauf, Alicia; Hatz, Rudolf A; Lindner, Michael

    2015-01-01

    Preoperative bronchoscopic tumour ablation has been suggested as a beneficial treatment for bronchopulmonary carcinoid tumours, although data regarding its effects and long-term outcome are lacking. In our case-matched cohort study with 208 patients with bronchopulmonary carcinoid tumours we investigated the role of preoperative bronchoscopic interventions before subsequent surgery and analysed the safety of this Procedure of Endobronchial Preparation for Parenchyma-sparing Surgery (PEPPS) based on metastasis and recurrence rates as well as survival data from 1991 to 2010. The subsequent surgery was classified into parenchyma-sparing procedures and classical lobectomies, bilobectomies and pneumonectomies. Data were obtained from the tumour registry and medical reports. Outcomes were the frequency of parenchyma-sparing surgery after bronchoscopic treatment as well as rates of metastasis, recurrence and survival. 132 of 208 carcinoids were located centrally. Among them, 77 patients could be recanalised preoperatively. After bronchoscopic preparation, the rate of subsequent parenchyma-sparing surgery methods was higher (p=0.021). The effect was measured by the number of segments removed. The 10-year survival rate was 89% (typical carcinoids) and 68% (atypical carcinoids), respectively. After applying PEPPS, long-term survival was slightly higher (p=0.23). Metastasis and recurrence rates showed no relevant differences between the bronchoscopically treated or non-treated groups, or between the two types of surgery classes or between the PEPPS and non-PEPPS groups. After preoperative bronchoscopic treatment, parenchyma-sparing surgery techniques can be applied more frequently. Furthermore, we detected no negative effects after PEPPS based on metastasis, recurrence and survival rates.

  17. Carcinoid tumours of the lung and the ‘PEPPS’ approach: evaluation of preoperative bronchoscopic tumour debulking as preparation for subsequent parenchyma-sparing surgery

    PubMed Central

    Neuberger, Michael; Hapfelmeier, Alexander; Schmidt, Michael; Gesierich, Wolfgang; Reichenberger, Frank; Morresi-Hauf, Alicia; Hatz, Rudolf A; Lindner, Michael

    2015-01-01

    Background Preoperative bronchoscopic tumour ablation has been suggested as a beneficial treatment for bronchopulmonary carcinoid tumours, although data regarding its effects and long-term outcome are lacking. Methods In our case-matched cohort study with 208 patients with bronchopulmonary carcinoid tumours we investigated the role of preoperative bronchoscopic interventions before subsequent surgery and analysed the safety of this Procedure of Endobronchial Preparation for Parenchyma-sparing Surgery (PEPPS) based on metastasis and recurrence rates as well as survival data from 1991 to 2010. The subsequent surgery was classified into parenchyma-sparing procedures and classical lobectomies, bilobectomies and pneumonectomies. Data were obtained from the tumour registry and medical reports. Outcomes were the frequency of parenchyma-sparing surgery after bronchoscopic treatment as well as rates of metastasis, recurrence and survival. Results 132 of 208 carcinoids were located centrally. Among them, 77 patients could be recanalised preoperatively. After bronchoscopic preparation, the rate of subsequent parenchyma-sparing surgery methods was higher (p=0.021). The effect was measured by the number of segments removed. The 10-year survival rate was 89% (typical carcinoids) and 68% (atypical carcinoids), respectively. After applying PEPPS, long-term survival was slightly higher (p=0.23). Metastasis and recurrence rates showed no relevant differences between the bronchoscopically treated or non-treated groups, or between the two types of surgery classes or between the PEPPS and non-PEPPS groups. Conclusions After preoperative bronchoscopic treatment, parenchyma-sparing surgery techniques can be applied more frequently. Furthermore, we detected no negative effects after PEPPS based on metastasis, recurrence and survival rates. PMID:26203359

  18. Evolution of [(18)F]fluorodeoxyglucose and [(18)F]fluoroazomycin arabinoside PET uptake distributions in lung tumours during radiation therapy.

    PubMed

    Di Perri, Dario; Lee, John A; Bol, Anne; Hanin, François-Xavier; Janssens, Guillaume; Labar, Daniel; Robert, Annie; Sterpin, Edmond; Geets, Xavier

    2017-04-01

    Dose painting (DP) aims to improve radiation therapy (RT) outcome by targeting radioresistant tumour regions identified through functional imaging, e.g., positron emission tomography (PET). Importantly, the expected benefit of DP relies on the ability of PET imaging to identify tumour areas which could be consistently targeted throughout the treatment. In this study, we analysed the spatial stability of two potential DP targets in lung cancer patients undergoing RT: the tumour burden surrogate [(18)F]fluorodeoxyglucose (FDG) and the hypoxia surrogate [(18)F]fluoroazomycin arabinoside (FAZA). Thirteen patients with unresectable lung tumours underwent FDG and FAZA 4D-PET/CT before (pre), and during the second (w2) and third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP) for further analysis. The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax) and the hypoxic volume (HV: FAZA SUV >1.4) were delineated within the gross tumour volume (GTVCT). The stability of FDG and FAZA PET uptake distributions during RT was subsequently assessed through volume-overlap analysis and voxel-based correlation analysis. The volume-overlap analysis yielded median overlapping fraction (OF) of 0.86 between MTVpre and MTVw2 and 0.82 between MTVpre and MTVw3. In patients with a detectable HV, median OF was 0.82 between HVpre and HVw2 and 0.90 between HVpre and HVw3. The voxel-based correlation analysis yielded median Spearman's correlation coefficient (rS) of 0.87 between FDGpre and FDGw2 and 0.83 between FDGpre and FDGw3. Median rS was 0.78 between FAZApre and FAZAw2 and 0.79 between FAZApre and FAZAw3. FDG and FAZA PET uptake distributions were spatially stable during the 3 first weeks of RT in patients with unresectable lung cancer, both based on volume- and voxel-based indicators. This might allow for a consistent targeting of high FDG or FAZA PET uptake regions as part of a DP strategy.

  19. High kallikrein-related peptidase 6 in non-small cell lung cancer cells: an indicator of tumour proliferation and poor prognosis

    PubMed Central

    Nathalie, Heuzé-Vourc’h; Chris, Planque; Serge, Guyetant; Catherine, Coco; Benjamin, Brillet; Claire, Blechet; Christelle, Parent; Briollais, Laurent; Pascale, Reverdiau; Marie-Lise, Jourdan; Yves, Courty

    2009-01-01

    The human kallikrein-related peptidases (KLK) are serine proteases whose concentrations are often abnormal in common human malignancies and contribute to neoplastic progression through multifaceted roles. However, little attention has been paid to their synthesis and involvement in the development and dissemination of lung cancer, the leading cause of cancer mortality worldwide. We have analysed the production of KLK6 in normal lung and tumour tissues from patients with non-small cell lung cancer (NSCLC). KLK6 immunoreactivity was restricted to epithelial cells of the normal bronchi, but most of the cancer samples were moderately or highly immunoreactive, regardless of the histological subtype. In contrast, little or no KLK6 was detected in NSCLC cells. We have developed NSCLC lines expressing wild-type KLK6 in order to investigate the role of KLK6 in lung cancer biology, and analysed its impact on proliferation. Ectopic KLK6 dramatically enhanced NSCLC cell growth and KLK6-producing NSCLC cells had accelerated cell cycles, between the G1 and S phases. This was accompanied by a marked increase in cyclin E and decrease in p21. KLK6 production was also associated with enhanced synthesis of c-Myc, which is known to promote cell-cycle progression. Finally, examination of specimens from patients with NSCLC revealed that KLK6 mRNA is overexpressed in tumour tissue, and high KLK6 concentrations were associated with lower survival rates. We conclude that a high concentration of KLK6 is an indicator of tumour proliferation and an independent predictive factor in NSCLC. PMID:19426157

  20. High kallikrein-related peptidase 6 in non-small cell lung cancer cells: an indicator of tumour proliferation and poor prognosis.

    PubMed

    Nathalie, Heuzé-Vourc'h; Chris, Planque; Serge, Guyetant; Catherine, Coco; Benjamin, Brillet; Claire, Blechet; Christelle, Parent; Briollais, Laurent; Pascale, Reverdiau; Marie-Lise, Jourdan; Yves, Courty

    2009-09-01

    The human kallikrein-related peptidases (KLK) are serine proteases whose concentrations are often abnormal in common human malignancies and contribute to neoplastic progression through multifaceted roles. However, little attention has been paid to their synthesis and involvement in the development and dissemination of lung cancer, the leading cause of cancer mortality worldwide. We have analysed the production of KLK6 in normal lung and tumour tissues from patients with non-small cell lung cancer (NSCLC). KLK6 immunoreactivity was restricted to epithelial cells of the normal bronchi, but most of the cancer samples were moderately or highly immunoreactive, regardless of the histological subtype. In contrast, little or no KLK6 was detected in NSCLC cells. We have developed NSCLC lines expressing wild-type KLK6 in order to investigate the role of KLK6 in lung cancer biology, and analysed its impact on proliferation. Ectopic KLK6 dramatically enhanced NSCLC cell growth and KLK6-producing NSCLC cells had accelerated cell cycles, between the G1 and S phases. This was accompanied by a marked increase in cyclin E and decrease in p21. KLK6 production was also associated with enhanced synthesis of c-Myc, which is known to promote cell-cycle progression. Finally, examination of specimens from patients with NSCLC revealed that KLK6 mRNA is overexpressed in tumour tissue, and high KLK6 concentrations were associated with lower survival rates. We conclude that a high concentration of KLK6 is an indicator of tumour proliferation and an independent predictive factor in NSCLC.

  1. Changes in Sedimentation of Surfactant in Ventilated Excised Rat Lungs

    PubMed Central

    Thet, Lyn Aung; Clerch, Linda; Massaro, Gloria D.; Massaro, Donald

    1979-01-01

    We ventilated excised rat lungs at a constant tidal volume (CTV); they developed areas of atelectasis which could be reversed by a large inflation (CTV + I) or prevented by the addition of positive end-expiratory pressure to the CTV. To explore the possibility that these modes of ventilation led to changes in surfactant, we lavaged the lungs and centrifuged the returns at 500 g; we measured the amount of disaturated phosphatidylcholine (DSPC) in the resultant pellet and supernatant fluid as a marker for surfactant. We found 16.9±1.5 (mean±SE), 38.0±2.4, 18.3±1.6, and 21.7±2.3% of the total lavage DSPC, in the pellet from freshly excised, CTV, CTV + I, and positive end-expiratory pressure to the CTV lungs, respectively. The total amount of lavage DSPC was the same in all groups. The ultrastructure of acellular material pelleted by sequential centrifugation of lavage returns at 500, 1,000, and 60,000 g was examined. We found mostly tubular myelin in the 500-g and 1,000-g pellets, but no tubular myelin in the 60,000-g pellet. Air inflation pressure-volume measurements from the degassed state revealed that the opening pressure and recoil pressures up to 75% of total lung capacity were significantly higher in the CTV than in the CTV + I lungs. There were no differences between these groups in air deflation or in saline inflation and deflation pressure-volume measurements. Our findings suggest that CTV leads to increases in the tubular myelin form of surfactant and that this leads to increased surface tension in alveoli which results in alveolar collapse. Images PMID:379047

  2. WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis.

    PubMed

    Han, Qiang; Lin, Xuyong; Zhang, Xiupeng; Jiang, Guiyang; Zhang, Yong; Miao, Yuan; Rong, Xuezhu; Zheng, Xiaoying; Han, Yong; Han, Xu; Wu, Jingjing; Kremerskothen, Joachim; Wang, Enhua

    2017-08-01

    The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer. Moreover, the overexpression of WWC3 inhibited the proliferation and invasiveness of lung cancer cells. These effects were mediated by the inhibition and stimulation of the Wnt and Hippo pathways, respectively, in vitro and in vivo. Specifically, WWC3 interacts with Dishevelled (Dvl) proteins, prevents casein kinase 1ϵ from phosphorylating Dvls, and inhibits β-catenin nuclear translocation to inhibit the Wnt pathway. Deleting the WW and C-terminal PDZ-binding domains of WWC3 abrogated these effects. Moreover, the interaction of WWC3 with Dvls reduced the interaction between WWC3 and large tumour suppressor 1 (LATS1), as well as decreasing LATS1 phosphorylation to increase the nuclear importation of yes-associated protein (YAP) and attenuate the Hippo pathway. Deleting the WW domain of WWC3 abrogated this effect. These findings demonstrate the molecular interplay between WWC3, Dvls, and LATS1, and reveal a link between the Wnt and Hippo pathways, which provides a potential target for clinical intervention in lung cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. Thoracic duct ligation in the rat attenuates lung injuries in acute pancreatitis.

    PubMed

    Zhang, D; Tsui, N; Li, Y; Wang, F

    2013-09-01

    In acute pancreatitis (AP), inflammatory cells and products disseminated in abdominal lymph and blood induce systemic inflammation. Interruption of abdominal lymph flow, and thereby reduction of lymphatic dissemination, could alter the course of the disease. Therefore, we investigated whether thoracic duct ligation (TDL) in a rat model of cerulein-induced AP results in reduced lung damage as a marker for reduction of systemic dissemination through the lymphatic system. Thirty-four male rats were assigned to TDL (TDL-rats, n=8), AP (AP-rats, n=8), TDL+AP (TDL+AP-rats, n=9) or sham TDL (Ctr-rats, n=9) groups. TDL and sham TDL were established first. Two days later, AP was induced in AP- and TDL+AP-rats by a series of subcutaneous injections of cerulein. Vehicle was injected in the same manner in Ctr- and TDL-rats as controls. Rats were sacrificed six hours after the end of the serial injections. Histological examination showed that AP-induced damage to the pancreas and ileum were similar in AP- and TDL+AP-rats whereas lung damage was less severe in TDL+AP-rats than in AP-rats. Assays demonstrated that: hepatic and pulmonary myeloperoxidase activities were increased in AP-rats but not in the TDL+AP-rats; more Il-6 was found in AP-rat than TDL+AP-rat lungs; and lung-lavage fluid from AP-rats yielded more angiopoietin-2 than TDL+AP-rats. In conclusion, prior TDL in the rat attenuates lung damage in acute pancreatitis.

  4. Inhibitory Effect of Various Breads on DMH-Induced Aberrant Crypt Foci and Colorectal Tumours in Rats

    PubMed Central

    Qi, Guangying; Zeng, Sien; Takashima, Tiri; Nozoe, Koichiro; Shobayashi, Megumi; Kakugawa, Koji; Murakami, Kaori; Jikihara, Hiroshi; Zhou, Lihua; Shimamoto, Fumio

    2015-01-01

    Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of three kinds of bread on DMH-induced colorectal tumours in F344 rats. F344 rats were divided into four groups (Steinmetz Three-Grain bread, Steinmetz Country bread, White bread, and MF). All groups were injected with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight) once a week for 8 consecutive weeks from 5 weeks of age. To investigate the antioxidant effect of bread, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging rate of bread and the serum levels of 8-hydroxy-deoxyguanosine (8-OHdG) in rats were examined. The number of colorectal aberrant crypt foci (ACF) and the incidence of colorectal tumours were studied after 34 weeks of DMH treatment. The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group. Steinmetz Three-Grain bread and Steinmetz Country bread have various ingredient combinations that may inhibit colorectal cancer progression. PMID:26075268

  5. Inhibitory effect of various breads on DMH-induced aberrant crypt foci and colorectal tumours in rats.

    PubMed

    Qi, Guangying; Zeng, Sien; Takashima, Tiri; Nozoe, Koichiro; Shobayashi, Megumi; Kakugawa, Koji; Murakami, Kaori; Jikihara, Hiroshi; Zhou, Lihua; Shimamoto, Fumio

    2015-01-01

    Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of three kinds of bread on DMH-induced colorectal tumours in F344 rats. F344 rats were divided into four groups (Steinmetz Three-Grain bread, Steinmetz Country bread, White bread, and MF). All groups were injected with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight) once a week for 8 consecutive weeks from 5 weeks of age. To investigate the antioxidant effect of bread, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging rate of bread and the serum levels of 8-hydroxy-deoxyguanosine (8-OHdG) in rats were examined. The number of colorectal aberrant crypt foci (ACF) and the incidence of colorectal tumours were studied after 34 weeks of DMH treatment. The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group. Steinmetz Three-Grain bread and Steinmetz Country bread have various ingredient combinations that may inhibit colorectal cancer progression.

  6. Pavlovian conditioning of lung anaphylactic response in rats.

    PubMed

    Palermo-Neto, J; Guimarães, R K

    2000-12-29

    The present experiment was undertaken to verify if it is possible to impose Pavlovian conditioning on a lung anaphylactic response (LAR) in rats. Two experiments were done. In the 1st, egg albumin (OVA) aerosol inhalation, which induces signs and symptoms of LAR in OVA- sensitized rats, was paired with an audiovisual cue (conditional stimulus, CS). After reexposure to the CS, the signs and symptoms of LAR were quantitatively measured using a scoring system specially developed for this evaluation; the levels of stress response and anxiety were also quantified. Results showed that the rats reexposed to CS only, displayed LAR scores not significantly different from those reexposed to both CS and the antigen; animals of these groups showed significantly higher LAR scores than rats that received no OVA aerosol challenge. High levels of stress and anxiety were observed 30-40 min after the challenge with OVA aerosol. In the 2nd experiment, rats sensitized with OVA and submitted or not to Pavlovian conditioning were observed in the open-field and in the plus maze apparatus in the absence of OVA aerosol but in the presence of the CS; after behavioral observations the animals were sacrificed for serum corticosterone level determination. Both behavioral and biochemical data showed high levels of stress and anxiety in rats for which the antigen was previously paired with the CS; these changes were not observed in animals which received the antigen 24 h after the presentation of the CS (unpaired) or in those exposed to PBS aerosol (the OVA vehicle) only. The present data show not only that LAR can be submitted to Pavlovian conditioning, but also and importantly, that high levels of stress and anxiety are related to the course of LAR.

  7. [Increased expression of fatty acid binding protein 4 in lungs of preterm rats after hyperoxic lung injury].

    PubMed

    Wang, Wei; Cui, Zhi-Rui; Cai, Li-Xia; Luo, Xiao-Ping

    2014-11-01

    To study the expression of fatty acid binding protein 4 (FABP4) in lungs and bronchoalveolar lavage fluid (BALF) of preterm rats exposed to 60% O2 and to elucidate the relationship between the changes of FABP4 expression and the pathogenesis of bronchopulmonary dysplasia (BPD). Hyperoxic lung injury was induced by exposing to 60% O2 in Spraque-Dawley rats within 6 hours after birth. Rats exposed to air were used as the control group. The lungs from groups aged postnatal days 3, 7 and 14 were removed and dissected from the main bronchi for analysis. Eight rats of each group were used to assess expression of FABP4 in lungs by immunohistochemistry and ELISA. Lung FABP4 mRNA levels were measured by semi-quantitative reverse transcription polymerase chain reaction. The levels of FABP4 in BALF were measured using ELISA. FABP4 immunoreactivity was detected in the majority of alveolar macrophages, bronchial epithelial cells and endothelial cells. FABP4 protein levels in lung tissues in the hyperoxic exposure group increased significantly compared with the control group on days 3, 7 and 14 after birth (P<0.05), and FABP4 mRNA levels in lung tissues also increased significantly in the hyperoxic exposure group compared with the control group on days 7 and 14 after birth (P<0.05). The hyperoxic exposure group demonstrated increased FABP4 levels in BALF compared with the control group on days 7 and 14 after birth (P<0.05). FABP4 levels increase in preterm rat lungs after hyperoxic lung injury, which may contribute to the pathogenesis of BPD.

  8. Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

    PubMed Central

    2010-01-01

    Background Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats. Methods For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent). Results Microarray gene expression analysis showed that Defcr4, Igfbp5, Mmp7, Nos2, S100A8 and S100A9 were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while Slc26a3, Mptx, Retlna and Muc2 were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including Apc. Conclusion The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of

  9. CO2 relaxation of the rat lung parenchymal strip.

    PubMed

    Emery, Michael J; Eveland, Randy L; Min, Jin-Hye; Hildebrandt, Jacob; Swenson, Erik R

    2013-03-01

    Evidence from liquid-filled rat lungs supported the presence of CO2-dependent, active relaxation of parenchyma under normoxia by unknown mechanisms (Emery et al., 2007). This response may improve matching of alveolar ventilation (V˙A) to perfusion (Q˙) by increasing compliance and V˙A in overperfused (high CO2) regions, and decrease V˙A in underperfused regions. Here, we have more directly studied CO2-dependent parenchymal relaxation and tested a hypothesized role for actin-myosin interaction in this effect. Lung parenchymal strips (∼1.5mm×1.5mm×15mm) from 16 rats were alternately exposed to normoxic hypocapnia ( [Formula: see text] ) or hypercapnia ( [Formula: see text] ). Seven specimens were used to construct length-tension curves, and nine were tested with and without the myosin blocker 2,3-butanedione monoxime (BDM). The results demonstrate substantial, reversible CO2-dependent changes in parenchyma strip recoil (up to 23%) and BDM eliminates this effect, supporting a potentially important role for parenchymal myosin in V˙A/Q˙ matching. Published by Elsevier B.V.

  10. Uptake of exogenous spermidine by rat lungs perfused in situ

    SciTech Connect

    Rannels, D.E.; Addison, J.L.

    1987-01-01

    Uptake of the polyamine spermidine (SPD) from the pulmonary circulation was characterized by using ventilated rat lungs perfused in situ with Krebs-Henseleit-bicarbonate buffer containing 4.5% bovine serum albumin, 5.6 mM glucose, and 20 amino acids at plasma levels. (/sup 14/C)SPD was accumulated by the lungs in a time- and concentration-dependent manner. The pathway of SPD uptake exhibited saturation kinetics with an apparent K/sub m/ in the range of 1 ..mu..M and a V/sub max/ of 450-540 pmol/g lung min. SPD uptake was inhibited by the naturally occurring polyamines putrescine and spermine (SPM) and by the inhibitor of polyamine synthesis, methyglyoxal bis(guanylhydrazone) (MGBG). Inhibition of SPD uptake by SPM followed competitive kinetics; although MGBG was also a competitive inhibitor of SPD uptake, MGBG was less effective than SPM. These observations indicate that SPD is taken up from the pulmonary circulation by a carrier-mediated pathway that is inhibited by other natural polyamines and by MGBG and exhibits by other natural polyamines and by MGBG and exhibits substrate affinity in the range of plasma SPD concentrations.

  11. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

  12. Inflammatory effects of inhaled sulfur mustard in rat lung

    SciTech Connect

    Malaviya, Rama; Sunil, Vasanthi R.; Cervelli, Jessica; Anderson, Dana R.; Holmes, Wesley W.; Conti, Michele L.; Gordon, Ronald E.; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-10-15

    Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4 mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48 h or 7 days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor-{alpha} (TNF{alpha}), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNF{alpha} and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.

  13. Effects of amiloride on sodium flux in isolated rat lungs

    SciTech Connect

    Goodman, B.E.; Crandeall, E.D.

    1986-03-05

    Cultured alveolar epithelial cell monolayers actively transport sodium (Na) from apical to basolateral surface. The process can be stimulated by terbutaline and inhibited by amiloride. In this study, the isolated perfused rat lung was used to investigate the presence of these phenomena in intact mammalian alveolar epithelium. Adult male Sprague-Dawley rats (250-350 g) were tracheostomized and ventilated with 95%O/sub 2/:5% CO/sub 2/. Two ml Krebs-Ringer-bicarbonate solution (KRB) with or without terbutaline (5 x 10/sup -6/M) were instilled into the trachea Lungs were then perfused via the pulmonary artery with KRB. At t=0, 3 ml KRB containing 0.6uCi /sup 22/Na and 0.6uCi /sup 14/C-sucrose were lavaged into the trachea. Samples of the recirculated perfusate were taken periodically thereafter. At t=20 min, amiloride (10/sup -3/M) was added to the perfusate. Samples were counted and apparent permeability x surface area products (PA) calculated. Control PA for /sup 22/Na was 3.72 (+/-0.15) x 10/sup -4/ ml/s. Amiloride inhibited /sup 22/Na flux by 30% (PA=2.62(+/-0.17) x 10/sup -4/ ml/s). Terbutaline stimulated /sup 22/Na flux by 59% (PA=5.92(+/-0.46) x 10/sup -4/ ml/s). Amiloride inhibited this pre-stimulated /sup 22/Na flux by 46% (PA=3.19(+/-0.37) x 10/sup -4/ ml/s). PA for sucrose was unchanged by any of these drugs. These data are consistent with the presence of a regulable component of active sodium transport from airspace to vascular space in intact mammalian lungs.

  14. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples

    PubMed Central

    Ellison, Gillian; Zhu, Guanshan; Moulis, Alexandros; Dearden, Simon; Speake, Georgina; McCormack, Rose

    2013-01-01

    Aims Activating mutations in the gene encoding epidermal growth factor receptor (EGFR) can confer sensitivity to EGFR tyrosine kinase inhibitors such as gefitinib in patients with advanced non-small-cell lung cancer. Testing for mutations in EGFR is therefore an important step in the treatment-decision pathway. We reviewed reported methods for EGFR mutation testing in patients with lung cancer, initially focusing on studies involving standard tumour tissue samples. We also evaluated data on the use of cytology samples in order to determine their suitability for EGFR mutation analysis. Methods We searched the MEDLINE database for studies reporting on EGFR mutation testing methods in patients with lung cancer. Results Various methods have been investigated as potential alternatives to the historical standard for EGFR mutation testing, direct DNA sequencing. Many of these are targeted methods that specifically detect the most common EGFR mutations. The development of targeted mutation testing methods and commercially available test kits has enabled sensitive, rapid and robust analysis of clinical samples. The use of screening methods, subsequent to sample micro dissection, has also ensured that identification of more rare, uncommon mutations is now feasible. Cytology samples including fine needle aspirate and pleural effusion can be used successfully to determine EGFR mutation status provided that sensitive testing methods are employed. Conclusions Several different testing methods offer a more sensitive alternative to direct sequencing for the detection of common EGFR mutations. Evidence published to date suggests cytology samples are viable alternatives for mutation testing when tumour tissue samples are not available. PMID:23172555

  15. Tumour oxygen dynamics measured simultaneously by near-infrared spectroscopy and 19F magnetic resonance imaging in rats

    NASA Astrophysics Data System (ADS)

    Xia, Mengna; Kodibagkar, Vikram; Liu, Hanli; Mason, Ralph P.

    2006-01-01

    Simultaneous near-infrared spectroscopy (NIRS) and magnetic resonance imaging (MRI) were used to investigate the correlation between tumour vascular oxygenation and tissue oxygen tension dynamics in rat breast 13762NF tumours with respect to hyperoxic gas breathing. NIRS directly detected global variations in the oxygenated haemoglobin concentration (Δ[HbO2]) within tumours and oxygen tension (pO2) maps were achieved using 19F MRI of the reporter molecule hexafluorobenzene. Multiple correlations were examined between rates and magnitudes of vascular (Δ[HbO2]) and tissue (pO2) responses. Significant correlations were found between response to oxygen and carbogen breathing using either modality. Comparison of results for the two methods showed a correlation between the vascular perfusion rate ratio and the mean pO2 values (R2 > 0.7). The initial rates of increase of Δ[HbO2] and the slope of dynamic pO2 response, d(pO2)/dt, of well-oxygenated voxels in response to hyperoxic challenge were also correlated. These results demonstrate the feasibility of simultaneous measurements using NIRS and MRI. As expected, the rate of pO2 response to oxygen is primarily dependent upon the well perfused rather than poorly perfused vasculature. Presented in part at the 12th annual meeting of the International Society of Magnetic Resonance in Medicine, Kyoto, 2004.

  16. In vivo fluorescence imaging of the transport of charged chlorine6 conjugates in a rat orthotopic prostate tumour

    PubMed Central

    Hamblin, M R; Rajadhyaksha, M; Momma, T; Soukos, N S; Hasan, T

    1999-01-01

    Polymeric drug conjugates are used in cancer therapy and, varying their molecular size and charge, will affect their in vivo transport and extravasation in tumours. Partitioning between tumour vasculature and tumour tissue will be of particular significance in the case of photosensitizer conjugates used in photodynamic therapy, where this partitioning can lead to different therapeutic effects. Poly-l-lysine chlorine6 conjugates (derived from polymers of averageMr 5000 and 25 000) were prepared both in a cationic state and by poly-succinylation in an anionic state. A fluorescence scanning laser microscope was used to follow the pharmacokinetics of these conjugates in vivo in an orthotopic rat prostate cancer model obtained with MatLyLu cells. Fluorescence was excited with the 454–528 nm group of lines of an argon laser and a 570 nm long pass filter used to isolate the emission. Results showed that the conjugates initially bound to the walls of the vasculature, before extravasating into the tissue, and eventually increasing in fluorescence. The anionic conjugates produced tissue fluorescence faster than the cationic ones, and surprisingly, the largerMr conjugates produced tissue fluorescence faster than the smaller ones with the same charge. These results are consistent with differences in aggregation state between conjugates. © 1999 Cancer Research Campaign PMID:10496351

  17. The Effect of Variation in Carcinogenic Dosage on the Induction of Tumours in the Dorsal and Vulval Skin of Female Rats

    PubMed Central

    Glucksmann, A.; Cherry, C. P.

    1971-01-01

    The response to 5, 10, 20 or 40 weekly paintings with DMBA of the dorsal and vulval skin in intact and castrate rats is compared. Squamous and basal celled tumours appear faster in the dorsal than the vulval region with 5, 10, or 20 paintings, but at the same rate with 40 doses. The rate of induction of epithelial tumours is optimal with 20 applications dorsally, but increases with dose at the vulva. Progression of malignancy of squamous celled tumours is greater and faster in the dorsal than in the vulval region. For basal celled neoplasms of the vulva there is a peak value in malignant conversion at 20 doses, but otherwise there is no consistent difference in the pattern at the two sites. Castration reduces the incidence of basal celled tumours of the vulva in rats painted weekly for life, but does not affect the incidence of epithelial tumours of the skin. Sarcomas occur in 29% of rats in the dorsal region, but in only 0·4% at the vulva. Sarcomatous changes in the stroma of epitheliomas are also more frequent in the dorsal skin. Local factors rather than variation in individual sensitivity account for the differences with region in the carcinogenic response as shown by their persistence in rats treated simultaneously at both sites. ImagesFig. 11Fig. 12Fig 13Fig 14 PMID:5144538

  18. Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival.

    PubMed Central

    Koukourakis, M. I.; Giatromanolaki, A.; Kakolyris, S.; O'Byrne, K. J.; Apostolikas, N.; Skarlatos, J.; Gatter, K. C.; Harris, A. L.

    1998-01-01

    Angiogenesis is recognized as an important step in tumour pathogenesis that is related to invasion and metastatic spread and which consequently results in poor clinical outcome. In this study, we have examined the role of tumour stroma-activated fibroblasts and macrophage infiltration in the development of the angiogenic and metastatic phenotype in non-small-cell lung cancer (NSCLC). A total of 141 cases of early stage I-II NSCLC treated with surgery alone were analysed. The JC-70 (anti-CD31) MAb was used for the assessment of vascular grade. The P-GF.44C MAb was used to assess thymidine phosphorylase (TP) reactivity in cancer cells, stromal fibroblasts and macrophages. Cancer cell TP overexpression related to high vascular grade and to advanced T stage (P = 0.0004 and P = 0.02). Expression of TP in stromal fibroblasts also correlated with high angiogenesis (P = 0.01), but was independent of cancer cell expression. Fibroblast TP overexpression was related to abundant stroma (P = 0.003), suggesting that TP may be a marker of active stroma. Moreover, intense macrophage infiltration was associated with fibroblast TP reactivity, regardless of the amount of stroma, suggesting that macrophages may be a major contributor to TP expression in stroma. Survival analysis showed that cancer cell TP overexpression was related to poor prognosis (P = 0.005). Although stroma TP is related to angiogenesis, in the low vascular grade group it defined a group of patients with better prognosis (P = 0.02). It may be that fibroblast TP reactivity is an indirect marker of tumour infiltration by functional macrophages, which have an antitumour effect. We conclude that stromal macrophage and fibroblast TP reactivity may have an important role in non-small-cell lung cancer behaviour. Understanding the role of stromal fibroblasts and inflammatory cells and their interaction with oncoprotein expression is essential for the elucidation of lung cancer pathogenesis. Images Figure 1 PMID:9635852

  19. Interferon-gamma and tumour necrosis factor induce expression of major histocompatibility complex antigen on rat retinal astrocytes.

    PubMed Central

    el-Asrar, A M; Maimone, D; Morse, P H; Lascola, C; Reder, A T

    1991-01-01

    Cultured rat retinal astrocytes were tested by indirect immunofluorescence staining for their ability to express class I and II major histocompatibility complex (MHC) antigens under basal culture conditions and after three days of stimulation with two recombinant cytokines, rat interferon-gamma (IFN-gamma) and human tumour necrosis factor alpha (TNF alpha). Under basal culture conditions low levels of class I antigens were detected on a small percentage of cells, but there was no visible class II. IFN-gamma and TNF alpha stimulation enhanced class I expression. TNF alpha had no effect on class II expression, whereas IFN-gamma induced the expression of class II in a dose dependent manner. These findings suggest that retinal astrocytes might play a part in immunological events occurring in the retina. Images PMID:1908315

  20. Interferon-gamma and tumour necrosis factor induce expression of major histocompatibility complex antigen on rat retinal astrocytes.

    PubMed

    el-Asrar, A M; Maimone, D; Morse, P H; Lascola, C; Reder, A T

    1991-08-01

    Cultured rat retinal astrocytes were tested by indirect immunofluorescence staining for their ability to express class I and II major histocompatibility complex (MHC) antigens under basal culture conditions and after three days of stimulation with two recombinant cytokines, rat interferon-gamma (IFN-gamma) and human tumour necrosis factor alpha (TNF alpha). Under basal culture conditions low levels of class I antigens were detected on a small percentage of cells, but there was no visible class II. IFN-gamma and TNF alpha stimulation enhanced class I expression. TNF alpha had no effect on class II expression, whereas IFN-gamma induced the expression of class II in a dose dependent manner. These findings suggest that retinal astrocytes might play a part in immunological events occurring in the retina.

  1. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver

    PubMed Central

    Eyal, S; Lamb, J G; Smith-Yockman, M; Yagen, B; Fibach, E; Altschuler, Y; White, H S; Bialer, M

    2006-01-01

    Background and purpose: The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent. However, HDAC inhibitors may interact with anticancer drugs through induction of P-glycoprotein (P-gp, MDR1) expression. In this study we assessed whether valproic acid induces P-gp function in tumour cells. We also investigated effects of valproic acid on the mRNA for P-gp and the cytochrome P450, CYP3A, in rat livers. >Experimental approach: Effects of valproic acid on P-gp were assessed in three tumour cell lines, SW620, KG1a and H4IIE. Accumulation of acetylated histone H3 in rats' livers treated for two or seven days with valproic acid was evaluated using a specific antibody. Hepatic expression of the P-gp genes, mdr1a, mdr1b and mdr2, was determined by real-time polymerase chain reaction. The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays. Key results: Valproic acid (0.5–2.0 mM) induced P-gp expression and function up to 4-fold in vitro. The effect of a series of valproic acid derivatives on P-gp expression in SW620 and KG1a cells correlated with their HDAC inhibition potencies. Treatment of rats with 1 mmol kg−1 valproic acid for two and seven days increased hepatic histone acetylation (1.3- and 3.5-fold, respectively) and the expression of mdr1a and mdr2 (2.2–4.1-fold). Valpromide (0.5–2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression. Conclusions: Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver. The clinical significance of this increase merits further investigation. PMID:16894351

  2. A Low-Protein Diet Enhances Angiotensin II Production in the Lung of Pregnant Rats but Not Nonpregnant Rats

    PubMed Central

    Gao, Haijun; Tanchico, Daren Tubianosa; Yallampalli, Uma; Yallampalli, Chandrasekhar

    2016-01-01

    Pulmonary angiotensin II production is enhanced in pregnant rats fed a low-protein (LP) diet. Here we assessed if LP diet induces elevations in angiotensin II production in nonpregnant rats and whether Ace expression and ACE activity in lungs are increased. Nonpregnant rats were fed a normal (CT) or LP diet for 8, 12, or 17 days and timed pregnant rats fed for 17 days from Day 3 of pregnancy. Plasma angiotensin II, expressions of Ace and Ace2, and activities of these proteins in lungs, kidneys, and plasma were measured. These parameters were compared among nonpregnant rats or between nonpregnant and pregnant rats fed different diets. Major findings are as follows: (1) plasma angiotensin II levels were slightly higher in the LP than CT group on Days 8 and 12 in nonpregnant rats; (2) expression of Ace and Ace2 and abundance and activities of ACE and ACE2 in lungs, kidneys, and plasma of nonpregnant rats were unchanged by LP diet except for minor changes; (3) the abundance and activities of ACE in lungs of pregnant rats fed LP diet were greater than nonpregnant rats, while those of ACE2 were decreased. These results indicate that LP diet-induced increase in pulmonary angiotensin II production depends on pregnancy. PMID:27195150

  3. Lung allograft rejection in the rat. V. Inhaled stimuli aggravate the rejection response

    SciTech Connect

    Prop, J.; Jansen, H.M.; Wildevuur, C.R.; Nieuwenhuis, P.

    1985-07-01

    Responses to inhaled stimuli in lung allografts might intensify the rejection response against the grafts. Therefore, the authors investigated the rejection of lung allografts in rats exposed to various degrees of stimuli via the airways. A group of these rats was selectively decontaminated to eliminate infection of the graft. Stimuli provided were intrabronchially injected purified protein derivative in sensitized rats and dust inhaled from sawdust used as bedding in the cages. Both intrabronchially injected purified protein derivative and stimuli inhaled from sawdust were found to aggravate lung allograft rejection, thus shortening mean graft survival from 32 to 11 days. Selective decontamination did prolong lung graft survival (p less than 0.05) because it lowered the overall immune reactivity of the recipient rats. For clinical lung transplantation, these observations suggest that patients should be selectively decontaminated and protected against inhalation of exogenous stimuli during a rejection episode.

  4. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs* **

    PubMed Central

    Torres, Ronaldo Lopes; Torres, Iraci Lucena da Silva; Laste, Gabriela; Ferreira, Maria Beatriz Cardoso; Cardoso, Paulo Francisco Guerreiro; Belló-Klein, Adriane

    2014-01-01

    Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID:25029646

  5. Assessment of lung toxicity caused by bleomycin and amiodarone by Tc-99m HMPAO lung scintigraphy in rats.

    PubMed

    Gumuser, G; Vural, K; Varol, T; Parlak, Y; Tuglu, I; Topal, G; Sayit, E

    2013-08-01

    The purpose of the study was to determine the lung toxicity caused by amiodarone (AD) and bleomycin (BLM) in rats, by means of Tc-99m HMPAO lung scintigraphy. Thirty albino rats were randomly divided into five groups. After AD or BLM was dissolved with isotonic saline (SF), a 0.5 ml solution was applied to the right bronchus via a catheter. Group 1 (n = 5 rats) received a single dose of AD, group 2 (n = 5) received two doses of AD, group 3 (n = 9) received BLM, group 4 (n = 3) received hydrochloric acid (HCl), and group 5 (n = 8) received SF. Rats in groups 1, 2, 3 and 5 were given 37 MBq Tc-99m HMPAO from the tail vein on days 7, 14, 21 and 28, and at 4 and 24 h in group 4. Static images of 10 min duration were obtained at 30 and 60 min by a double-headed gamma camera (Infinia, GE, Tirat Hacermel, Israel) on 256 × 256 matrix. Regular regions of interests were drawn over the right lung (RL), left lung (LL) and the liver (Li), and lung/liver (L/Li) ratios were calculated. After the scintigraphic imaging procedures were completed, rats were killed. Lung tissues were evaluated on a scale of (+) to (+++++) for edema, alveolar structural integrity and infiltration by inflammatory cells. Groups 2 and 3 showed statistically significant differences in RL/Li and LL/Li ratios, whereby RL/Li was higher than LL/Li (p < 0.05). There were no significant differences in RL/Li and LL/Li ratios in group 5 (p > 0.05). In histopathological examination, minimal damage or artifacts were observed in group 5. In group 4, almost all pathological findings were present in the right lung. Statistically significant (p < 0.01) histological differences were found when groups 1 and 5 were compared. More significant (p < 0.001) pathological effects were noted when groups 2 and 3 were compared to both groups 5 and 1. Injury was more prominent in the lung tissues of the control rats that were given HCl. Increased RL/Li ratios and histopathological findings were consistent

  6. Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ.

    PubMed

    Kao, Shang Jyh; Wang, David; Yeh, Diana Yu-Wung; Hsu, Kang; Hsu, Yung Hsiang; Chen, Hsing I

    2004-08-01

    Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.

  7. Kinetics of reversible-sequestration of leukocytes by the isolated perfused rat lung

    SciTech Connect

    Goliaei, B.

    1980-08-01

    The kinetics and morphology of sequestration and margination of rat leukocytes were studied using an isolated perfused and ventilated rat lung preparation. Whole rat blood, bone marrow suspension, or leukocyte suspensions, were used to perfuse the isolated rat lung. The lung was also perfused with latex particle suspensions and the passage of particles through the lung capillaries was studied. When a leukocyte suspension was perfused through the lung in the single-pass mode, the rate of sequestration decreased as more cells were perfused. In contrast, latex particles of a size comparable to that of leukocytes were totally stopped by the lung. When the leukocyte suspension was recirculated through the lung, cells were rapidly removed from circulation until a steady state was reached, after which no net removal of cells by the lung occurred. These results indicate that leukocytes are reversibly sequestered from circulation. The sequestered cells marginated and attached to the luminal surface of the endothelium of post-capillary venules and veins. A mathematical model was developed based on the assumption that the attachment and detachment of leukocytes to blood vessel walls follows first-order kinetics. The model correctly predicts the following characteristics of the system: (a) the kinetics of the sequestration of leukocytes by the lung; (b) the existence of a steady state when a suspension of leukocytes is recirculated through the lung; and (c) the independence of the fraction of cells remaining in circulation from the starting concentration for all values of starting concentration. (ERB)

  8. Isolation of CD146+ Resident Lung Mesenchymal Stromal Cells from Rat Lungs.

    PubMed

    Collins, Jennifer J P; Möbius, Marius A; Thébaud, Bernard

    2016-06-17

    Mesenchymal stromal cells (MSCs) are increasingly recognized for their therapeutic potential in a wide range of diseases, including lung diseases. Besides the use of bone marrow and umbilical cord MSCs for exogenous cell therapy, there is also increasing interest in the repair and regenerative potential of resident tissue MSCs. Moreover, they likely have a role in normal organ development, and have been attributed roles in disease, particularly those with a fibrotic nature. The main hurdle for the study of these resident tissue MSCs is the lack of a clear marker for the isolation and identification of these cells. The isolation technique described here applies multiple characteristics of lung resident MSCs (L-MSCs). Upon sacrifice of the rats, lungs are removed and rinsed multiple times to remove blood. Following mechanical dissociation by scalpel, the lungs are digested for 2-3 hr using a mix of collagenase type I, neutral protease and DNase type I. The obtained single cell suspension is subsequently washed and layered over density gradient medium (density 1.073 g/ml). After centrifugation, cells from the interphase are washed and plated in culture-treated flasks. Cells are cultured for 4-7 days in physiological 5% O2, 5% CO2 conditions. To deplete fibroblasts (CD146(-)) and to ensure a population of only L-MSCs (CD146(+)), positive selection for CD146(+) cells is performed through magnetic bead selection. In summary, this procedure reliably produces a population of primary L-MSCs for further in vitro study and manipulation. Because of the nature of the protocol, it can easily be translated to other experimental animal models.

  9. Rat lung inflammatory responses after in vivo and in vitro exposure to various stone particles.

    PubMed

    Becher, R; Hetland, R B; Refsnes, M; Dahl, J E; Dahlman, H J; Schwarze, P E

    2001-09-01

    Rat lung alveolar macrophages and type 2 cells were exposed for 20 h in vitro to various stone particles with differing contents of metals and minerals (a type of mylonite, gabbro, feldspar, and quartz). The capability to induce the release of the inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2) was investigated. We found marked differences in potency between the various particles, with mylonite being most potent overall, followed by gabbro, and with feldspar and quartz having an approximately similar order of lower potency. The results also demonstrated differences in cytokine release pattern between the two cell types. For all particle types including quartz, type 2 cells showed the most marked increase in MIP-2 and IL-6 secretion, whereas the largest increase in TNF-alpha release was observed in macrophages. To investigate possible correlations between in vitro and in vivo inflammatory responses, rats were instilled with the same types of particles and bronchoalveolar lavage (BAL) fluid was collected after 20 h. The results demonstrated a correlation between the in vitro cytokine responses and the number of neutrophilic cells in the BAL fluid. The BAL fluid also showed a strong MIP-2 response to mylonite. However, this was the only particle type to give a significant cytokine response in the BAL fluid. We further examined whether a similar graded inflammatory response would be continued in type 2 cells and alveolar macrophages isolated from the exposed animals. Again a differential cytokine release pattern was observed between type 2 cells and macrophages, although the order of potency between particle types was altered. In conclusion, various stone particles caused differential inflammatory responses after both in vitro and in vivo exposure, with mylonite being the most potent stone particle. The results suggest the alveolar type 2 cell to be an important participant in the

  10. Prenatal dexamethasone exposure in rats results in long-term epigenetic histone modifications and tumour necrosis factor-α production decrease.

    PubMed

    Yu, Hong-Ren; Kuo, Ho-Chang; Chen, Chih-Cheng; Sheen, Jiunn-Ming; Tiao, Mao-Meng; Chen, Yu-Chieh; Chang, Kow-Aung; Tain, You-Lin; Huang, Li-Tung

    2014-12-01

    Glucocorticoid (GC) is often given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, reports and related research regarding the prolonged effects of prenatal GC on the development of immunity are very limited. Some data, derived from infants whose mothers were given immunosuppressants during pregnancy for the treatment of autoimmune disorders, suggest that prenatal exposure to GC may have only a limited effect on the development of the immune system. What is unknown is whether the immune modulation effects of prenatal GC might appear at a later childhood stage and beyond. Here we evaluated the immune programming influenced by prenatal GC. Pregnant Sprague-Dawley rats received dexamethasone (DEX; 0.1 mg/kg/day) or saline at gestational days 14-20. Male offspring were killed at day 7 or day 120 after birth. Spleens were collected for immune study. Of the inflammation mediators, matrix metalloproteinase-9, tumour necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor mRNAs decreased in the prenatal DEX group at an early stage after birth. Upon concanavalin A stimulation, prenatal DEX treatment reduced TNF-α production, but not interferon-γ production, by splenocytes at day 120 after birth compared with the vehicle group. Decreased levels of active chromatin signs (acetylation of histone H3 lysines, H3K4me1/3, and H3K36me3) in TNF-α promoter were compatible with the expressions of TNF-α. Our results suggest that prenatal DEX has a profound and lasting impact on the developing immune system even to the adult stage. Epigenetic histone modifications regulate TNF-α expression following prenatal DEX in rats.

  11. [Effects of pathogenic wind-dampness on lung tissue cytokines in rats with syndrome due to pathogenic cold invading lung].

    PubMed

    Zhang, Wei; Cao, Jing-tao; Liu, Hai-yu

    2008-07-01

    To explore the effects of wind and dampness pathogens on cytokines in the lung tissue of rats with cold syndrome due to different gradient cold pathogens. One hundred and four Wistar rats of SPF grade were randomly divided into 13 groups: normal temperature group, six cold pathogen groups and six cold plus wind-dampness pathogen (wind of grade 5 and 90%-100% relative humidity) groups. The cold pathogens were constant low temperature (including 10 degrees C, 0 degree C, -10 degrees C) and temperature change (including 20 to 10 degrees C, 20 to 0 degrees C, and 20 to -10 degrees C). The rats in different groups were kept in a temperature-controlled box under the corresponding condition for 2 hours on the first day of experiment. Then, the rats were all raised in normal temperature for 4 days and the rats' behaviors were observed. The contents of tumor necrosis factor alpha (TNF-alpha), interleukin-6(IL-6) and interleukin-4 (IL-4) in lung homogenate were measured by radioimmunoassay and the content of interferon-gamma (IFN-gamma) was detected by enzyme-linked immunosorbent assay. In comparison with cold pathogen groups, contents of TNF-alpha, IL-6 and IL-4 were obviously increased in lung homogenate of rats in cold plus wind-dampness pathogen groups (P<0.01), and the content of IFN-gamma and IFN-gamma/IL-4 ratio were obviously decreased (P<0.01). Wind-dampness pathogen can seriously aggravate the injury to lung tissue caused by cold pathogen, and the unbalance of Th(1)/Th(2) in lung homogenate of rats.

  12. The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

    PubMed Central

    Xu, Jie; Zhou, Weihua; Yang, Fei; Chen, Guoan; Li, Haomin; Zhao, Yongchao; Liu, Pengyuan; Li, Hua; Tan, Mingjia; Xiong, Xiufang; Sun, Yi

    2017-01-01

    β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation. PMID:28090088

  13. The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

    PubMed

    Lai, Yi-Hua; Yu, Sung-Liang; Chen, Hsuan-Yu; Wang, Chi-Chung; Chen, Huei-Wen; Chen, Jeremy J W

    2013-05-01

    HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate < 0.05) that are dominantly involved in the cell cycle, apoptosis and adhesion-related biological signalling, including mitogen-activated protein kinase, focal adhesion and tight junction pathways, indicating the diverse effects of andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

  14. Apoptotic Cell Death in Rat Lung Following Mustard Gas Inhalation.

    PubMed

    Andres, Devon Katherine; Keyser, Brian M; Melber, Ashley A; Benton, Betty Jean; Hamilton, Tracey A; Kniffin, Denise M; Martens, Magaret E; Ray, Radharaman

    2017-03-30

    To investigate apoptosis as a mechanism of sulfur mustard (SM) inhalation injury in animals, we studied different caspases (caspase-8, -9, -3 and -6) in the lungs from a ventilated rat SM aerosol inhalation model. SM activated all four caspases in cells obtained from bronchoalveolar lavage fluid (BALF) as early as 6 hr after exposure. Caspase-8, which is known to initiate the extrinsic Fas-mediated pathway of apoptosis, was increased 5-fold between 6 to 24 hr, decreasing to the unexposed-control level at 48 hr. The initiator, caspase-9, in the intrinsic mitochondrial pathway of apoptosis as well as the executioner caspases, caspase-3 and -6, all peaked (p<0.01) at 24 hr; caspase-3 and -6 remained elevated, but caspase-9 decreased to unexposed-control level at 48 hr. To study further the Fas pathway, we examined soluble as well as membrane-bound Fas ligand (sFas-L, mFas-L, respectively) and Fas receptor (Fas-R) in both BALF cells and BALF. SFas-L increased significantly at 24 hr after SM exposure in both BALF cells (p<0.01) and BALF (p<0.05). However, mFas-L increased only in BALF cells between 24 to 48 hr (p<0.1, <0.001, respectively). Fas-R increased only in BALF cells by 6 hr (p<0.01) after SM exposure. Apoptosis in SM-inhaled rat lung specimens was also confirmed by both immunohistochemical staining using cleaved caspse-3 and -9 antibodies and TUNEL staining as early as 6 hr in the proximal trachea and bronchi, but not before 48 hr in distal airways. These findings suggest pathogenic mechanisms at the cellular and molecular levels and logical therapeutic target(s) for SM inhalation injury in animals.

  15. In-vivo imaging of the morphology and blood perfusion of brain tumours in rats with UHR-OCT (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Bizheva, Kostadinka; Tan, Bingyao; Fisher, Carl J.; Mason, Erik; Lilge, Lothar D.

    2017-02-01

    Brain tumors are characterized with morphological changes at cellular level such as enlarged, non-spherical nuclei, microcalcifications, cysts, etc., and are highly vascularized. In this study, two research-grade optical coherence tomography (OCT) systems operating at 800 nm and 1060 nm with axial resolution of 0.95 µm and 3.5 µm in biological tissue respectively, were used to image in vivo and ex vivo the structure of brain tumours in rats. Female Fischer 344 rats were used for this study, which has received ethics clearance by the Animal Research Ethics Committees of the University of Waterloo and the University Health Network, Toronto. Brain tumours were induced by injection of rat brain cancer cell line (RG2 glioma) through a small craniotomy. Presence of brain tumours was verified by MRI imaging on day 7 post tumour cells injection. The in vivo OCT imaging session was conducted on day 14 of the study with the 1060 nm OCT system and both morphological OCT, Doppler OCT and OMAG images were acquired from the brain tumour and the surrounding healthy brain tissue. After completion of the imaging procedure, the brains were harvested, fixed in formalin and reimaged after 2 weeks with the 800 nm OCT system. The in vivo and ex vivo OCT morphological images were correlated with H and E histology. Results from this study demonstrate that UHR-OCT can distinguish between healthy and cancerous brain tissue based on differences in structural and vascular pattern.

  16. Serum copper concentration as an index of lung injury in rats exposed to hemithorax irradiation

    SciTech Connect

    Ward, W.F.; Molteni, A.; Fitzsimons, E.J.; Hinz, J.

    1988-06-01

    Serum copper concentration was evaluated as an index of lung injury (monitored by lung prostacyclin production) with respect to the effects of time, dose, dose fractionation, and penicillamine dose modification in rats irradiated to the right hemithorax. Both lung PGI2 production and serum Cu concentration increased with increasing /sup 60/Co gamma-ray dose in animals sacrificed 2 or 6 months postirradiation, and the highest values for both responses were observed at the latter autopsy time. At 2 months postirradiation, the elevations in lung PGI2 production and serum Cu concentration also were spared similarly when total radiation doses were delivered in five equal daily fractions as compared to single doses. Finally, the ability of D-penicillamine to ameliorate the radiation-induced hyperproduction of PGI2 by rat lung was accompanied by an attenuation of the dose-dependent increase in serum Cu concentration at 2 months postirradiation in the drug-treated rats. In contrast, serum iron concentration was independent of time, dose, and penicillamine. At 2 months after irradiation, there also was a dose-dependent increase in lung hydroxyproline (collagen) content, the magnitude of which correlated closely with serum copper concentration in individual animals. Thus serum copper concentration is an accurate and minimally invasive index of lung injury in rats irradiated to the hemithorax and can predict lung hydroxyproline (collagen) content in individual irradiated rats.

  17. When does the lung die? Kfc, cell viability, and adenine nucleotide changes in the circulation-arrested rat lung.

    PubMed

    Jones, D R; Becker, R M; Hoffmann, S C; Lemasters, J J; Egan, T M

    1997-07-01

    Lungs harvested from cadaveric circulation-arrested donors may increase the donor pool for lung transplantation. To determine the degree and time course of ischemia-reperfusion injury, we evaluated the effect of O2 ventilation on capillary permeability [capillary filtration coefficient (Kfc)], cell viability, and total adenine nucleotide (TAN) levels in in situ circulation-arrested rat lungs. Kfc increased with increasing postmortem ischemic time (r = 0.88). Lungs ventilated with O2 1 h postmortem had similar Kfc and wet-to-dry ratios as controls. Nonventilated lungs had threefold (P < 0.05) and sevenfold (P < 0.0001) increases in Kfc at 30 and 60 min postmortem compared with controls. Cell viability decreased in all groups except for 30-min postmortem O2-ventilated lungs. TAN levels decreased with increasing ischemic time, particularly in nonventilated lungs. Loss of adenine nucleotides correlated with increasing Kfc values (r = 0.76). This study indicates that lungs retrieved 1 h postmortem may have normal Kfc with preharvest O2 ventilation. The relationship between Kfc and TAN suggests that vascular permeability may be related to lung TAN levels.

  18. SBRT of lung tumours: Monte Carlo simulation with PENELOPE of dose distributions including respiratory motion and comparison with different treatment planning systems.

    PubMed

    Panettieri, Vanessa; Wennberg, Berit; Gagliardi, Giovanna; Duch, Maria Amor; Ginjaume, Mercè; Lax, Ingmar

    2007-07-21

    The purpose of this work was to simulate with the Monte Carlo (MC) code PENELOPE the dose distribution in lung tumours including breathing motion in stereotactic body radiation therapy (SBRT). Two phantoms were modelled to simulate a pentagonal cross section with chestwall (unit density), lung (density 0.3 g cm(-3)) and two spherical tumours (unit density) of diameters respectively of 2 cm and 5 cm. The phase-space files (PSF) of four different SBRT field sizes of 6 MV from a Varian accelerator were calculated and used as beam sources to obtain both dose profiles and dose-volume histograms (DVHs) in different volumes of interest. Dose distributions were simulated for five beams impinging on the phantom. The simulations were conducted both for the static case and including the influence of respiratory motion. To reproduce the effect of breathing motion different simulations were performed keeping the beam fixed and displacing the phantom geometry in chosen positions in the cranial and caudal and left-right directions. The final result was obtained by combining the different position with two motion patterns. The MC results were compared with those obtained with three commercial treatment planning systems (TPSs), two based on the pencil beam (PB) algorithm, the TMS-HELAX (Nucletron, Sweden) and Eclipse (Varian Medical System, Palo Alto, CA), and one based on the collapsed cone algorithm (CC), Pinnacle(3) (Philips). Some calculations were also carried out with the analytical anisotropic algorithm (AAA) in the Eclipse system. All calculations with the TPSs were performed without simulated breathing motion, according to clinical practice. In order to compare all the TPSs and MC an absolute dose calibration in Gy/MU was performed. The analysis shows that the dose (Gy/MU) in the central part of the gross tumour volume (GTV) is calculated for both tumour sizes with an accuracy of 2-3% with PB and CC algorithms, compared to MC. At the periphery of the GTV the TPSs

  19. SBRT of lung tumours: Monte Carlo simulation with PENELOPE of dose distributions including respiratory motion and comparison with different treatment planning systems

    NASA Astrophysics Data System (ADS)

    Panettieri, Vanessa; Wennberg, Berit; Gagliardi, Giovanna; Amor Duch, Maria; Ginjaume, Mercè; Lax, Ingmar

    2007-07-01

    The purpose of this work was to simulate with the Monte Carlo (MC) code PENELOPE the dose distribution in lung tumours including breathing motion in stereotactic body radiation therapy (SBRT). Two phantoms were modelled to simulate a pentagonal cross section with chestwall (unit density), lung (density 0.3 g cm-3) and two spherical tumours (unit density) of diameters respectively of 2 cm and 5 cm. The phase-space files (PSF) of four different SBRT field sizes of 6 MV from a Varian accelerator were calculated and used as beam sources to obtain both dose profiles and dose-volume histograms (DVHs) in different volumes of interest. Dose distributions were simulated for five beams impinging on the phantom. The simulations were conducted both for the static case and including the influence of respiratory motion. To reproduce the effect of breathing motion different simulations were performed keeping the beam fixed and displacing the phantom geometry in chosen positions in the cranial and caudal and left-right directions. The final result was obtained by combining the different position with two motion patterns. The MC results were compared with those obtained with three commercial treatment planning systems (TPSs), two based on the pencil beam (PB) algorithm, the TMS-HELAX (Nucletron, Sweden) and Eclipse (Varian Medical System, Palo Alto, CA), and one based on the collapsed cone algorithm (CC), Pinnacle3 (Philips). Some calculations were also carried out with the analytical anisotropic algorithm (AAA) in the Eclipse system. All calculations with the TPSs were performed without simulated breathing motion, according to clinical practice. In order to compare all the TPSs and MC an absolute dose calibration in Gy/MU was performed. The analysis shows that the dose (Gy/MU) in the central part of the gross tumour volume (GTV) is calculated for both tumour sizes with an accuracy of 2-3% with PB and CC algorithms, compared to MC. At the periphery of the GTV the TPSs overestimate

  20. Effect of the oestrogen receptor antagonist fulvestrant on the cirrhotic rat lung.

    PubMed

    Oswald-Mammosser, Monique; Rashid, Sherzad; Boehm, Nelly; Agin, Arnaud; Geny, Bernard; Schini-Kerth, Valérie; Charloux, Anne

    2015-06-01

    It has been postulated that cirrhosis-related lung vasodilatation and the subsequent hepatopulmonary syndrome are partly explained by an increased estradiol level through an enhanced endothelial formation of nitric oxide (NO). In this study, we assessed whether the oestrogen receptor antagonist fulvestrant (F) improves cirrhosis-related lung abnormalities. Cirrhosis was induced in rats by chronic bile duct ligation (CBDL). Four groups were studied: CBDL, CBDL+F, sham, and sham+F. Histological, immunohistochemical, and Western blot analyses were performed on lung samples. In the lung, the endothelial NO synthase and the nitrotyrosine protein expressions were increased in CBDL as compared to sham rats. Both parameters were significantly reduced by fulvestrant in the CBDL rats. Surprisingly, the level of pVASP (an indirect marker of NO formation and action) was decreased in CBDL rats, and fulvestrant had no effect on this parameter. The level of the vascular endothelial growth factor, the diameter of small lung vessels, and the number of macrophages were increased in CBDL lungs in comparison with sham lungs, and these parameters were unaffected by fulvestrant treatment. In conclusion, fulvestrant may not be relevant to improve lung abnormalities in cirrhosis because NO may not be biologically active and because key events contributing to the lung abnormalities are not affected by fulvestrant.

  1. Direct detection of radical generation in rat liver nuclei on treatment with tumour-promoting hydroperoxides and related compounds.

    PubMed

    Greenley, T L; Davies, M J

    1994-04-12

    EPR spin trapping has been employed to directly detect radical production in isolated rat liver nuclei on exposure to a variety of hydroperoxides and related compounds which are known, or suspect, tumour promoters. The hydroperoxides, in the absence of reducing equivalents, undergo oxidative cleavage, generating peroxyl radicals. In the presence of NADPH (and to a lesser extent NADH) reductive cleavage of the O-O bond generates alkoxyl radicals. These radicals undergo subsequent rearrangements and reactions (dependent on the structure of the alkoxyl radical), generating carbon-centred radicals. Acyl peroxides and peracids appear to undergo only reductive cleavage of the O-O bond. With peracids this cleavage can generate aryl carboxyl (RCO2.) or hydroxyl radicals (HO.); with acyl peroxides, aryl carboxyl radicals are formed and, in the case of t-butyl peroxybenzoate, alkoxyl radicals (RO.). The radicals detected with each peroxide are similar in type to those detected in the rat liver microsomal fraction, although the extent of radical production is lower. The subsequent reactions of the initially generated radicals are similar to those determined in homogeneous chemical systems, suggesting that they are in free solution. Experiments with NADPH/NADH, heat denaturation of the nuclei and various inhibitors suggest that radical generation is an enzymatic process catalysed by haemoproteins, in particular cytochrome P-450, and that NADPH/cytochrome P-450 reductase is involved in the reductive cleavage of the O-O bond. The generation of these radicals by the rat liver nuclear fraction is potentially highly damaging for the cell due to the proximity of the generating source to DNA. Several previous studies have shown that some of the radicals detected in this study, such as aryl carboxyl and aryl radicals, can damage DNA, via various reactions which result in the generation of strand breaks and adducts to DNA bases: these processes are suggested to play an important role

  2. Molecular Profiling of Circulating Tumour Cells Identifies Notch1 as a Principal Regulator in Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Mariscal, Javier; Alonso-Nocelo, Marta; Muinelo-Romay, Laura; Barbazan, Jorge; Vieito, Maria; Abalo, Alicia; Gomez-Tato, Antonio; Maria de los Angeles, Casares de Cal; Garcia-Caballero, Tomas; Rodriguez, Carmela; Brozos, Elena; Baron, Francisco; Lopez-Lopez, Rafael; Abal, Miguel

    2016-01-01

    Knowledge on the molecular mechanisms underlying metastasis colonization in Non-Small Cell Lung Cancer (NSCLC) remains incomplete. A complete overview integrating driver mutations, primary tumour heterogeneity and overt metastasis lacks the dynamic contribution of disseminating metastatic cells due to the inaccessibility to the molecular profiling of Circulating Tumour Cells (CTCs). By combining immunoisolation and whole genome amplification, we performed a global gene expression analysis of EpCAM positive CTCs from advanced NSCLC patients. We identified an EpCAM+ CTC-specific expression profile in NSCLC patients mostly associated with cellular movement, cell adhesion and cell-to-cell signalling mediated by PI3K/AKT, ERK1/2 and NF-kB pathways. NOTCH1 emerged as a driver connecting active signalling pathways, with a reduced number of related candidate genes (NOTCH1, PTP4A3, LGALS3 and ITGB3) being further validated by RT-qPCR on an independent cohort of NSCLC patients. In addition, these markers demonstrated high prognostic value for Progression-Free Survival (PFS). In conclusion, molecular characterization of EpCAM+ CTCs from advanced NSCLC patients provided with highly specific biomarkers with potential applicability as a “liquid biopsy” for monitoring of NSCLC patients and confirmed NOTCH1 as a potential therapeutic target to block lung cancer dissemination. PMID:27901069

  3. Long non-coding RNA 00312 regulated by HOXA5 inhibits tumour proliferation and promotes apoptosis in Non-small cell lung cancer.

    PubMed

    Zhu, Qingqing; Lv, Tangfeng; Wu, Ying; Shi, Xuefei; Liu, Hongbing; Song, Yong

    2017-09-01

    Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. The abnormal expression of many long non-coding RNAs (lncRNAs) has been reported involved in the progression of various tumours, which can be used as diagnostic indicators or antitumour targets. Here, we found that the long non-coding RNA 00312 was down-regulated in paired NSCLC tissues and correlated with poor clinical outcome; decreased linc00312 expression in NSCLC was associated with larger and later stage tumours. Functional experiments showed that linc00312 could inhibit cell proliferation and promote apoptosis in vitro and in vivo. Furthermore, we found that HOXA5 could bind in the promoter of linc00312 and up-regulated the expression of it. Moreover, linc00312 was down-regulated in the plasma of NSCLC patients compared with that of healthy volunteers or other pulmonary diseases patients. Taken together, our findings indicated that linc00312 could be a novel diagnosis biomarker and a promising therapeutic target for NSCLC. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  4. Low expression of MRP1/GS-X pump ATPase in lymphocytes of Walker 256 tumour-bearing rats is associated with cyclopentenone prostaglandin accumulation and cancer immunodeficiency.

    PubMed

    Kolberg, Angela; Rosa, Tatiana Gomes; Puhl, Minéia Taíse; Scola, Gustavo; da Rocha Janner, Daiane; Maslinkiewicz, Alexandre; Lagranha, Denise Jacques; Heck, Thiago Gomes; Curi, Rui; de Bittencourt, Paulo Ivo Homem

    2006-01-01

    Immunosuppression is a life-threatening complication of late cancer stages. In this regard, overproduction in the host plasma of the anti-inflammatory cyclopentenone prostaglandins (CP-PGs), which are strongly antiproliferative at high concentrations, may impair immune function. In fact, lymphoid tissues of tumour-bearing rats accumulated large amounts of CP-PGs while the tumour tissue itself did not. Expression of the CP-PG-induced 72-kDa heat shock protein (hsp70) was elevated in lymphocytes from tumour-bearing animals related to controls. As the capacity for CP-PG uptake by lymphocytes is the same as tumour cells, we investigated whether the latter could overexpress the multidrug resistance-associated protein (MRP1/GS-X pump) which extrudes CP-PGs towards the extracellular space as glutathione S-conjugates. Walker 256 tumour cells extruded 15-fold more S-conjugates than lymphocytes from the same rats (p < 0.001). This did not appear to be related to deficiency in lymphocyte glutathione (GSH) metabolism, since the major GSH metabolic routes are consistent with CP-PG conjugation in lymphocytes. This was not the case, however, for the MRP1/GS-X pump activity in lymphocyte membranes (in pmol/min/mg protein: 3.1 +/- 1.7 from normal rats, 0.2 +/- 0.2 from tumour-bearing animals vs 64.3 +/- 7.0 in tumour cells) which was confirmed by Western blot analysis for MRP1 protein. Transfection of lymphocytes with MRP1 gene completely abolished CP-PG (0-40 microM) toxicity. Taken together, these findings suggest that CP-PG accumulation in lymphocytes may be, at least partially, responsible for cancer immunodeficiency. Clinical approaches for overexpressing MRP1/GS-X pump in lymphocytes could then play a role as a tool for the management of cancer therapeutics.

  5. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats.

    PubMed

    Al-Harbi, Naif O; Imam, Faisal; Nadeem, Ahmed; Al-Harbi, Mohammed M; Korashy, Hesham M; Sayed-Ahmed, Mohammed M; Hafez, Mohamed M; Al-Shabanah, Othman A; Nagi, Mahmoud N; Bahashwan, Saleh

    2015-01-01

    Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20 μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p < 0.01) and MPO activity (p < 0.001), whereas marked decrease in glutathione (GSH) content (p < 0.001), glutathione reductase (GR) (p < 0.001) and glutathione peroxidase (p < 0.01) activity. These changes were significantly (p < 0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100 mg/kg, respectively). Riboflavin (100 mg/kg, p.o.) showed similar protective effects as dexamethasone (1 mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p < 0.001) and levels of CAT mRNA expression was decreased significantly (p < 0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p < 0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.

  6. Morphological effects of nitrogen dioxide on the rat lung

    SciTech Connect

    Hayashi, Y.; Kohno, T.; Ohwada, H.

    1987-08-01

    Morphological studies of the rat lung exposed to 20 ppm NO/sub 2/ for 20 hr (experiment 1), to 0.5 ppm for 19 months (experiment 2), and to 10 ppm for 14 days (experiment 3) were conducted. Changes in the mast cells of the tracheas and main bronchi of rats exposed to 0.5 ppm (experiment 4) were also observed. In the alveolus, cytoplasmic blebbing occurred in a small number of type I cells immediately after exposure to 20 ppm NO/sub 2/ for 20 hr, and remarkable vacuolar change was observed 3 days after 10 ppm exposure. Exposure to 0.5 ppm did not cause degeneration. Swelling and hyperplasia of type II cells were observed. The cells gradually became flat and began a transition from type II to type I cells. These intermediate-type cells were noticed in experiments 1 and 2, but no intermediate-type cells were found in experiment 3. In each experiment, pinocytotic vesicles of endothelial cells in capillaries, followed by interstitial edema in the alveolar walls, were observed. In addition to these changes, desquamation of endothelium and widening of the endothelial junction of endothelial cells occurred in experiment 3. The early changes observed in the animals exposed to 0.5 ppm NO/sub 2/ were the numerical and histochemical changes of mast cells in the trachea and main bronchus.

  7. Rat models of asthma and chronic obstructive lung disease.

    PubMed

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.

  8. Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

    PubMed Central

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes,, Don; Black, Sylvester M.

    2015-01-01

    The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and “pearls of wisdom”/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID:25741794

  9. Effect of Ergothioneine on Acute Lung Injury and Inflammation in Cytokine Insufflated Rats

    PubMed Central

    Repine, John E.; Elkins, Nancy D.

    2012-01-01

    Objective The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine---a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. Method Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg L-ergothioneine intravenously 1 hour before or 18 hours after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24 hours after cytokine insufflation. Results Ergothioneine pre- and post- treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. Conclusion Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS. PMID:22197759

  10. Influence of vitamin E on polyamine metabolism in ozone-exposed rat lungs

    SciTech Connect

    Elsayed, N.M.

    1987-06-01

    The influence of vitamin E (E) on lung polyamine metabolism of rats exposed to ozone (O/sub 3/) was examined. Rats fed diets either E-deficient or supplemented with 1000 IU E/kg were exposed to 0.5 +/- 0.05 ppm O/sub 3/ or filtered room air continuously for 5 days. They were then sacrificed and their lungs were analyzed for biochemical changes. Lung E content was strongly associated with the dietary level, and increased (36%, P less than 0.05) after O/sub 3/ exposure only in E-supplemented rats. Lung polyamine metabolism was not affected in the air-control rats by E level, but increased after O/sub 3/ exposure in both dietary groups. The activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase were elevated above air controls. However, the increases were significant only for E-deficient rats when compared to E-supplemented rats. After O/sub 3/ exposure, putrescine increased significantly in both dietary groups; spermidine increased but was significantly higher only in the E-deficient group; and spermine remained unchanged in both dietary groups. Elevated E content of supplemented rat lungs after O/sub 3/ exposure may represent its mobilization under oxidant stress. Increased polyamine metabolism of E-deficient rats suggests either a greater sensitivity to injury by O/sub 3/ or a possible antioxidant function for polyamines compensating for E deficiency.

  11. Production of interleukin-1 like activity by neutrophils derived from rat lung.

    PubMed Central

    Kusaka, Y; Donaldson, K

    1990-01-01

    Interleukin-1 like activity was produced by neutrophils obtained by bronchoalveolar lavage from experimentally inflamed rat lung. Activity was released spontaneously from neutrophils at high levels but it was enhanced by stimulation with endotoxin in vitro. PMID:2141440

  12. Malignant neoplasms in rats fed lasiocarpine.

    PubMed Central

    Rao, M. S.; Reddy, J. K.

    1978-01-01

    Lasiocarpine, a pyrrolizidine alkaloid, was fed at a dietary concentration of 50/10(6) for 55 weeks, to 20 male F-344 rats. Malignant tumours developed in 17/20 animals between 48 and 59 weeks. Forty-five percent (9/20) developed angiosarcomas of the liver and 35% (7/20) had hepatocellular carcinomas. Other tumours included malignant adnexas tumour of the skin (1 rat) and lympohoma (1 rat). Lung metastases were observed in 4 animals with angiosarcoma of the liver and one animal with hepatocellular carcinoma. From one animal, angiosarcoma was successfully transplanted through 4 generations. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:204322

  13. Targeted Aerosolized Delivery of Ascorbate in the Lungs of Chlorine-Exposed Rats

    PubMed Central

    Bracher, Andreas; Doran, Stephen F.; Squadrito, Giuseppe L.; Postlethwait, Edward M.; Bowen, Larry

    2012-01-01

    Abstract Background Chlorine (Cl2)-induced lung injury is a serious public health threat that may result from industrial and household accidents. Post-Cl2 administration of aerosolized ascorbate in rodents decreased lung injury and mortality. However, the extent to which aerosolized ascorbate augments depleted ascorbate stores in distal lung compartments has not been assessed. Methods We exposed rats to Cl2 (300 ppm for 30 min) and returned them to room air. Within 15–30 min postexposure, rats breathed aerosolized ascorbate and desferal or vehicle (mean particle size 3.3 μm) through a nose-only exposure system for 60 min and were euthanized. We measured the concentrations of reduced ascorbate in the bronchoalveolar lavage (BAL), plasma, and lung tissues with high-pressure liquid chromatography, protein plasma concentration in the BAL, and the volume of the epithelia lining fluid (ELF). Results Cl2-exposed rats that breathed aerosolized vehicle had lower values of ascorbate in their BAL, ELF, and lung tissues compared to air-breathing rats. Delivery of aerosolized ascorbate increased reduced ascorbate in BAL, ELF, lung tissues, and plasma of both Cl2 and air-exposed rats without causing lung injury. Based on mean diameter of aerosolized particles and airway sizes we calculated that approximately 5% and 1% of inhaled ascorbate was deposited in distal lung regions of air and Cl2-exposed rats, respectively. Significantly higher ascorbate levels were present in the BAL of Cl2-exposed rats when aerosol delivery was initiated 1 h post-Cl2. Conclusions Aerosol administration is an effective, safe, and noninvasive method for the delivery of low molecular weight antioxidants to the lungs of Cl2-exposed individuals for the purpose of decreasing morbidity and mortality. Delivery is most effective when initiated 1 h postexposure when the effects of Cl2 on minute ventilation subside. PMID:22393907

  14. Poster — Thur Eve — 12: Implementation of a Clinical Lung Tumour High Dose Containment Verification Procedure using Respiratory Cone-Beam CT (4DCBCT) on a Varian TrueBeam Linac

    SciTech Connect

    Beaudry, J.; Bergman, A.

    2014-08-15

    Lung tumours move due to respiratory motion. This is managed during planning by acquiring a 4DCT and capturing the excursion of the GTV (gross tumour volume) throughout the breathing cycle within an IGTV (Internal Gross Tumour Volume) contour. Patients undergo a verification cone-beam CT (CBCT) scan immediately prior to treatment. 3D reconstructed images do not consider tumour motion, resulting in image artefacts, such as blurring. This may lead to difficulty in identifying the tumour on reconstructed images. It would be valuable to create a 4DCBCT reconstruction of the tumour motion to confirm that does indeed remain within the planned IGTV. CBCT projections of a Quasar Respiratory Motion Phantom are acquired in Treatment mode (half-fan scan) on a Varian TrueBeam accelerator. This phantom contains a mobile, low-density lung insert with an embedded 3cm diameter tumour object. It is programmed to create a 15s periodic, 2cm (sup/inf) displacement. A Varian Real-time Position Management (RPM) tracking-box is placed on the phantom breathing platform. Breathing phase information is automatically integrated into the projection image files. Using in-house Matlab programs and RTK (Reconstruction Tool Kit) open-source toolboxes, the projections are re-binned into 10 phases and a 4DCBCT scan reconstructed. The planning IGTV is registered to the 4DCBCT and the tumour excursion is verified to remain within the planned contour. This technique successfully reconstructs 4DCBCT images using clinical modes for a breathing phantom. UBC-BCCA ethics approval has been obtained to perform 4DCBCT reconstructions on lung patients (REB#H12-00192). Clinical images will be accrued starting April 2014.

  15. Depressed glucose utilization in lungs of BB wistar spontaneously diabetic rats

    SciTech Connect

    Uhal, B.D.; Moxley, M.A.; Longmore, W.J.

    1986-03-05

    Lungs of BB wistar spontaneously diabetic rats were perfused with (/sup 14/C(U))glucose in modified Krebs Ringer bicarbonate medium for 1.5 hours. Lungs from non-diabetic BB Wistar rats were perfused simultaneously and served as controls. The perfusions were terminated by rapid freezing of the tissue in liquid N/sub 2/ followed by separation of surfactant and residual lung fractions. The rates of glucose incorporation into surfactant DSPC, PG, and PE were decreased 4.7, 2.4 and 2.5-fold, respectively, in lungs of spontaneously diabetic rats when expressed as final product specific activities. The rate of glucose incorporation into residual PC was also reduced by 2.3-fold. Expressed as moles incorporated per gram wet weight of lung, incorporations into surfactant DSPC, PG and residual PC were also reduced by 4.1, 6.3 and 3.8-fold respectively. These data; (1) agree with previous studies of the lungs of streptozotocin and alloxan-diabetic rats; (2) show that the depressed glucose utilization for lipid synthesis observed previously is not due to streptozotocin or alloxan toxicity; (3) suggest that the BB Wistar rat will provide a useful model for the study of the effects of insulin-dependent diabetes on lung metabolism.

  16. Creation of Lung-Targeted Dexamethasone Immunoliposome and Its Therapeutic Effect on Bleomycin-Induced Lung Injury in Rats

    PubMed Central

    Li, Nan; Hu, Yang; Zhang, Yuan; Xu, Jin-Fu; Li, Xia; Ren, Jie; Su, Bo; Yuan, Wei-Zhong; Teng, Xin-Rong; Zhang, Rong-Xuan; Jiang, Dian-hua; Mulet, Xavier; Li, Hui-Ping

    2013-01-01

    Objective Acute lung injury (ALI), is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM)-loaded immunoliposome (NLP) functionalized with pulmonary surfactant protein A (SP-A) antibody (SPA-DXM-NLP) in an animal model. Methods DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. Results The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. Conclusions The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice. PMID:23516459

  17. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats

    PubMed Central

    Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Suguihara, Cleide; Young, Karen C.

    2015-01-01

    Background Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. Whether antagonism of CXCR4 will alleviate lung inflammation in neonatal hyperoxia-induced lung injury is unknown. Objective To determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods Newborn rats exposed to normoxia (RA) or hyperoxia (FiO2=0.9) from postnatal day 2 (P2)-P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis, and inflammation were evaluated at P16. Results As compared to RA, hyperoxic-PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in bronchoalveolar lavage fluid macrophage and neutrophil count and reduced lung myeloperoxidase activity. Conclusion CXCR4 antagonism decreases lung inflammation and improves alveolar as well as vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID:25825119

  18. Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-03-01

    The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose

  19. Comparison of lung burdens of inhaled particles of rats exposed during the day or night

    SciTech Connect

    Hesseltine, G.R.; Wolff, R.K.; Hanson, R.L.; McClellan, R.O.; Mauderly, J.L.

    1985-01-01

    Inhalation studies frequently involve daytime exposures of nocturnal animals to toxicants. Such exposures may result in different respiratory tract depositions than would be obtained if rodents were exposed at night. Our study assessed the effect of night versus day exposures on lung burdens of particles inhaled by Fischer 344 rats. One group of 15 female rats was exposed to 0.3 micron volume median diameter particles of gallium oxide (Ga2O3) for 11.2 h during the day and a second group of 15 female rats was exposed to the same aerosol for 11.2 h at night. Gallium in the lungs at the end of exposure was measured by electrothermal atomic absorption spectrometry. Rats exposed during the night had significantly (p less than 0.05) higher lung burdens than day-exposed rats when burdens were expressed as either microgram Ga2O3/lung (mean +/- SD = 896 +/- 175 versus 698 +/- 150) or microgram Ga2O3/g lung (mean +/- SD = 683 +/- 134 versus 465 +/- 103). The greater amount of material in lungs of rats exposed at night probably reflected increased ventilation accompanying nocturnal activity.

  20. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

    PubMed Central

    Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

    2015-01-01

    Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

  1. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome.

    PubMed

    Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G; Britton, Steven L; Hellman, Judith

    2015-01-01

    Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses.

  2. A rat model for isolated bilateral lung contusion from blunt chest trauma.

    PubMed

    Raghavendran, Krishnan; Davidson, Bruce A; Helinski, Jadwiga D; Marschke, Cristi J; Manderscheid, Patricia; Woytash, James A; Notter, Robert H; Knight, Paul R

    2005-11-01

    Lung contusion affects 17%-25% of adult blunt trauma patients, and is the leading cause of death from blunt thoracic injury. A small animal model for isolated bilateral lung contusion has not been developed. We induced lung contusion in anesthetized rats by dropping a 0.3-kg weight onto a precordial protective shield to direct the impact force away from the heart and toward the lungs. Lung injury was characterized as a function of chest impact energy (1.8-2.7 J) by measurements of arterial oxygenation, bronchoalveolar lavage (BAL) albumin and cytology, pressure-volume mechanics, and histopathology. Histology confirmed bilateral lung contusion without substantial cardiac muscle trauma. Rats receiving 2.7 J of chest impact energy had 33% mortality that exceeded prospectively defined limits for sublethal injury. Hypoxemia in rats with maximal sublethal injury (2.45 J) met criteria for acute lung injury at < or =24 h, improving by 48 h. BAL albumin levels were highest at < or =24 h, and remained elevated along with increased BAL leukocytes and decreased lung volumes at 48 h. We concluded that an impact energy of 2.45 J induces isolated, bilateral lung contusion and provides a useful model for future mechanistic pathophysiological assessments.

  3. Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model.

    PubMed

    Mestas, Jean-Louis; Fowler, R Andrew; Evjen, Tove J; Somaglino, Lucie; Moussatov, Alexei; Ngo, Jacqueline; Chesnais, Sabrina; Røgnvaldsson, Sibylla; Fossheim, Sigrid L; Nilssen, Esben A; Lafon, Cyril

    2014-09-01

    The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

  4. Tea polyphenols prevent lung from preneoplastic lesions and effect p53 and bcl-2 gene expression in rat lung tissues.

    PubMed

    Gu, Qihua; Hu, Chengping; Chen, Qiong; Xia, Ying

    2013-01-01

    Lung cancer is one of the cancers that have the highest incidence and the highest mortality rate, and it is of great interest to identify ways to prevent its occurrence. We had established an animal model by using 3,4-benzopyrene intra-pulmonary injection in our previous study, and had observed that the rats lung carcinoma incidence and multiplicity were significantly reduced by green tea administration. This study further investigated the effect of tea polyphenols on rat lung preneoplastic lesions using the lung carcinoma model established by 3,4-benzopyrene intra-pulmonary injection. Sprague-Dawley rats of the same age were randomly divided into 10 groups and treated with 3,4-benzopyrene by intra-pulmonary injection. Five groups were given 0.3% solution of tea polyphenols (equivalent to 1.2% of green tea) in drinking water, while the other 5 groups were given pure drinking water. The rats were sacrificed at 0, 1, 4, 8 and 16 weeks after carcinogen treatment. In the control groups of rats, local bronchial inflammation were observed at 1 week after 3,4-benzopyrene treatment. From 4 weeks to 16 weeks after carcinogen treatment, hyperplasia, cell hyperproliferation, heterogeneity were observed in the bronchial epithelium. Meanwhile, the expression of p53 mRNA and protein, as well as the level of bcl-2, increased in the bronchial epithelial lesion. Tea polyphenols treatment significantly alleviated the bronchial epithelial lesions. At the same time, tea polyphenols treatment enhanced p53 expression, but reduced bcl-2 expression. These results indicated that tea polyphenols may have preventive effect against lung preneoplasm lesions, possibly through regulating the expression of some critical genes such as p53 and bcl-2.

  5. Interactions of ozone and antineoplastic drugs on rat lung fibroblasts and Walker rat carcinoma cells

    SciTech Connect

    Wenzel, D.G.; Morgan, D.L.

    1983-05-01

    Cultured rat lung fibroblasts (F-cells) and Walker rat carcinoma cells (WRC-cells) labeled with /sup 51/Cr were exposed to the following antitumor drugs alone or with O/sub 3/: carmustine (BCNU), doxorubicin (Dox), cisplatin (CPt), mitomycin C (Mit C) or vitamin K/sub 3/ (Vit K). Release of /sup 51/Cr (cell injury) was greater for F-cells than WRC-cells with any single treatment. Pretreatment with any drug (400 microM), except for Vit K with WRC-cells, did not significantly increase O/sub 3/-induced loss of /sup 51/Cr. Co-exposure of F-cells to drugs and O/sub 3/ resulted in a marked potentiation of O/sub 3/-induced injury with Vit K, and an inhibition with Dox.

  6. Nitric oxide modulation of pulmonary vascular resistance is red blood cell dependent in isolated rat lungs.

    PubMed

    Uncles, D R; Daugherty, M O; Frank, D U; Roos, C M; Rich, G F

    1996-12-01

    Nitric oxide (NO) or endothelium-derived relaxing factor may play an important role in modulating pulmonary vascular resistance (PVR), although previous studies have produced conflicting results. Endogenous NO inhibition causes an increase in PVR in intact animals but not in saline-perfused isolated lungs. We hypothesized that blood is essential for NO to serve as a modulator of PVR. Therefore, the effects of endogenous NO inhibition (N omega-nitro-L-arginine methyl ester [L-NAME]) were determined in isolated rat lungs as related to the presence of different blood components under normoxic conditions and after 1 wk of hypoxia (fraction of inspired oxygen [FIO2] = 10%). Exogenously administered inhaled NO was evaluated in isolated lungs from normoxic and hypoxic rats. In normoxic rats, L-NAME (10-100 microM) caused a dose-dependent increase in PVR in whole (hematocrit [Hct] 40%) and diluted (Hct 12%) blood-perfused lungs. L-NAME (10-800 microM) had no effect in isolated lungs perfused with a modified salt solution of equal viscosity to blood either alone, or containing plasma (50%) or free oxyhemoglobin (10 microM). In whole blood perfused lungs, L-NAME (100 microM) increased PVR more in hypoxic versus normoxic isolated lungs (141% vs 100%). Inhaled NO decreased PVR in isolated lungs from hypoxic rats and partially reversed the effects of L-NAME, but had no effect in normoxic lungs. In conclusion, endogenous and inhaled NO modulate PVR in isolated rat lungs and this role is increased by prolonged hypoxia. The response to inhibition of endogenous NO is dependent on the presence of red blood cells and is independent of the changes in viscosity or the presence of oxyhemoglobin or plasma.

  7. Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress

    PubMed Central

    Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh; Jacobs, Elizabeth R.; Audi, Said

    2012-01-01

    Abstract. Ventilation with enhanced fractions of O2 (hyperoxia) is a common and necessary treatment for hypoxemia in patients with lung failure, but prolonged exposure to hyperoxia causes lung injury. Ischemia-reperfusion (IR) injury of lung tissue is common in lung transplant or crush injury to the chest. These conditions are associated with apoptosis and decreased survival of lung tissue. The objective of this work is to use cryoimaging to evaluate the effect of exposure to hyperoxia and IR injury on lung tissue mitochondrial redox state in rats. The autofluorescent mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are electron carriers in ATP generation. These intrinsic fluorophores were imaged for rat lungs using low-temperature fluorescence imaging (cryoimaging). Perfused lungs from four groups of rats were studied: normoxia (control), control perfused with an mitochondrial complex IV inhibitor (potassium cyanide, KCN), rats exposed to hyperoxia (85% O2) for seven days, and from rats subjected to lung IR in vivo 24 hours prior to study. Each lung was sectioned sequentially in the transverse direction, and the images were used to reconstruct a three-dimensional (3-D) rendering. In KCN perfused lungs the respiratory chain was more reduced, whereas hyperoxic and IR lung tissue have a more oxidized respiratory chain than control lung tissue, consistent with previously measured mitochondrial dysfunction in both hyperoxic and IR lungs. PMID:22559688

  8. Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress

    NASA Astrophysics Data System (ADS)

    Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh; Jacobs, Elizabeth R.; Audi, Said; Ranji, Mahsa

    2012-04-01

    Ventilation with enhanced fractions of O2 (hyperoxia) is a common and necessary treatment for hypoxemia in patients with lung failure, but prolonged exposure to hyperoxia causes lung injury. Ischemia-reperfusion (IR) injury of lung tissue is common in lung transplant or crush injury to the chest. These conditions are associated with apoptosis and decreased survival of lung tissue. The objective of this work is to use cryoimaging to evaluate the effect of exposure to hyperoxia and IR injury on lung tissue mitochondrial redox state in rats. The autofluorescent mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are electron carriers in ATP generation. These intrinsic fluorophores were imaged for rat lungs using low-temperature fluorescence imaging (cryoimaging). Perfused lungs from four groups of rats were studied: normoxia (control), control perfused with an mitochondrial complex IV inhibitor (potassium cyanide, KCN), rats exposed to hyperoxia (85% O2) for seven days, and from rats subjected to lung IR in vivo 24 hours prior to study. Each lung was sectioned sequentially in the transverse direction, and the images were used to reconstruct a three-dimensional (3-D) rendering. In KCN perfused lungs the respiratory chain was more reduced, whereas hyperoxic and IR lung tissue have a more oxidized respiratory chain than control lung tissue, consistent with previously measured mitochondrial dysfunction in both hyperoxic and IR lungs.

  9. Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors.

    PubMed

    Suzui, Masumi; Futakuchi, Mitsuru; Fukamachi, Katsumi; Numano, Takamasa; Abdelgied, Mohamed; Takahashi, Satoru; Ohnishi, Makoto; Omori, Toyonori; Tsuruoka, Shuji; Hirose, Akihiko; Kanno, Jun; Sakamoto, Yoshimitsu; Alexander, David B; Alexander, William T; Jiegou, Xu; Tsuda, Hiroyuki

    2016-07-01

    Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 25 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. For the present study, 10-week-old F344/Crj male rats were divided into five groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2 weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors.

  10. Effect of chronic hyperoxic exposure on duroquinone reduction in adult rat lungs.

    PubMed

    Audi, Said H; Bongard, Robert D; Krenz, Gary S; Rickaby, David A; Haworth, Steven T; Eisenhauer, Jessica; Roerig, David L; Merker, Marilyn P

    2005-11-01

    NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a dominant role in the reduction of the quinone compound 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) to durohydroquinone (DQH2) on passage through the rat lung. Exposure of adult rats to 85% O2 for > or =7 days stimulates adaptation to the otherwise lethal effects of >95% O2. The objective of this study was to examine whether exposure of adult rats to hyperoxia affected lung NQO1 activity as measured by the rate of DQ reduction on passage through the lung. We measured DQH2 appearance in the venous effluent during DQ infusion at different concentrations into the pulmonary artery of isolated perfused lungs from rats exposed to room air or to 85% O2. We also evaluated the effect of hyperoxia on vascular transit time distribution and measured NQO1 activity and protein in lung homogenate. The results demonstrate that exposure to 85% O2 for 21 days increases lung capacity to reduce DQ to DQH2 and that NQO1 is the dominant DQ reductase in normoxic and hyperoxic lungs. Kinetic analysis revealed that 21-day hyperoxia exposure increased the maximum rate of pulmonary DQ reduction, Vmax, and the apparent Michaelis-Menten constant for DQ reduction, Kma. The increase in Vmax suggests a hyperoxia-induced increase in NQO1 activity of lung cells accessible to DQ from the vascular region, consistent qualitatively but not quantitatively with an increase in lung homogenate NQO1 activity in 21-day hyperoxic lungs. The increase in Kma could be accounted for by approximately 40% increase in vascular transit time heterogeneity in 21-day hyperoxic lungs.

  11. Four-dimensional magnetic resonance imaging for the determination of tumour movement and its evaluation using a dynamic porcine lung phantom.

    PubMed

    Remmert, G; Biederer, J; Lohberger, F; Fabel, M; Hartmann, G H

    2007-09-21

    A method of four-dimensional (4D) magnetic resonance imaging (MRI) has been implemented and evaluated. It consists of retrospective sorting and slice stacking of two-dimensional (2D) images using an external signal for motion monitoring of the object to be imaged. The presented method aims to determine the tumour trajectories based on a signal that is appropriate for monitoring the movement of the target volume during radiotherapy such that the radiation delivery can be adapted to the movement. For evaluation of the 4D-MRI method, it has been applied to a dynamic lung phantom, which exhibits periodic respiratory movement of a porcine heart-lung explant with artificial pulmonary nodules. Anatomic changes of the lung phantom caused by respiratory motion have been quantified, revealing hysteresis. The results demonstrate the feasibility of the presented method of 4D-MRI. In particular, it enables the determination of trajectories of periodically moving objects with an uncertainty in the order of 1 mm.

  12. NOTE: Four-dimensional magnetic resonance imaging for the determination of tumour movement and its evaluation using a dynamic porcine lung phantom

    NASA Astrophysics Data System (ADS)

    Remmert, G.; Biederer, J.; Lohberger, F.; Fabel, M.; Hartmann, G. H.

    2007-09-01

    A method of four-dimensional (4D) magnetic resonance imaging (MRI) has been implemented and evaluated. It consists of retrospective sorting and slice stacking of two-dimensional (2D) images using an external signal for motion monitoring of the object to be imaged. The presented method aims to determine the tumour trajectories based on a signal that is appropriate for monitoring the movement of the target volume during radiotherapy such that the radiation delivery can be adapted to the movement. For evaluation of the 4D-MRI method, it has been applied to a dynamic lung phantom, which exhibits periodic respiratory movement of a porcine heart-lung explant with artificial pulmonary nodules. Anatomic changes of the lung phantom caused by respiratory motion have been quantified, revealing hysteresis. The results demonstrate the feasibility of the presented method of 4D-MRI. In particular, it enables the determination of trajectories of periodically moving objects with an uncertainty in the order of 1 mm.

  13. Inhaled nitric oxide exacerbated phorbol-induced acute lung injury in rats.

    PubMed

    Lin, Hen I; Chu, Shi Jye; Hsu, Kang; Wang, David

    2004-01-01

    In this study, we determined the effect of inhaled nitric oxide (NO) on the acute lung injury induced by phorbol myristate acetate (PMA) in isolated rat lung. Typical acute lung injury was induced successfully by PMA during 60 min of observation. PMA (2 microg/kg) elicited a significant increase in microvascular permeability, (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/body weight ratio, pulmonary arterial pressure (PAP) and protein concentration of the bronchoalveolar lavage fluid. Pretreatment with inhaled NO (30 ppm) significantly exacerbated acute lung injury. All of the parameters reflective of lung injury increased significantly except PAP (P<0.05). Coadministration of Nomega-nitro-L-arginine methyl ester (L-NAME) (5 mM) attenuated the detrimental effect of inhaled NO in PMA-induced lung injury, except for PAP. In addition, L-NAME (5 mM) significantly attenuated PMA-induced acute lung injury except for PAP. These experimental data suggest that inhaled NO significantly exacerbated acute lung injury induced by PMA in rats. L-NAME attenuated the detrimental effect of inhaled NO.

  14. Fluorescence spectroscopy and cryoimaging of rat lung tissue mitochondrial redox state

    NASA Astrophysics Data System (ADS)

    Sepehr, R.; Audi, S.; Staniszewski, K.; Maleki, S.; Ranji, M.

    2011-07-01

    The objective of this study was to demonstrate the utility of optical cryoimaging and fluorometry to evaluate tissue redox state of the mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavin Adenine Dinucleotide) in intact rat lungs. The ratio (NADH/FAD), referred to as mitochondrial redox ratio (RR), is a measure of the lung tissue mitochondrial redox state. Isolated rat lungs were connected to a ventilation-perfused system. Surface NADH and FAD fluorescence signals were acquired before and after lung perfusion in the absence (control perfusate) or presence of potassium cyanide (KCN, complex IV inhibitor) to reduce the mitochondrial respiratory chain (state 5 respiration). Another group of lungs were perfused with control perfusate or KCN-containing perfusate as above, after which the lungs were deflated and frozen rapidly for subsequent 3D cryoimaging. Results demonstrate that lung treatment with KCN increased lung surface NADH signal by 22%, decreased FAD signal by 8%, and as result increased RR by 31% as compared to control perfusate (baseline) values. Cryoimaging results also show that KCN increased mean lung tissue NADH signal by 37%, decreased mean FAD signal by 4%, and increased mean RR by 47%. These results demonstrate the utility of these optical techniques to evaluate the effect of pulmonary oxidative stress on tissue mitochondrial redox state in intact lungs.

  15. Content of bioelements in the lungs and liver in rats with alimentary obesity.

    PubMed

    Trunova, V A; Sidorina, A V; Zvereva, V V; Churin, B V; Starkova, E V; Sorokoletov, D S

    2016-01-01

    The synchrotron radiation X-ray fluorescence technique (SRXRF) was applied to the determination of K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, and Sr concentrations in the liver and lungs in Wistar rats. The animals in the experiment included (1) healthy rats, (2) rats with alimentary obesity (AO), and (3) rats with alimentary obesity that were being given zinc sulphate with water for a long time (АО+Zn). Each group was divided into two subgroups. The experiment with the first subgroup was terminated with the animals in the state of physiological hunger and subsequent retrieval of liver and lung tissue, while the animals of the second subgroup were sacrificed two hours after ingestion of lard. The rats in physiological hunger manifested intergroup differences in the content of the bioelements (BEs) neither in the liver nor in the lungs. The rats with AO, as compared with the healthy animals, demonstrated in physiological hunger redistribution of inter-element correlations (IECs), which is an indirect reflection of sustained metabolic disorder. Additional zinc in the rats' ration did not affect their body weight and the concentration of the BEs (including zinc) in the liver and the lungs. However, the IECs in the tissues of these animals in physiological hunger also changed. This redistribution differed from that in the rats with AO. The IECs soon after ingestion of lard also changed, which also reflects sustained changes in the metabolism in the animals.

  16. Genome‑wide analysis of DNA methylation in rat lungs with lipopolysaccharide‑induced acute lung injury.

    PubMed

    Zhang, Xiao-Qiang; Lv, Chang-Jun; Liu, Xiang-Yong; Hao, Dong; Qin, Jing; Tian, Huan-Huan; Li, Yan; Wang, Xiao-Zhi

    2013-05-01

    Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are associated with high morbidity and mortality in patients, however, the precise pathogenesis of ALI/ARDS remains unknown. Lipopolysaccharide (LPS) exhibits a number of critical functions and may be associated with the DNA methylation of genes in the lungs. In the present study a genome‑wide analysis of DNA methylation was performed in rat lungs with LPS‑induced ALI/ARDS. Normal and LPS‑induced lung tissues with ALI were analyzed using methylated DNA immunoprecipitation and a rat DNA methylation promoter plus CpG island microarray and the candidate genes were validated by quantitative reverse transcriptase polymerase chain reaction (qRT‑PCR). Aberrant DNA methylation of the promoter regions of 1,721 genes and the CpG islands of 990 genes was identified when normal lung tissues and lung tissues with LPS‑induced ALI/ARDS were compared. These genes were commonly located on chromosomes 1, 3, 5, 7 and 10 (P<0.01). Methylation level and CpG density were compared and it was found that genes associated with high CpG density promoters had a high ratio of methylation. Furthermore, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In addition, three genes (Mapk3, Pak1 and Rac2) were validated in the control and lung tissues with ALI by RT‑PCR. The results indicate that aberrant DNA methylation of lung tissues may be involved in the pathophysiology of LPS‑induced ALI/ARDS. Future studies are required to evaluate the therapeutic and prognostic value of the current novel observations in ALI/ARDS.

  17. Effects of olmesartan therapy on the expression of lung adrenoceptors in rats with chronic heart failure.

    PubMed

    Li, Y F; Jiang, Z L; Cao, F F; Liu, F

    2015-03-01

    Adrenergic receptors (AR) play important roles in regulating lung function. However, there are few reports concerning AR expression and the protective effect of angiotensin II receptor blockers (ARB) on the lung in chronic heart failure (CHF). In this study, we aimed to investigate the protective effects of the ARB olmesartan on the lung in CHF. Wistar rats were randomly divided into four groups: normal control, sham-operated rats, rats with CHF induced by ligating the left anterior descending coronary arteries, and rats with CHF treated with olmesartan (1 mg/kg) once daily for 8 weeks. Heart function, plasma renin activity (PRA) and angiotensin II (Ang II) levels, lung microscopic structure inspection and mRNA and protein expressions of α1A-, β1- and β2-AR in lung were tested. Compared with the CHF group, PRA and Ang II levels were decreased while heart function and mRNA and protein expression of α1A-AR, β1-AR and β2-AR were up-regulated in the olmesartan group (p<0.05 or p<0.01). The inflammation and cell proliferation in CHF lung tissue were reduced in the olmesartan group. Olmesartan may play a beneficial role in protecting lung in CHF by up-regulating AR and decreasing levels of PRA and Ang II. © The Author(s) 2014.

  18. Effects of dietary linseed, evening primrose or fish oils on fatty acid and prostaglandin E2 contents in the rat livers and 7,12-dimethylbenz[a]anthracene-induced tumours.

    PubMed

    Jelińska, Małgorzata; Tokarz, Andrzej; Oledzka, Regina; Czorniuk-Sliwa, Alicja

    2003-04-17

    We examined the influence of diets supplemented with fish and vegetable oils on fatty acid and prostaglandin E2 (PGE2) contents in livers of non-7,12-dimethylbenz[a]anthracene (DMBA)- and DMBA-treated rats, and in DMBA-induced tumours. Decreased concentrations of saturated fatty acids and increased unsaturated fatty acid levels were observed in liver phospholipids of rats fed these oils. There was a marked difference in the concentrations of fatty acids found in the tumours and those present in liver lipids. Oleic acid was the main unsaturated fatty acid found in the tumour tissue. Both liver and tumour PGE2 contents were clearly correlated to the diet. The PGE2 concentrations were decreased in livers and tumours of rats fed fish (FO) and linseed oils (LO).

  19. Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line

    SciTech Connect

    Li Hui; Berlo, Damien van; Shi Tingming; Speit, Guenter; Knaapen, Ad M.; Borm, Paul J.A.; Albrecht, Catrin; Schins, Roel P.F.

    2008-02-15

    Chronic inhalation of high concentrations of respirable quartz particles has been implicated in various lung diseases including lung fibrosis and cancer. Generation of reactive oxygen species (ROS) and oxidative stress is considered a major mechanism of quartz toxicity. Curcumin, a yellow pigment from Curcuma longa, has been considered as nutraceutical because of its strong anti-inflammatory, antitumour and antioxidant properties. The aim of our present study was to investigate whether curcumin can protect lung epithelial cells from the cytotoxic, genotoxic and inflammatory effects associated with quartz (DQ12) exposure. Electron paramagnetic resonance (EPR) measurements using the spin-trap DMPO demonstrated that curcumin reduces hydrogen peroxide-dependent hydroxyl-radical formation by quartz. Curcumin was also found to reduce quartz-induced cytotoxicity and cyclooxygenase 2 (COX-2) mRNA expression in RLE-6TN rat lung epithelial cells (RLE). Curcumin also inhibited the release of macrophage inflammatory protein-2 (MIP-2) from RLE cells as observed upon treatment with interleukin-1 beta (IL-1{beta}) and tumour necrosis factor-alpha (TNF{alpha}). However, curcumin failed to protect the RLE cells from oxidative DNA damage induced by quartz, as shown by formamidopyrimidine glycosylase (FPG)-modified comet assay and by immunocytochemistry for 8-hydroxydeoxyguanosine. In contrast, curcumin was found to be a strong inducer of oxidative DNA damage itself at non-cytotoxic and anti-inflammatory concentrations. In line with this, curcumin also enhanced the mRNA expression of the oxidative stress response gene heme oxygenase-1 (ho-1). Curcumin also caused oxidative DNA damage in NR8383 rat alveolar macrophages and A549 human lung epithelial cells. Taken together, these observations indicate that one should be cautious in considering the potential use of curcumin in the prevention or treatment of lung diseases associated with quartz exposure.

  20. Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line.

    PubMed

    Li, Hui; van Berlo, Damien; Shi, Tingming; Speit, Günter; Knaapen, Ad M; Borm, Paul J A; Albrecht, Catrin; Schins, Roel P F

    2008-02-15

    Chronic inhalation of high concentrations of respirable quartz particles has been implicated in various lung diseases including lung fibrosis and cancer. Generation of reactive oxygen species (ROS) and oxidative stress is considered a major mechanism of quartz toxicity. Curcumin, a yellow pigment from Curcuma longa, has been considered as nutraceutical because of its strong anti-inflammatory, antitumour and antioxidant properties. The aim of our present study was to investigate whether curcumin can protect lung epithelial cells from the cytotoxic, genotoxic and inflammatory effects associated with quartz (DQ12) exposure. Electron paramagnetic resonance (EPR) measurements using the spin-trap DMPO demonstrated that curcumin reduces hydrogen peroxide-dependent hydroxyl-radical formation by quartz. Curcumin was also found to reduce quartz-induced cytotoxicity and cyclooxygenase 2 (COX-2) mRNA expression in RLE-6TN rat lung epithelial cells (RLE). Curcumin also inhibited the release of macrophage inflammatory protein-2 (MIP-2) from RLE cells as observed upon treatment with interleukin-1 beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha). However, curcumin failed to protect the RLE cells from oxidative DNA damage induced by quartz, as shown by formamidopyrimidine glycosylase (FPG)-modified comet assay and by immunocytochemistry for 8-hydroxydeoxyguanosine. In contrast, curcumin was found to be a strong inducer of oxidative DNA damage itself at non-cytotoxic and anti-inflammatory concentrations. In line with this, curcumin also enhanced the mRNA expression of the oxidative stress response gene heme oxygenase-1 (ho-1). Curcumin also caused oxidative DNA damage in NR8383 rat alveolar macrophages and A549 human lung epithelial cells. Taken together, these observations indicate that one should be cautious in considering the potential use of curcumin in the prevention or treatment of lung diseases associated with quartz exposure.

  1. Purification and characterization of carboxylesterases from rat lung.

    PubMed Central

    Gaustad, R; Sletten, K; Løvhaug, D; Fonnum, F

    1991-01-01

    Carboxylesterase (EC 3.1.1.1) has played an important part in our understanding of the toxicokinetic behaviour of the organophosphorus cholinesterase inhibitors. Carboxylesterases are a heterogeneous group of enzymes that can be separated on the basis of their isoelectric points and by their substrate-specificity. We have purified the isoenzyme (pI 5.8) present in greatest activity in rat lung to near homogeneity. The enzyme was purified by (NH4)2SO4 precipitation, gel filtration, chromatofocusing, separation on anion- and cation-exchangers and hydrophobic-interaction chromatography. The purified enzyme has a molecular mass of approx. 180 kDa with subunits of 60 kDa. The substrate and inhibitor specificities of the enzyme have been characterized. Edman degradation revealed the first 19 amino acid residues of the enzyme. The N-terminus was found to be tyrosine. Inhibition of the enzyme by organophosphorus compounds differed greatly from that of cholinesterases, despite the partial analogy at the N-terminal region. Images Fig. 2. PMID:2012599

  2. Radiation injury in rat lung. IV. Modification by d-penicillamine

    SciTech Connect

    Ward, W.F.; Molteni, A.; Ts'ao, C.; Solliday, N.H.

    1984-05-01

    To determine whether d-penicillamine, known to reduce fibrosis in irradiated rat lung, also ameliorates radiation injury in the pulmonary endothelium, the authors measured angiotensin-converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI/sub 2/) production in the lungs of penicillamine-treated and untreated rats from 2 weeks to 6 months after a single dose of 25 Gy of /sup 60/Co ..gamma.. rays to the right hemithorax. Both ACE and PLA activity in the irradiated right lung of untreated rats decreased dramatically between the 1st and 2nd months after exposure, then reached a plateau through 6 months at approximately 25 and 50% of the normal level, respectively. For the first 2 months after irradiation, penicillamine-treated animals exhibited significantly higher activites of both ACE and PLA than did untreated rats. From 3 to 6 months after irradiation, however, the only significant drug effect on these enzymes was a 25% increase in PLA activity at 6 months. PGI/sub 2/ production by the irradiated lung of untreated rats increased continuously, and at 6 months was approximately 10 times higher than normal. Penicillamine significantly reduced this hypersecretion, and at 6 months after irradiation, PGI/sub 2/ production by the lungs of drug-treated rats was only half that of untreated animals. Thus the antifibrotic agent d-penicillamine delays the onset of radiation-induced enzyme dysfunction in the pulmonary endothelium.

  3. Prognostic value of fluorine-18 fludeoxyglucose positron emission tomography parameters differs according to primary tumour location in small-cell lung cancer

    PubMed Central

    Nobashi, Tomomi; Koyasu, Sho; Kubo, Takeshi; Ishimori, Takayoshi; Kim, Young H; Yoshizawa, Akihiko; Togashi, Kaori

    2016-01-01

    Objective: To investigate the prognostic value of fluorine-18 fludeoxyglucose (FDG) positron emission tomography (PET) parameters for small-cell lung cancer (SCLC), according to the primary tumour location, adjusted by conventional prognostic factors. Methods: From 2008 to 2013, we enrolled consecutive patients with histologically proven SCLC, who had undergone FDG-PET/CT prior to initial therapy. The primary tumour location was categorized into central or peripheral types. PET parameters and clinical variables were evaluated using univariate and multivariate analysis. Results: A total of 69 patients were enrolled in this study; 28 of these patients were categorized as having the central type and 41 patients as having the peripheral type. In univariate analysis, stage, serum neuron-specific enolase, whole-body metabolic tumour volume (WB-MTV) and whole-body total lesion glycolysis (WB-TLG) were found to be significant in both types of patients. In multivariate analysis, the independent prognostic factor was found to be stage in the central type, but WB-MTV and WB-TLG in the peripheral type. Kaplan–Meier analysis demonstrated that patients with peripheral type with limited disease and low WB-MTV or WB-TLG showed significantly better overall survival than all of the other groups (p < 0.0083). Conclusion: The FDG-PET volumetric parameters were demonstrated to be significant and independent prognostic factors in patients with peripheral type of SCLC, while stage was the only independent prognostic factor in patients with central type of SCLC. Advances in knowledge: FDG-PET is a non-invasive method that could potentially be used to estimate the prognosis of patients, especially those with peripheral-type SCLC. PMID:26756811

  4. Chemotherapy of non-small cell lung carcinoma guided by an in vitro drug resistance assay measuring total tumour cell kill.

    PubMed Central

    Wilbur, D. W.; Camacho, E. S.; Hilliard, D. A.; Dill, P. L.; Weisenthal, L. M.

    1992-01-01

    Specimens from 45 patients with previously-untreated non-small cell lung cancer (NSCLC) were tested for in vitro chemosensitivity to ten drugs utilising the DiSC assay, which measures cell kill in the total (largely non-dividing) tumour cell population. Thirty-five assays were successful and 25 patients with advanced disease subsequently received chemotherapy with the 'best' three drugs selected by the assay. Six patients were Karnofsky performance status 60 or less and the median pretreatment weight loss was 8.5%. Nine patients had a partial response (response rate = 36%; 95% confidence interval = 17-55%) and the median survival of all patients was 202 days. Specimens from responding patients were significantly more sensitive in the assay to drugs in general (especially to etoposide and to 'natural product' drugs) and to the drugs used in treatment than were specimens from non-responding patients. In vitro drug resistance differences between responding and non-responding patients were of greater significance than were differences between other clinical and laboratory measurements. Assay results classified patients into two cohorts, having relatively high and low probabilities of responding to chemotherapy. Assay results also identified patient cohorts with above average and below average durations of survival. Five patients (20%) were found to have tumours with extreme drug resistance (EDR), defined as assay results for the average of all ten tested drugs falling greater than one standard deviation more resistant than the median for all tumours assayed, and none of these patients with EDR responded to chemotherapy. PMID:1310250

  5. High tumour contamination of leukaphereses in patients with small cell carcinoma of the lung: a comparison of immunocytochemistry and RT-PCR.

    PubMed

    Perey, L; Benhattar, J; Peters, R; Jaunin, P; Leyvraz, S

    2001-11-30

    In small-cell lung carcinoma (SCLC) tumour cell contamination of leukaphereses is unknown. The present study was performed to define appropriate markers for reverse transcriptase polymerase chain reaction (RT-PCR), then to assess the contamination rate of leukaphereses and corresponding bone marrow samples. Immunocytochemistry (ICC) and RT-PCR methods were also compared. Among the 33 patients included, analyses were performed in 16 who had multiple leukaphereses and 17 who had only bone marrow. Leukapheresis products and bone marrow were analysed by ICC using several specific monoclonal antibodies against neural-cell adhesion molecule (N-CAM), epithelial glycoprotein (EGP-40) and cytokeratins (CK). Samples were also analyzed by RT-PCR for expression for N-CAM, synaptophysin, neuron-specific enolase, chromogranin, cytokeratin-18/-19, CEA, EGP-40, apomucin type 1 (MUC-1) and human endothelial cell-specific molecule (ESM-1). Using ICC staining, contaminating tumour cells were detected in 34% of leukaphereses (27% in patients with limited disease and 43% in those with extensive disease). N-CAM was the most reliable marker for detection of contamination. For RT-PCR, CK-19 and CEA were the only appropriate markers. Positive signal rate in leukaphereses increased to 78% (89% for patients with limited disease and 67% for extensive disease). In bone marrow, both techniques were in agreement whereas in leukaphereses, RT-PCR was better than ICC. A high rate of tumour cell contamination was demonstrated not only in bone marrow but also in leukaphereses from SCLC patients. The most appropriate technique was RT-PCR mainly in patients with limited disease. (c) 2001 Cancer Research Campaign

  6. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis.

    PubMed

    Saddoughi, Sahar A; Gencer, Salih; Peterson, Yuri K; Ward, Katherine E; Mukhopadhyay, Archana; Oaks, Joshua; Bielawski, Jacek; Szulc, Zdzislaw M; Thomas, Raquela J; Selvam, Shanmugam P; Senkal, Can E; Garrett-Mayer, Elizabeth; De Palma, Ryan M; Fedarovich, Dzmitry; Liu, Angen; Habib, Amyn A; Stahelin, Robert V; Perrotti, Danilo; Ogretmen, Besim

    2013-01-01

    Mechanisms that alter protein phosphatase 2A (PP2A)-dependent lung tumour suppression via the I2PP2A/SET oncoprotein are unknown. We show here that the tumour suppressor ceramide binds I2PP2A/SET selectively in the nucleus and including its K209 and Y122 residues as determined by molecular modelling/simulations and site-directed mutagenesis. Because I2PP2A/SET was found overexpressed, whereas ceramide was downregulated in lung tumours, a sphingolipid analogue drug, FTY720, was identified to mimick ceramide for binding and targeting I2PP2A/SET, leading to PP2A reactivation, lung cancer cell death, and tumour suppression in vivo. Accordingly, while molecular targeting of I2PP2A/SET by stable knockdown prevented further tumour suppression by FTY720, reconstitution of WT-I2PP2A/SET expression restored this process. Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis. The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720. Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1(-/-) MEFs. Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1. Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  7. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis

    PubMed Central

    Saddoughi, Sahar A; Gencer, Salih; Peterson, Yuri K; Ward, Katherine E; Mukhopadhyay, Archana; Oaks, Joshua; Bielawski, Jacek; Szulc, Zdzislaw M; Thomas, Raquela J; Selvam, Shanmugam P; Senkal, Can E; Garrett-Mayer, Elizabeth; De Palma, Ryan M; Fedarovich, Dzmitry; Liu, Angen; Habib, Amyn A; Stahelin, Robert V; Perrotti, Danilo; Ogretmen, Besim

    2013-01-01

    Mechanisms that alter protein phosphatase 2A (PP2A)-dependent lung tumour suppression via the I2PP2A/SET oncoprotein are unknown. We show here that the tumour suppressor ceramide binds I2PP2A/SET selectively in the nucleus and including its K209 and Y122 residues as determined by molecular modelling/simulations and site-directed mutagenesis. Because I2PP2A/SET was found overexpressed, whereas ceramide was downregulated in lung tumours, a sphingolipid analogue drug, FTY720, was identified to mimick ceramide for binding and targeting I2PP2A/SET, leading to PP2A reactivation, lung cancer cell death, and tumour suppression in vivo. Accordingly, while molecular targeting of I2PP2A/SET by stable knockdown prevented further tumour suppression by FTY720, reconstitution of WT-I2PP2A/SET expression restored this process. Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis. The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720. Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1−/− MEFs. Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1. PMID:23180565

  8. Exogenous surfactant restores lung function but not peripheral immunosuppression in ventilated surfactant-deficient rats.

    PubMed

    Vreugdenhil, Harriet A; Lachmann, Burkhard; Haitsma, Jack J; Zijlstra, Jitske; Heijnen, Cobi J; Jansen, Nicolaas J; van Vught, Adrianus J

    2006-01-01

    The authors have previously shown that mechanical ventilation can result in increased pulmonary inflammation and suppressed peripheral leukocyte function. In the present study the effect of surfactant therapy on pulmonary inflammation and peripheral immune function in ventilated surfactant-deficient rats was assessed. Surfactant deficiency was induced by repeated lung lavage, treated rats with surfactant or left them untreated, and ventilated the rats during 2 hours. Nonventilated rats served as healthy control group. Expression of macrophage inflammatory protein (MIP)-2 was measured in bronchoalveolar lavage (BAL), interleukin (IL)-1beta, and heat shock protein 70 (HSP70) were measured in total lung homogenates. Outside the lung phytohemagglutinin (PHA)-induced lymphocyte proliferation, interferon (IFN)-gamma and IL-10 production, and natural killer activity were measured in splenocytes. After 2 hours of mechanical ventilation, expression of MIP-2, IL-1beta, and HSP70 increased significantly in the lungs of surfactant-deficient rats. Outside the lung, mitogen-induced proliferation and production of IFN-gamma and IL-10 reduced significantly. Only natural killer cell activity remained unaffected. Surfactant treatment significantly improved lung function, but could not prevent increased pulmonary expression of MIP-2, IL-1beta, and HSP70 and decreased peripheral mitogen-induced lymphocyte proliferation and IFN-gamma and IL-10 production in vitro. In conclusion, 2 hours of mechanical ventilation resulted in increased lung inflammation and partial peripheral leukocyte suppression in surfactant-deficient rats. Surfactant therapy ameliorated lung function but could not prevent or restore peripheral immunosuppression. The authors postulate that peripheral immunosuppression may occur in ventilated surfactant deficient patients, which may enhance susceptibility for infections.

  9. Loss of lysophosphatidic acid receptor-3 enhances cell migration in rat lung tumor cells

    SciTech Connect

    Hayashi, Mai; Okabe, Kyoko; Yamawaki, Yasuna; Teranishi, Miki; Honoki, Kanya; Mori, Toshio; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2011-02-18

    Research highlights: {yields} Loss of the Lpar3 expression due to aberrant DNA methylation occurred in rat lung tumor cells. {yields} The Lpar3 inhibited cell migration of rat lung tumor cells. {yields} The Lpar3 may act as a negative regulator of rat lung tumor cells. -- Abstract: Lysophosphatidic acid (LPA) indicates several biological effects, such as cell proliferation, differentiation and migration. LPA interacts with G protein-coupled transmembrane LPA receptors. In our previous report, we detected that loss of the LPA receptor-1 (Lpar1) expression is due to its aberrant DNA methylation in rat tumor cell lines. In this study, to assess an involvement of the other LPA receptor, Lpar3, in the pathogenesis of rat lung tumor cells, we measured the expression levels of the Lpar3 gene and its DNA methylation status by reverse transcription (RT)-polymerase chain reaction (PCR) and bisulfite sequencing analyses, respectively. RLCNR lung adenocarcinoma cells showed reduced expression of the Lpar3, compared with normal lung tissues. In the 5' upstream region of the Lpar3, normal lung tissues were unmethylated. By contrast, RLCNR cells were highly methylated, correlating with reduced expressions of the Lpar3. Based on these results, we generated the Lpar3-expressing RLCNR-a3 cells and measured the cell migration ability. Interestingly, the cell migration of RLCNR-a3 cells was significantly lower than that of RLCNR cells. This study suggests that loss of the Lpar3 due to aberrant DNA methylation may be involved in the progression of rat lung tumor cells.

  10. Expression of urocortin in rat lung and its effect on pulmonary vascular permeability.

    PubMed

    Wu, Yuqing; Xu, Yinyan; Zhou, Hong; Tao, Jin; Li, Shengnan

    2006-04-01

    Urocortin (UCN), a newly identified, 40-amino-acid, corticotropin-releasing hormone (CRH) structurally related peptide, has been demonstrated to be expressed in the central nervous system and many peripheral tissues of rats and man. This study aimed to investigate the expression profile of UCN in rat lung and the effect of UCN on lung vascular permeability. The expression of UCN mRNA was detected by reverse transcriptase PCR (RT-PCR). UCN peptide was measured by immunohistochemistry and Western blot analysis. We found that both UCN mRNA and peptide were obviously expressed in rat lung. Immunohistochemistry results showed that UCN peptide is mainly expressed in bronchial epithelium mucosa and alveolar epithelium. We also found that rats receiving inhalation aerosol of UCN had a significant elevation of lung vascular permeability compared with rats receiving vehicle and ovalbumin (OVA) by the Evans blue (EB) technique. UCN aerosol inhalation resulted in obvious pulmonary congestion and edema observed under light microscope by hematoxylin and eosin (HE) staining. The nonselective peptide CRH receptor antagonist astressin markedly reduced lung vascular permeability triggered by UCN. Enhanced pulmonary vascular permeability induced by UCN was markedly inhibited by pretreatment with the mast-cell stabilizer cromolyn and histamine-1 (H1) receptor antagonist azelastine respectively, but not by the leukotriene receptor antagonist montelukast. In summary, in the present study, we demonstrated for the first time that UCN is expressed in rat lung and contributes to an increase in lung vascular permeability through activation of CRH receptors. Mast cells and histamine may be involved in this effect of UCN. Peripherally produced UCN in lung may act as an autocrine and paracrine proinflammatory factor.

  11. Lung hypoplasia and surfactant system immaturity induced in the fetal rat by prenatal exposure to nitrofen.

    PubMed

    Alfanso, L F; Arnaiz, A; Alvarez, F J; Qi, B; Diez-Pardo, J A; Vallis-i-Soler, A; Tovar, J A

    1996-01-01

    We studied the biochemical maturity of the lungs of fetuses born to rats exposed to nitrofen on day 9.5 of gestation. In comparison with controls, nitrofen-treated fetuses had pulmonary hypoplasia (decreased lung/body weight), lung hypocellularity (low DNA content) and cellular atrophy (low protein/DNA and phospholipid/DNA) on gestational days 19 and 21. Treated animals with congenital diaphragmatic hernia (CDH) also had cell atrophy and surfactant immaturity (decreased disaturated phosphatidylcholine/DNA) near term. Our data demonstrate that nitrofen causes lung hypoplasia and some degree of surfactant system immaturity that is particularly prominent in fetuses with CDH.

  12. The effect of adriamycin and 4'-deoxydoxorubicin on cell survival of human lung tumour cells grown in monolayer and as spheroids.

    PubMed

    Kerr, D J; Wheldon, T E; Kerr, A M; Freshney, R I; Kaye, S B

    1986-09-01

    Using growth delay and clonogenic cell survival as end points, we have shown that the 3-dimensional structure of human lung tumour spheroids confers a degree of resistance to the anthracyclines adriamycin and 4'-deoxydoxorubicin, relative to cells grown as monolayer. 4'-deoxydoxorubicin induces a longer growth delay and greater clonogenic cell kill than adriamycin in spheroids, although it is no more cytotoxic in monolayer (exponential and plateau phase). There is a log linear relationship between clonogenic cell survival and duration of adriamycin exposure in monolayers, and biphasic curve with a lesser degree of cell kill for disaggregated spheroid cells. Using fluorescent microscopy we have demonstrated, qualitatively, that the more lipophilic analogue partitions into the spheroid more rapidly and to a greater degree than adriamycin. It is possible that adriamycin penetration is a relatively important aspect of spheroid drug resistance, which may be related to intraspheroidal pH gradients, and that we have partially overcome this by using a lipophilic analogue.

  13. The Effects of Dexamethasone and L-NAME on Acute Lung Injury in Rats with Lung Contusion.

    PubMed

    Kozan, Ahmet; Kilic, Nermin; Alacam, Hasan; Guzel, Ahmet; Guvenc, Tolga; Acikgoz, Mehmet

    2016-10-01

    The therapeutic efficiency of an anti-inflammatory agent, dexamethasone (DXM), and a nitric oxide synthase (NOS) inhibitor, Nitro-L-arginine methyl ester (L-NAME), in lung tissue injury after lung contusion was investigated. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), YKL-40, an inflammatory peptide, inducible NOS (iNOS), and Clara cell protein 16 (CC-16) were evaluated. Immunohistochemical analyses were also performed, and the lung tissue was examined histopathologically. The study consisted of eight groups of Sprague-Dawley rats (n = 10 in each group), weighing 250-300 g: (1) control, (2) contusion, (3) control + DXM, (4) contusion + DXM, (5) control + L-NAME (6) contusion + L-NAME, (7) control + DXM + L-NAME, and (8) contusion + DXM + L-NAME. A previously developed lung contusion model was used, in addition to the control group. The rats were administered DXM and L-NAME intraperitoneally (i.p.) at doses of 15 and 60 mg/kg/day, respectively. DXM and L-NAME administration decreased the iNOS level in the contusion groups. DXM increased the levels of YKL-40 and IL-10 in both the control and contusion groups, with higher levels in the contusion groups. L-NAME increased the serum level of IL-10 in the lung contusion groups. DXM increased the synthesis of CC-16 in the control and contusion groups. The combined use of a high-dose steroid and NOS inhibitor resulted in the death of the rats. Steroids can increase the level of cytokines, such as YKL-40 and IL-10, and the synthesis of CC-16 and prevent pneumonia, ALI/ARDS, and sepsis in lung contusion.

  14. Effect of chronic excess of tumour necrosis factor-alpha on contractile proteins in rat skeletal muscle.

    PubMed

    Cheema, I R; Hermann, C; Postell, S; Barnes, P

    2000-01-01

    The effect of chronic tumour necrosis factor-alpha (TNF-alpha) treatment on the synthesis of specific myofibrillar proteins such as heavy chain myosin, light chain myosin and G-actin in rat diaphragm were evaluated. Muscles (diaphragm) from control and experimental groups (TNF-alpha i.v. at 50 microg/kg body wt for 5 days) were incubated in the presence of 35S-methionine for 2 h. Myofibrillar protein extracts were prepared and protein was electrophoresed on sodium dodecyl sulphate-polyacrylamide gels. Heavy chain myosin, light chain myosin and G-actin were identified by Western blot analysis using specific monoclonal antibodies. Polyacrylamide gel electrophoresis (PAGE) followed by Western blot analysis revealed two types of heavy chain myosin (206 and 212 kD), all four types of light chain myosin (15, 16.5, 18 and 20 kD) and a single type of G-actin (42 kD). Chronic TNF-alpha treatment produced a significant decline in the synthesis of all types of myofibrillar proteins, namely heavy chain myosin, light chain myosin and G-actin. TNF-alpha impaired peptide-chain initiation in diaphragm muscle which was reversed by the branched-chain amino acids (BCAA) therapy of TNF-alpha treated rats. These findings indicate a significant role for TNF-alpha in the translational regulation of protein synthesis in skeletal muscle.

  15. Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model

    PubMed Central

    Huang, Kun-Lun; Lan, Chou-Chin; Hsu, Yu-Juei; Wu, Geng-Chin; Peng, Chia-Hui

    2017-01-01

    Lung ischemia reperfusion injury (LIRI) is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD) on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75%) diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR)-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS), proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB) activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF). The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway. PMID:28291795

  16. Induction of Lipocalin2 in a Rat Model of Lung Irradiation

    PubMed Central

    Sultan, Sadaf; Ahmad, Shakil; Rave-Fränk, Margret; Malik, Ihtzaz Ahmed; Hess, Clemens F.; Christiansen, Hans; Cameron, Silke

    2016-01-01

    Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1β and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement. PMID:27136530

  17. In vivo tomographic imaging of lung colonization of tumour in mouse with simultaneous fluorescence and X-ray CT.

    PubMed

    Zhang, Bin; Gao, Fuping; Wang, Mengjiao; Cao, Xu; Liu, Fei; Wang, Xin; Luo, Jianwen; Wang, Guangzhi; Bai, Jing

    2014-01-01

    Non-invasive in vivo imaging of diffuse and wide-spread colonization within the lungs, rather than distinct solid primary tumors, is still a challenging work. In this work, a lung colonization mouse model bearing A549 human lung tumor was simultaneously scanned by a dual-modality fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) system in vivo. A two steps method which incorporates CT structural information into the FMT reconstruction procedure is employed to provide concurrent anatomical and functional information. By using the target-specific fluorescence agent, the fluorescence tomographic results show elevated fluorescence intensity deep within the lungs which is colonized with diffuse and wide-spread tumors. The results were confirmed with ex vivo fluorescence reflectance imaging and histological examination of the lung tissues. With FMT reconstruction combined with the CT information, the dual-modality FMT/micro-CT system is expected to offer sensitive and noninvasive imaging of diffuse tumor colonization within the lungs in vivo. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Oncological outcomes in rats given nephrocarcinogenic exposure to dietary ochratoxin a, followed by the tumour promoter sodium barbital for life: a pilot study.

    PubMed

    Mantle, Peter G; Dobrota, Miloslav; Gillett, Cheryl E; Odell, Edward W; Pinder, Sarah E

    2010-04-01

    The potent experimental renal carcinogenesis of ochratoxin A (OTA) in male rats makes the dietary contaminant a potential factor in human oncology. We explored whether the tumour promoter sodium barbitate could shorten the otherwise long latency between exposure to toxin and tumourigenesis. Young rats, of a hybrid in which mononuclear leukaemia was rare, were given feed contaminated (5 ppm) with OTA for 36 weeks to initiate renal tumourigenesis. Some individuals were thereafter given sodium barbitate (500 ppm in drinking water) for life. Pathological outcomes were studied at or near the end of natural life. Renal tumours in males given barbitate became evident after latency of one year, but only slightly before those without barbitate. In contrast, female mammary tumourigenesis was advanced by at least 6 months synchronously in all rats given the OTA-barbitate regimen compared to tumourigenesis in controls. Diagnosis of malignant mammary angiosarcoma in a female given the OTA-barbitate regimen is a new finding in the rat. The long latency of OTA-induced renal tumourigenesis was not notably susceptible to accelerated promotion by barbitate, contrasting with an apparently marked effect of barbitate on development of mammary tumours.

  19. Resistance exercise modulates lipid plasma profile and cytokine content in the adipose tissue of tumour-bearing rats.

    PubMed

    Donatto, F F; Neves, R X; Rosa, F O; Camargo, R G; Ribeiro, H; Matos-Neto, E M; Seelaender, M

    2013-02-01

    Cancer cachexia is a multifactorial syndrome characterised by progressive weight loss, frequently accompanied by anorexia, sarcopenia, and chronic systemic inflammation. The white adipose tissue is markedly affected by cachexia and contributes to this syndrome throught the secretion of pro-inflammatory factors which reach the adjacent tissues and the circulation. A nonpharmacologic intervention that may attenuate cancer cachexia is chronic physical activity, but the effect of resistance training upon adipose tissue inflammation in cachexia has never been examined. For that purpose we designed a protocol in which animals were randomly assigned to a control group (CT, n=7), a Tumour bearing group (TB, n=7), a Resistance Trained group (RT, n=7) and a Resistance Trained tumour bearing group (RTTB, n=7). Trained rats climbed a vertical ladder with an extra load attached to the tail, representing 75-90% of total body mass, 3 times per week, for 8 weeks. In the 6 th week of resistance training, tumour cells (3 × 10(7) Walker 256 carcinosarcoma) were inoculated in the tumour groups. Body, adipose tissue, muscle and tumour mass was determined, as well a blood biochemical parameters, and the hormone and cytokine profile assessed. The glycogen content of the liver and muscle was measured. IL-10, IL-6 and TNF-α protein expression was evaluated in the mesenteric adipose tissue (MEAT) examined. Resistance training increased by 9% body weight gain in RTTB (final weight 310.8 ± 9.8 g), when compared with TB (final weight 288.3 ± 4.9 g). LDL-c levels were decreased in RTTB (0.28 ± 0.9 mmol/L) by 43% when compared with TB (0.57 ± 0.1 mmol/L). HDL-c levels were increased in RTTB (1.31 ± 0.12 mmol/L) by 15% in regard to CT (1.13 ± 0.7 mmol/L) and 22% as compared with TB (1.07 ± 0.07 mmol/L). RTTB testosterone levels (577 ± 131 ng/mL) were 55% higher when compared with CT (254 ± 41.3 ng/mL) and 63% higher when compared with TB (221 ± 23.1 ng/mL). Adiponectin levels were

  20. Radiation injury in rat lung: I. Prostacyclin (PGI/sub 2/) production, arterial perfusion, and ultrastructure

    SciTech Connect

    Ts'ao, C.; Ward, W.F.; Port, C.D.

    1983-11-01

    Pulmonary prostacyclin (PGI/sub 2/) production, arterial perfusion, and ultrastructure were correlated in rats sacrificed from 1 day to 6 months after a single exposure of 25 Gy of gamma rays to the right hemithorax. PGI/sub 2/ production by the irradiated lung decreased to approximately half the normal value 1 day after irradiation (P < 0.05), then increased steadily throughout the study. By 6 months postirradiation, the right lung produced two to three times as much PGI/sub 2/ as did either shielded left lung or sham-irradiated lungs (P < 0.05). Perfusion scans revealed hyperemia of the right lung from 1 to 14 days after irradiation. From its peak at 14 days postirradiation, however, perfusion of the irradiated lung decreased steadily, then reached a plateau from 3 to 6 months at less than half that in the shielded left lung. Electron micrographs of the right lung revealed perivascular edema from 1 to 30 days after irradiation. The right lung then exhibited changes typical of radiation pneumonitis followed by progressive interstitial fibrosis. Platelet aggregates were not observed at any time. Thus, decreased PGI/sub 2/ production is an immediate but transient response of the lung to radiation injury. Then from 2 to 6 months after irradiation, the fibrotic, hypoperfused lung produces increasing amounts of the potent vasodilator and antithrombotic agent, PGI/sub 2/. Pulmonary PGI/sub 2/ production and arterial perfusion are inversely correlated for at least 6 months after hemithoracic irradiation.

  1. Role of glutathione in lung retention of 99mTc-hexamethylpropyleneamine oxime in two unique rat models of hyperoxic lung injury.

    PubMed

    Audi, Said H; Roerig, David L; Haworth, Steven T; Clough, Anne V

    2012-08-15

    Rat exposure to 60% oxygen (O(2)) for 7 days (hyper-60) or to >95% O(2) for 2 days followed by 24 h in room air (hyper-95R) confers susceptibility or tolerance, respectively, of the otherwise lethal effects of subsequent exposure to 100% O(2). The objective of this study was to determine if lung retention of the radiopharmaceutical agent technetium-labeled-hexamethylpropyleneamine oxime (HMPAO) is differentially altered in hyper-60 and hyper-95R rats. Tissue retention of HMPAO is dependent on intracellular content of the antioxidant GSH and mitochondrial function. HMPAO was injected intravenously in anesthetized rats, and planar images were acquired. We investigated the role of GSH in the lung retention of HMPAO by pretreating rats with the GSH-depleting agent diethyl maleate (DEM) prior to imaging. We also measured GSH content and activities of mitochondrial complexes I and IV in lung homogenate. The lung retention of HMPAO increased by ≈ 50% and ≈ 250% in hyper-60 and hyper-95R rats, respectively, compared with retention in rats exposed to room air (normoxic). DEM decreased retention in normoxic (≈ 26%) and hyper-95R (≈ 56%) rats compared with retention in the absence of DEM. GSH content increased by 19% and 40% in hyper-60 and hyper-95R lung homogenate compared with normoxic lung homogenate. Complex I activity decreased by ≈ 50% in hyper-60 and hyper-95R lung homogenate compared with activity in normoxic lung homogenate. However, complex IV activity was increased by 32% in hyper-95R lung homogenate only. Furthermore, we identified correlations between the GSH content in lung homogenate and the DEM-sensitive fraction of HMPAO retention and between the complex IV/complex I activity ratio and the DEM-insensitive fraction of HMPAO retention. These results suggest that an increase in the GSH-dependent component of the lung retention of HMPAO may be a marker of tolerance to sustained exposure to hyperoxia.

  2. Role of glutathione in lung retention of 99mTc-hexamethylpropyleneamine oxime in two unique rat models of hyperoxic lung injury

    PubMed Central

    Roerig, David L.; Haworth, Steven T.; Clough, Anne V.

    2012-01-01

    Rat exposure to 60% oxygen (O2) for 7 days (hyper-60) or to >95% O2 for 2 days followed by 24 h in room air (hyper-95R) confers susceptibility or tolerance, respectively, of the otherwise lethal effects of subsequent exposure to 100% O2. The objective of this study was to determine if lung retention of the radiopharmaceutical agent technetium-labeled-hexamethylpropyleneamine oxime (HMPAO) is differentially altered in hyper-60 and hyper-95R rats. Tissue retention of HMPAO is dependent on intracellular content of the antioxidant GSH and mitochondrial function. HMPAO was injected intravenously in anesthetized rats, and planar images were acquired. We investigated the role of GSH in the lung retention of HMPAO by pretreating rats with the GSH-depleting agent diethyl maleate (DEM) prior to imaging. We also measured GSH content and activities of mitochondrial complexes I and IV in lung homogenate. The lung retention of HMPAO increased by ∼50% and ∼250% in hyper-60 and hyper-95R rats, respectively, compared with retention in rats exposed to room air (normoxic). DEM decreased retention in normoxic (∼26%) and hyper-95R (∼56%) rats compared with retention in the absence of DEM. GSH content increased by 19% and 40% in hyper-60 and hyper-95R lung homogenate compared with normoxic lung homogenate. Complex I activity decreased by ∼50% in hyper-60 and hyper-95R lung homogenate compared with activity in normoxic lung homogenate. However, complex IV activity was increased by 32% in hyper-95R lung homogenate only. Furthermore, we identified correlations between the GSH content in lung homogenate and the DEM-sensitive fraction of HMPAO retention and between the complex IV/complex I activity ratio and the DEM-insensitive fraction of HMPAO retention. These results suggest that an increase in the GSH-dependent component of the lung retention of HMPAO may be a marker of tolerance to sustained exposure to hyperoxia. PMID:22628374

  3. Influence of long-term drinking alcohol on the cytokines in the rats with endogenous and exogenous lung injury.

    PubMed

    Liu, Y D; Liu, W; Liu, Z

    2013-02-01

    Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are syndromes of acute respiratory failure. Exploration of the impacts of long-term drinking alcohol on the cytokines of rats with endogenous and exogenous lung injuries. Through giving the model rats long-term drinking alcohol or water, we acquired the changes of the cytokines in the serum and bronchoalveolar lavage fluid (BALF) of these rats with lung injuries due to different incentives. The partial pressure of oxygen in rats with lung damage after long-term drinking alcohol were significantly lower than those drinking water group (p < 0.05); W/D values of groups drinking alcohol were significantly higher than those drinking water (p < 0.05); The levels of TNF-alpha, IL-6 and IL-10 in the serum and BALF were significantly higher in the group drinking alcohol (p < 0.01). While the cytokine levels in the serum of the rats with exogenous lung injury were higher than those of rats with endogenous lung injury (p < 0.05), the cytokines in the BALF of the rats with endogenous lung injury were higher than those with exogenous lung injury (p < 0.05). Long-term drinking alcohol can aggravate the inflammatory response induced by the exogenous lung injury. The expression of TNF-α, IL-6 and IL-10 are different according to the different ways that lead to the acute lung injury.

  4. 3D cine magnetic resonance imaging of rat lung ARDS using gradient-modulated SWIFT with retrospective respiratory gating

    NASA Astrophysics Data System (ADS)

    Kobayashi, Naoharu; Lei, Jianxun; Utecht, Lynn; Garwood, Michael; Ingbar, David H.; Bhargava, Maneesh

    2015-03-01

    SWeep Imaging with Fourier Transformation (SWIFT) with gradient modulation and DC navigator retrospective gating is introduced as a 3D cine magnetic resonance imaging (MRI) method for the lung. In anesthetized normal rats, the quasi-simultaneous excitation and acquisition in SWIFT enabled extremely high sensitivity to the fast-decaying parenchymal signals (TE=~4 μs), which are invisible with conventional MRI techniques. Respiratory motion information was extracted from DC navigator signals and the SWIFT data were reconstructed to 3D cine images with 16 respiratory phases. To test this technique's capabilities, rats exposed to > 95% O2 for 60 hours for induction of acute respiratory distress syndrome (ARDS), were imaged and compared with normal rat lungs (N=7 and 5 for ARDS and normal groups, respectively). SWIFT images showed lung tissue density differences along the gravity direction. In the cine SWIFT images, a parenchymal signal drop at the inhalation phase was consistently observed for both normal and ARDS rats due to lung inflation (i.e. decrease of the proton density), but the drop was less for ARDS rats. Depending on the respiratory phase and lung region, the lungs from the ARDS rats showed 1-24% higher parenchymal signal intensities relative to the normal rat lungs, likely due to accumulated extravascular water (EVLW). Those results demonstrate that SWIFT has high enough sensitivity for detecting the lung proton density changes due to gravity, different phases of respiration and accumulation of EVLW in the rat ARDS lungs.

  5. PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer

    PubMed Central

    Xiong, S; Zheng, Y; Jiang, P; Liu, R; Liu, X; Qian, J; Gu, J; Chang, L; Ge, D; Chu, Y

    2014-01-01

    Background: MicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation. Methods: NSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7. Results: In this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines. Conclusion: All these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7

  6. Natural antioxidant betanin protects rats from paraquat-induced acute lung injury interstitial pneumonia.

    PubMed

    Han, Junyan; Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further.

  7. Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model

    PubMed Central

    Kohama, Keisuke; Nakao, Atsunori; Terashima, Mariko; Aoyama-Ishikawa, Michiko; Shimizu, Takayuki; Harada, Daisuke; Nakayama, Mitsuo; Yamashita, Hayato; Fujiwara, Mayu; Kotani, Joji

    2014-01-01

    Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids. PMID:24688221

  8. Natural Antioxidant Betanin Protects Rats from Paraquat-Induced Acute Lung Injury Interstitial Pneumonia

    PubMed Central

    Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further. PMID:25861636

  9. Perturbations of triglycerides but not of cholesterol metabolism are prevented by anti-tumour necrosis factor treatment in rats bearing an ascites hepatoma (Yoshida AH-130).

    PubMed Central

    Dessì, S.; Batetta, B.; Spano, O.; Bagby, G. J.; Tessitore, L.; Costelli, P.; Baccino, F. M.; Pani, P.; Argilès, J. M.

    1995-01-01

    Rats transplanted with the ascites hepatoma Yoshida AH-130 developed a severely progressive cachexia, characterised by marked alterations in protein and lipid metabolism. In particular, high levels of serum triglycerides and free fatty acids were associated with altered levels and distribution of plasma cholesterol, with increased total and very low-density lipoprotein-low-density lipoprotein (VLDL-LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol. The tumour cells showed high rates of cholesterol synthesis and elevated content of free and esterified cholesterol, whereas total cholesterol synthesis was reduced in the host liver. To determine whether these perturbations could be related to the elevation of tumour necrosis factor alpha (TNF-alpha) previously shown in the AH-130 bearers (Tessitore L, Costelli P, Baccino FM 1993, Br J Cancer, 67, 15-23), either anti-TNF polyclonal antibodies or non-immune IgGs were injected daily after tumour transplantation. The anti-TNF treatment neither affected tumour growth nor prevented the serum cholesterol changes, while attenuating the hypertriglyceridaemia and the elevated serum free fatty acid levels. These data indicate that TNF does not appear to be directly involved in the altered cholesterol metabolism in AH-130 hosts, thus supporting the view that cholesterol metabolism and lipid metabolism are regulated differently during tumour growth. PMID:7577459

  10. Bronchoconstriction and endogenous nitric oxide in isolated lungs of spontaneously hypertensive rats.

    PubMed

    Kwasniewski, Fábio H; Landgraf, Richardt Gama; Bakhle, Yeshwant S; Jancar, Sonia

    2004-03-19

    Bronchoconstrictor responses were measured in lungs isolated from spontaneously hypertensive (SHR) and normotensive rats, perfused via the airways. Lungs from SHRs were more responsive than lungs from normotensive rats to methacholine, 5-hydroxytryptamine (5-HT), arachidonic acid or prostaglandin H(2). The responses of SHR airways to methacholine or 5-HT were unaffected by pretreatment in vivo with an inhibitor of nitric oxide (NO) synthase, N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 30 mg kg(-1)), although responses in normotensive airways to methacholine, but not to 5-HT, were enhanced. Antigen challenge of isolated lungs from actively sensitized rats elicited bronchoconstriction, not different between strains. Pretreatment with L-NAME increased the response to antigen challenge only in normotensive lungs. Compound 48/80 induced bronchoconstriction in lungs from either strain, equally. These responses to compound 48/80 were unaffected by L-NAME pretreatment. Thus, SHR airways lack relaxing factors and degranulation of mast cells in SHR lungs was not affected by endogenous NO.

  11. The role of ephrins-B1 and -B2 during fetal rat lung development.

    PubMed

    Peixoto, Francisca O; Pereira-Terra, Patrícia; Moura, Rute S; Carvalho-Dias, Emanuel; Correia-Pinto, Jorge; Nogueira-Silva, Cristina

    2015-01-01

    BACKGROUND/ AIMS: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters. © 2015 S. Karger AG, Basel.

  12. Clearance of free silica in rat lungs by spraying with chinese herbal kombucha.

    PubMed

    Fu, Nai-Fang; Luo, Chang-Hui; Wu, Jun-Cai; Zheng, Yan-Yan; Gan, Yong-Jin; Ling, Jian-An; Liang, Heng-Qiu; Liang, Dan-Yu; Xie, Jing; Chen, Xiao-Qin; Li, Xian-Jun; Pan, Rui-Hui; Chen, Zuo-Xing; Jiang, Sheng-Jun

    2013-01-01

    The effects of spraying with kombucha and Chinese herbal kombucha were compared with treatments with tetrandrine in a rat silicosis model. Silica dust (50 mg) was injected into the lungs of rats, which were then treated with one of the experimental treatments for a month. The rats were then killed and the effects of the treatments were evaluated by examining the extent and severity of the histopathological lesions in the animals' lungs, measuring their organ coefficients and lung collagen contents, determining the dry and wet weights of their lungs, and measuring the free silica content of the dried lungs. In addition, lavage was performed on whole lungs taken from selected rats, and the numbers and types of cells in the lavage fluid were counted. The most effective treatment in terms of the ability to reduce lung collagen content and minimize the formation of pulmonary histopathological lesions was tetrandrine treatment, followed by Chinese herbal kombucha and non-Chinese herbal kombucha. However, the lavage fluid cell counts indicated that tetrandrine treatment had severe adverse effects on macrophage viability. This effect was much less pronounced for the kombucha and Chinese herbal kombucha treatments. Moreover, the free silica levels in the lungs of animals treated with Chinese herbal kombucha were significantly lower than those for any other silica-exposed group. These preliminary results indicate that spraying with Chinese herbal kombucha preparations can effectively promote the discharge of silica dust from lung tissues. Chinese herbal kombucha inhalation may thus be a useful new treatment for silicosis and other pneumoconiosis diseases.

  13. Clearance of Free Silica in Rat Lungs by Spraying with Chinese Herbal Kombucha

    PubMed Central

    Fu, Nai-fang; Luo, Chang-hui; Wu, Jun-cai; Zheng, Yan-yan; Gan, Yong-jin; Ling, Jian-an; Liang, Heng-qiu; Liang, Dan-yu; Xie, Jing; Chen, Xiao-qin; Li, Xian-jun; Pan, Rui-hui; Chen, Zuo-Xing; Jiang, Sheng-jun

    2013-01-01

    The effects of spraying with kombucha and Chinese herbal kombucha were compared with treatments with tetrandrine in a rat silicosis model. Silica dust (50 mg) was injected into the lungs of rats, which were then treated with one of the experimental treatments for a month. The rats were then killed and the effects of the treatments were evaluated by examining the extent and severity of the histopathological lesions in the animals' lungs, measuring their organ coefficients and lung collagen contents, determining the dry and wet weights of their lungs, and measuring the free silica content of the dried lungs. In addition, lavage was performed on whole lungs taken from selected rats, and the numbers and types of cells in the lavage fluid were counted. The most effective treatment in terms of the ability to reduce lung collagen content and minimize the formation of pulmonary histopathological lesions was tetrandrine treatment, followed by Chinese herbal kombucha and non-Chinese herbal kombucha. However, the lavage fluid cell counts indicated that tetrandrine treatment had severe adverse effects on macrophage viability. This effect was much less pronounced for the kombucha and Chinese herbal kombucha treatments. Moreover, the free silica levels in the lungs of animals treated with Chinese herbal kombucha were significantly lower than those for any other silica-exposed group. These preliminary results indicate that spraying with Chinese herbal kombucha preparations can effectively promote the discharge of silica dust from lung tissues. Chinese herbal kombucha inhalation may thus be a useful new treatment for silicosis and other pneumoconiosis diseases. PMID:24023583

  14. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    SciTech Connect

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  15. Differential responses of targeted lung redox enzymes to rat exposure to 60 or 85% oxygen

    PubMed Central

    Gan, Zhuohui; Roerig, David L.; Clough, Anne V.

    2011-01-01

    Rat exposure to 60% O2 (hyper-60) or 85% O2 (hyper-85) for 7 days confers susceptibility or tolerance, respectively, of the otherwise lethal effects of exposure to 100% O2. The objective of this study was to determine whether activities of the antioxidant cytosolic enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex III are differentially altered in hyper-60 and hyper-85 lungs. Duroquinone (DQ), an NQO1 substrate, or its hydroquinone (DQH2), a complex III substrate, was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of DQH2 and DQ were measured. Based on inhibitor effects and kinetic modeling, capacities of NQO1-mediated DQ reduction (Vmax1) and complex III-mediated DQH2 oxidation (Vmax2) increased by ∼140 and ∼180% in hyper-85 lungs, respectively, compared with rates in lungs of rats exposed to room air (normoxic). In hyper-60 lungs, Vmax1 increased by ∼80%, with no effect on Vmax2. Additional studies revealed that mitochondrial complex I activity in hyper-60 and hyper-85 lung tissue homogenates was ∼50% lower than in normoxic lung homogenates, whereas mitochondrial complex IV activity was ∼90% higher in only hyper-85 lung tissue homogenates. Thus NQO1 activity increased in both hyper-60 and hyper-85 lungs, whereas complex III activity increased in hyper-85 lungs only. This increase, along with the increase in complex IV activity, may counter the effects the depression in complex I activity might have on tissue mitochondrial function and/or reactive oxygen species production and may be important to the tolerance of 100% O2 observed in hyper-85 rats. PMID:21551015

  16. Differential responses of targeted lung redox enzymes to rat exposure to 60 or 85% oxygen.

    PubMed

    Gan, Zhuohui; Roerig, David L; Clough, Anne V; Audi, Said H

    2011-07-01

    Rat exposure to 60% O(2) (hyper-60) or 85% O(2) (hyper-85) for 7 days confers susceptibility or tolerance, respectively, of the otherwise lethal effects of exposure to 100% O(2). The objective of this study was to determine whether activities of the antioxidant cytosolic enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex III are differentially altered in hyper-60 and hyper-85 lungs. Duroquinone (DQ), an NQO1 substrate, or its hydroquinone (DQH(2)), a complex III substrate, was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of DQH(2) and DQ were measured. Based on inhibitor effects and kinetic modeling, capacities of NQO1-mediated DQ reduction (V(max1)) and complex III-mediated DQH(2) oxidation (V(max2)) increased by ∼140 and ∼180% in hyper-85 lungs, respectively, compared with rates in lungs of rats exposed to room air (normoxic). In hyper-60 lungs, V(max1) increased by ∼80%, with no effect on V(max2). Additional studies revealed that mitochondrial complex I activity in hyper-60 and hyper-85 lung tissue homogenates was ∼50% lower than in normoxic lung homogenates, whereas mitochondrial complex IV activity was ∼90% higher in only hyper-85 lung tissue homogenates. Thus NQO1 activity increased in both hyper-60 and hyper-85 lungs, whereas complex III activity increased in hyper-85 lungs only. This increase, along with the increase in complex IV activity, may counter the effects the depression in complex I activity might have on tissue mitochondrial function and/or reactive oxygen species production and may be important to the tolerance of 100% O(2) observed in hyper-85 rats.

  17. Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2015-07-24

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  18. Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2014-08-26

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  19. Comparative microscopic study of human and rat lungs after overexposure to welding fume.

    PubMed

    Antonini, James M; Roberts, Jenny R; Schwegler-Berry, Diane; Mercer, Robert R

    2013-11-01

    Welding is a common industrial process used to join metals and generates complex aerosols of potentially hazardous metal fumes and gases. Most long-time welders experience some type of respiratory disorder during their time of employment. The use of animal models and the ability to control the welding fume exposure in toxicology studies have been helpful in developing a better understanding of how welding fumes affect health. There are no studies that have performed a side-by-side comparison of the pulmonary responses from an animal toxicology welding fume study with the lung responses associated with chronic exposure to welding fume by a career welder. In this study, post-mortem lung tissue was donated from a long-time welder with a well-characterized work background and a history of extensive welding fume exposure. To simulate a long-term welding exposure in an animal model, Sprague-Dawley rats were treated once a week for 28 weeks by intratracheal instillation with 2mg of a stainless steel, hard-surfacing welding fume. Lung tissues from the welder and the welding fume-treated rats were examined by light and electron microscopy. Pathological analysis of lung tissue collected from the welder demonstrated inflammatory cell influx and significant pulmonary injury. The poor and deteriorating lung condition observed in the welder examined in this study was likely due to exposure to very high levels of potentially toxic metal fumes and gases for a significant number of years due to work in confined spaces. The lung toxicity profile for the rats treated with welding fume was similar. For tissue samples from both the welder and treated rats, welding particle accumulations deposited and persisted in lung structures and were easily visualized using light microscopic techniques. Agglomerates of deposited welding particles mostly were observed within lung cells, particularly alveolar macrophages. Analysis of individual particles within the agglomerates showed that these

  20. Comparative Microscopic Study of Human and Rat Lungs After Overexposure to Welding Fume

    PubMed Central

    ANTONINI, JAMES M.; ROBERTS, JENNY R.; SCHWEGLER-BERRY, DIANE; MERCER, ROBERT R.

    2015-01-01

    Welding is a common industrial process used to join metals and generates complex aerosols of potentially hazardous metal fumes and gases. Most long-time welders experience some type of respiratory disorder during their time of employment. The use of animal models and the ability to control the welding fume exposure in toxicology studies have been helpful in developing a better understanding of how welding fumes affect health. There are no studies that have performed a side-by-side comparison of the pulmonary responses from an animal toxicology welding fume study with the lung responses associated with chronic exposure to welding fume by a career welder. In this study, post-mortem lung tissue was donated from a long-time welder with a well-characterized work background and a history of extensive welding fume exposure. To simulate a long-term welding exposure in an animal model, Sprague-Dawley rats were treated once a week for 28 weeks by intratracheal instillation with 2 mg of a stainless steel, hard-surfacing welding fume. Lung tissues from the welder and the welding fume-treated rats were examined by light and electron microscopy. Pathological analysis of lung tissue collected from the welder demonstrated inflammatory cell influx and significant pulmonary injury. The poor and deteriorating lung condition observed in the welder examined in this study was likely due to exposure to very high levels of potentially toxic metal fumes and gases for a significant number of years due to work in confined spaces. The lung toxicity profile for the rats treated with welding fume was similar. For tissue samples from both the welder and treated rats, welding particle accumulations deposited and persisted in lung structures and were easily visualized using light microscopic techniques. Agglomerates of deposited welding particles mostly were observed within lung cells, particularly alveolar macrophages. Analysis of individual particles within the agglomerates showed that these

  1. Quantifying Single Microvessel Permeability in Isolated Blood-perfused Rat Lung Preparation

    PubMed Central

    Kandasamy, Kathirvel; Parthasarathi, Kaushik

    2014-01-01

    The isolated blood-perfused lung preparation is widely used to visualize and define signaling in single microvessels. By coupling this preparation with real time imaging, it becomes feasible to determine permeability changes in individual pulmonary microvessels. Herein we describe steps to isolate rat lungs and perfuse them with autologous blood. Then, we outline steps to infuse fluorophores or agents via a microcatheter into a small lung region. Using these procedures described, we determined permeability increases in rat lung microvessels in response to infusions of bacterial lipopolysaccharide. The data revealed that lipopolysaccharide increased fluid leak across both venular and capillary microvessel segments. Thus, this method makes it possible to compare permeability responses among vascular segments and thus, define any heterogeneity in the response. While commonly used methods to define lung permeability require postprocessing of lung tissue samples, the use of real time imaging obviates this requirement as evident from the present method. Thus, the isolated lung preparation combined with real time imaging offers several advantages over traditional methods to determine lung microvascular permeability, yet is a straightforward method to develop and implement. PMID:25045895

  2. Protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury in a rat model.

    PubMed

    Liu, Wenwu; Liu, Kehuan; Ma, Chunqing; Yu, Jiangang; Peng, Zhaoyun; Huang, Guoyang; Cai, Zhiyu; Li, Runping; Xu, Weigang; Sun, Xuejun; Liu, Kan; Zheng, Juan

    2014-01-01

    Hyperbaric oxygen therapy is one of the most widely used clinical interventions to counteract insufficient pulmonary oxygen delivery in patients with severe lung injury. However, prolonged exposure to hyperoxia leads to inflammation and acute lung injury. This study aimed to investigate the protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury. Rats were intraperitoneally treated with sodium hydrosulphide (NaHS) at 28 μmol/kg immediately before hyperoxia exposure and then exposed to pure oxygen at 2.5 atmospheres absolute (atm abs) with continuous ventilation for six hours, Immediately after hyperoxia exposure, rats were sacrificed via anesthesia. The bronchoalveolar lavage fluid (BALF) was harvested for the detection of protein concentration and IL-1 content, and the lungs were collected for HE staining, TUNEL staining and detection of wet/dry weight ratio. Our results showed hyperbaric hyperoixa exposure could significantly damage the lung (HE staining), increase the protein and IL-13 in the BALF, elevate the wet/dry Weight ratio and raise the TUNEL positive cells. However, pre-treatment with hydrogen sulfide improved the lung morphology, reduced the TUNEL positive cells and attenuated the lung inflammation (reduction in IL-13 of BALF and HE staining). Taken together, our findings indicate that hydrogen sulfide pretreatment may exert protective effects on hyperbaric hyperoxia-induced lung injury.

  3. Hydrogen inhalation decreases lung graft injury in brain-dead donor rats.

    PubMed

    Zhou, Huacheng; Fu, Zhijie; Wei, Yuting; Liu, Jinfeng; Cui, Xiaoguang; Yang, Wanchao; Ding, Wengang; Pan, Peng; Li, Wenzhi

    2013-02-01

    The process of brain death induces acute lung injury in donors and aggravates ischemia-reperfusion injury (IRI) in grafts. Hydrogen, a new anti-oxidant, attenuates IRI in several organ transplant models. We examined whether 2% inhaled hydrogen would show favorable effects on lung grafts from brain-dead donor rats. Brain-dead donor rats inhaled mixed gases with either 50% oxygen and 50% nitrogen or mixed gases with 2% hydrogen, 50% oxygen and 48% nitrogen for 2 hours. The recipients inhaled the same gas as the donors and were euthanized 2 hours after lung transplantation. Hydrogen improved PaO(2)/FIO(2) and PVO(2)/FIO(2) from the arterial and pulmonary venous blood in recipients and decreased the lung injury score in grafts from brain-dead donors. Hydrogen decreased the amount of IL-8 and TNF-α in serum, inhibited the activity of malondialdehyde and myeloperoxidase, and increased the activity of superoxide dismutase in the lung grafts from brain-dead donors. Furthermore, hydrogen decreased the apoptotic index of the cells and inhibited the protein expression of intercellular adhesion molecule-1 and caspase-3 in lung grafts from brain-dead donors. Hydrogen can exert protective effects on lung grafts from brain-dead donors through anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  4. TRPV1 and neuropeptide receptor immunoreactivity and expression in the rat lung and brainstem after lung ischemia-reperfusion injury.

    PubMed

    Zhao, Qiong; Wang, Wenjian; Wang, Rurong; Cheng, Yan

    2016-06-01

    Activation of capsaicin-sensitive sensory nerves and TRPV1 present on them can ameliorate the ischemia-reperfusion injury in vital organs by evoking the release of neuropeptides including calcitonin gene-related peptide (CGRP) and substance P. However, the underlying changes in TRPV1 and neuropeptide receptor expressions, including calcitonin receptor-like receptor (CRLR) and neurokinin 1 receptor (NK1R), after lung ischemia-reperfusion injury (LIRI) remain uncharacterized. Thirty-two male Sprague-Dawley rats were randomly and equally divided into sham (sham thoracotomy) and ischemia-reperfusion (occlusion of the left pulmonary hilus for 1 h followed by reperfusion for 4 h) groups. Blood gas levels were measured and histopathologic examination was performed. Left lung lobes and brainstem tissue samples were harvested for use in quantitative real-time PCR, Western blot, and immunohistochemistry to measure TRPV1, CRLR, and NK1R transcript and protein levels. Additionally, CGRP and substance P protein levels were quantified in the lungs using enzyme-linked immunosorbent assay. LIRI exacerbated blood gas exchange and increased the pulmonary tissue injury score. Furthermore, LIRI increased CGRP levels in the lung, TRPV1-immunoreactivity (ir) in the bronchiolar epithelium and smooth muscle of the pulmonary artery, and the intensity of neuronal CRLR-ir and NK1R-ir in the commissural nucleus of the solitary tract. Similarly, LIRI significantly elevated both transcription and translation of TRPV1 in the lungs and CRLR and NK1R in the brainstem. Both transcription and translation of TRPV1 in the lungs and CRLR and NK1R in the brainstem of rats can be upregulated by LIRI in a rapid manner (within 5 h). Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Toxic effects of cadmium on the developing rat lung. II. Glycogen and phospholipid metabolism

    SciTech Connect

    Daston, G.P.

    1982-01-01

    Maternal exposure to Cd reduces lung weight and alters pulmonary surfactant accumulation in the fetus. This may lead to respiratory distress and death postnatally. In this study, the effects of maternal Cd administration on additional biochemical parameters of the fetal lung were investigated. Pregnant rats were given sc injections of 8 mg/kg CdCl/sub 2/ on d 12-15 of gestation and sacrificed throughout late gestation. Fetal lungs were examined for protein, DNA, and glycogen. Incorporation of choline into total and disaturated phosphatidylcholine and sphingomyelin were measured in fetal lung slices. The DNA content of the treated lungs was reduced, but the protein/DNA ratio was not altered. Thus the reduced lung weight was due to hypoplasia, not hypotrophy. Incorporation of choline into pulmonary sphingomyelin was not altered by the treatment. Choline incorporation into both total and disaturated phosphatidylcholine, the most important surfactant component, was reduced on the final days of gestation. Glycogen was reduced in both absolute quantity and cellular concentration in lungs of treated fetuses. Glucose derived from glycogen is a major metabolic substrate in the fetal lung and probably contributes greatly to phospholipid synthesis. The reduction in glucose concentration in lungs of treated fetuses may be a factor in the diminished synthesis of pulmonary surfactant phosphatidylcholine before birth. Prenatal Cd exposure causes pulmonary hypoplasia; reduces the amount of glycogen present in the fetal lung; and diminishes the rate of synthesis of pulmonary surfactant phosphatidylcholine.

  6. Effects of aminoguanidine and antioxidant erdosteine on bleomycin-induced lung fibrosis in rats.

    PubMed

    Yildirim, Zeki; Turkoz, Yusuf; Kotuk, Mahir; Armutcu, Ferah; Gurel, Ahmet; Iraz, Mustafa; Ozen, Suleyman; Aydogdu, Ismet; Akyol, Omer

    2004-09-01

    Reactive oxygen and nitrogen species have been implicated in the pathogenesis of bleomycin-induced lung fibrosis. The effects of aminoguanidine and erdosteine on the bleomycin-induced lung fibrosis were evaluated in rats. The animals were placed into five groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + aminoguanidine (200 mg/kg), bleomycin + erdosteine (10 mg/kg), and bleomycin + erdosteine + aminoguanidine. Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology, which is completely prevented by erdosteine and aminoguanidine. A strong staining for nitro tyrosine antibody in lung tissue and increased levels of lung NO were found in bleomycin group, that were significantly reduced by aminoguanidine and erdosteine. Aminoguanidine and erdosteine significantly prevented depletion of superoxide dismutase and glutathione peroxidase and elevated myeloperoxidase activities, malondialdehyde level in lung tissue produced by bleomycin. Data presented here indicate that aminoguanidine and erdosteine prevented bleomycin-induced lung fibrosis and that nitric oxide mediated tyrosine nitration of proteins plays a significant role in the pathogenesis of bleomycin-induced lung fibrosis. Also our data suggest that antifibrotic affect of antioxidants may be due to their inhibitory effect on nitric oxide generation in this model.

  7. Rat lung response to ozone and fine particulate matter (PM2.5) exposures.

    PubMed

    Wang, Guanghe; Zhao, Jinzhuo; Jiang, Rongfang; Song, Weimin

    2015-03-01

    Exposure to different ambient pollutants maybe more toxic to lung than exposure to a single pollutant. In this study, we discussed the inflammation and oxidative stress responses of rat lung caused by ozone and PM2.5 versus that of rats exposed to saline, ozone, or single PM2.5 . Wistar rats inhaled 0.8 ppm ozone or air for 4 h and then placed in air for 3 h following intratracheal instillation with 0, 0.2 (low dose), 0.8 (medium dose), 3.2 (high dose) mg/rat PM2.5 dissolved in sterile saline (0.25 mL/rat), repeated twice per week for 3 weeks, the cumulative doses of PM2.5 in animals were 1.2, 4.8, and 19.2 mg. Rats were sacrificed 24 h after the last (sixth) exposure. The collected bronchoalveolar lavage fluid (BALF) was analyzed for inflammatory cells and cytokines. Lung tissues were processed for light microscopic and transmission electron microscopic (TEM) examinations. Results showed that total cell number in BALF of PM2.5 -exposed groups were higher than control (p < 0.05). PM2.5 instillation caused dose-trend increase in tumor necrosis factor alpha (TNF-α), interleukin-6, lactate dehydrogenase, and total protein of BALF. Exposure to ozone alone only caused TNF-α significant change in above-mentioned indicators of lung injury. On the other hand, ozone could enhance PM2.5-induced inflammatory changes and pathological characters in rat lungs. SOD and GSH-Px activities in lung were reduced in PM2.5-exposed rats with and without prior ozone exposure compared to control. To determine whether the PM2.5 and ozone affect endothelium system, iNOS, eNOS, and ICAM-1 mRNA levels in lung were analyzed by real-time PCR. These data demonstrated that inflammation and oxidative stress were involved in toxicology mechanisms of PM2.5 in rat lung and ozone potentiated these effects induced by PM2.5. These results have implications for understanding the pulmonary effects induced by ozone and PM2.5.

  8. 3D Cine Magnetic Resonance Imaging of Rat Lung ARDS using Gradient-modulated SWIFT with Retrospective Respiratory Gating.

    PubMed

    Kobayashi, Naoharu; Lei, Jianxun; Utecht, Lynn; Garwood, Michael; Ingbar, David; Bhargava, Maneesh

    2015-02-21

    SWeep Imaging with Fourier Transformation (SWIFT) with gradient modulation and DC navigator retrospective gating is introduced as a 3D cine magnetic resonance imaging (MRI) method for the lung. The quasi-simultaneous excitation and acquisition in SWIFT enabled extremely high sensitivity to the fast-decaying parenchymal signals (TE=~4 μs), which are invisible with conventional MRI techniques. Based on respiratory motion information extracted from DC navigator signals, the SWIFT data were reconstructed to 3D cine images with 16 respiratory phases. To test the capability of the proposed technique, rats exposed to > 95% O2 for 60 hours for induction of acute respiratory distress syndrome (ARDS), were imaged and compared with normal rat lungs (N=7 and 5 for ARDS and normal group, respectively). SWIFT images showed lung tissue density difference along the gravity direction. In the cine SWIFT images, parenchymal signal drop at the inhalation phase was consistently observed for both normal and ARDS rats due to inflation of the lung (i.e. decrease of the proton density), but the drop was less for ARDS rats. Depending on the respiration phase and lung region, the lungs from the ARDS rats showed 1-24% higher parenchymal signal intensities relative to the normal rat lungs, which would be mainly from accumulation of extravascular water (EVLW). Those results demonstrate that SWIFT has high enough sensitivity for detecting the lung proton density changes due to gravity, different respiration phases and accumulation of EVLW in the rat ARDS lungs.

  9. Compensatory lung growth after bilobectomy in emphysematous rats

    PubMed Central

    Almeida, Francine Maria; Saraiva-Romanholo, Beatriz Mangueira; Vieira, Rodolfo Paula; Moriya, Henrique Takachi; Ligeiro-de-Oliveira, Ana Paula; Lopes, Fernanda DTQS; Castro-Faria-Neto, Hugo C.; Mauad, Thais; Martins, Milton Arruda; Pazetti, Rogerio

    2017-01-01

    Lung volume reduction surgery (LVRS) is an option for emphysematous patients who are awaiting lung transplantation. LVRS reduces nonfunctional portions of lung tissues and favors the compensatory lung growth (CLG) of the remaining lobes. This phenomenon diminishes dyspnea and improves both the respiratory mechanics and quality of life for the patients. An animal model of elastase-induced pulmonary emphysema was used to investigate the structural and functional lung response after LVRS. Bilobectomy was performed six weeks after elastase instillation. Two weeks after bilobectomy, CLG effects were evaluated by lung mechanics and histomorphometric analysis. After bilobectomy, the emphysematous animals presented decreased mean linear intercepts, increased elastic fiber proportion, and increased alveolar surface density, total volumes of airspace, tissue and respiratory region and absolute surface area. We conclude that bilobectomy promoted CLG in emphysematous animals, resulting in alveolar architecture repair. PMID:28750097

  10. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    SciTech Connect

    Hahn, F.F.; Kelly, G.

    1995-12-01

    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  11. Reduced Fhit protein expression and loss of heterozygosity at FHIT gene in tumours from smoking and asbestos-exposed lung cancer patients.

    PubMed

    Pylkkanen, Lea; Wolff, Henrik; Stjernvall, Tuula; Tuominen, Paivi; Sioris, Thanos; Karjalainen, Antti; Anttila, Sisko; Husgafvel-Pursiainen, Kirsti

    2002-02-01

    The FHIT gene, at 3p14.2, has been suggested to form a molecular target to damage induced by human lung carcinogens. We examined aberrant expression of the Fhit protein and allele loss at the FHIT gene in a series of lung cancer cases, mainly of non-small cell carcinoma (NSCLC) histology. We had detailed data on tobacco smoke exposure and occupational asbestos exposure available for the cases. The principal aim of the present study was to investigate whether absent or reduced Fhit expression or FHIT allele loss was associated with exposure to these pulmonary carcinogens. We detected reduced Fhit expression in 62% (33/53) of the cases analysed. Prevalence of allele loss at the FHIT locus was 22% (20/89). Reduced protein expression was common both in the asbestos-exposed (67%) and non-exposed cases (59%); [odds ratio (OR) 1.4, 95% confidence interval (CI) 0.4-4.9]. LOH frequencies differed somewhat between the two groups and were 25% vs. 16%, respectively (OR 1.8; 95% CI 0.5-5.9). Absent or reduced expression was common in smokers, with no significant difference found between current smokers and non-smokers (mainly former smokers) (OR 1.4, 95% CI 0.5-4.5). NSCLCs with squamous cell histology exhibited both aberrant expression (OR 3.1, 95% CI 0.9-10.3) and allele loss (OR 3.3, 95% CI 0.9-12.7) more frequently than adenocarcinoma. Finally, we found that FHIT allele loss was increased in stage II or more advanced disease (OR 2.5, 95% CI 0.9-7.4), and in poorly differentiated tumours (grade 3, OR 2.6, 95% CI 0.8-8.1). In conclusion, our present data support significance of FHIT inactivation in development of lung cancer.

  12. Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats.

    PubMed

    Spielmann, J; Hanke, J; Knauf, D; Ben-Eliyahu, S; Jacobs, R; Stangl, G I; Bähr, I; Kielstein, H

    2017-01-01

    Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. To induce obesity male F344-rats received a high-fat diet (34% fat) or a control diet (4% fat). Thereafter, syngeneic mammary adenocarcinoma cells (MADB106) or a vehicle were intravenously (i.v.) injected. 15 min after injection, half of each group of rats were killed, lungs removed and immunohistochemically stained. Numbers of NK cells, MADB106 cells and NK cell-tumor cell interactions were quantified. Twenty-one days after tumor-cell injection the other half group of rats was killed and lung metastases were counted and relative mRNA concentrations of different NK cell receptors were determined. After short-term MADB106-challenge, DIO fed animals showed significantly decreased NK cell numbers in the blood and NK cell-tumor cell interactions in the lung as compared to their control littermates. Twenty-one days after MADB106 injection, the lungs of the DIO fed rats showed significantly more lung metastases compared to control animals, accompanied by reduced relative mRNA concentrations of the activating NK cell receptor NKG2D. We conclude that induction of obesity in F344-rats leads to reduced lung NK cell function against tumor cells and results in significantly enhanced lung metastasis as compared to lean animals. It can be hypothesized that obesity-induced altered NK cell functions play an important role in cancer growth and metastasis.

  13. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

    PubMed Central

    Yadav, Amit K.; Doran, Stephen F.; Samal, Andrey A.; Sharma, Ruchita; Vedagiri, Kokilavani; Postlethwait, Edward M.; Squadrito, Giuseppe L.; Fanucchi, Michelle V.; Roberts, L. Jackson; Patel, Rakesh P.

    2011-01-01

    Nitrite (NO2−) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO2− in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO2− mitigate chlorine (Cl2)-induced lung injury in rats. Rats were exposed to Cl2 (400 ppm) for 30 min and returned to room air. NO2− (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F2-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl2 exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO2− resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F2-isoprostane levels increased at 6 and 24 h after Cl2 exposure in NO2−- and saline-injected rats. This is the first demonstration that systemic NO2− administration mitigates airway and epithelial injury. PMID:21148791

  14. [Protective effect of synthetic salidroside on acute lung injury in rats].

    PubMed

    Huang, Qian; Cai, Yan-Chun; Wei, Xiao-Li; Wu, Jin-Long; Mei, Ru-Huan; Hu, Xiao-Lan

    2017-06-25

    To study the protective effect and mechanism of synthetic salidroside on acute lung injury (ALI) induced by lipopolysaccharide (LPS), male Sprague-Dawley (SD) rats were randomly divided into saline control group, 3 mg/kg LPS model group, different doses of salidroside groups (5, 20 and 80 mg/kg), and 5 mg/kg dexamethasone group. Intratracheal LPS instillation was used to establish the ALI model 0.5 h after intraperitoneal injection of salidroside or dexamethasone, and the rats were sacrificed 6 h later. Lung wet/dry weight ratio (W/D) was calculated. Lung tissue pathology and lung injury score (LIS) were observed and evaluated through hematoxylin and eosin (HE) staining. The centrifugal sediment of bronchoalveolar lavage fluid (BALF) was used to count the polymorphonuclear leukocyte (PMN) number by Wright's staining, and the centrifugal supernatant of BALF was used to determine the contents of protein and inflammatory factors (TNF-α, IL-1β and IL-6). The contents of myeloperoxidase (MPO) and malondialdehyde (MDA) in lung tissue were determined. Western blot was used to detect the expression levels of phosphorylated and total nuclear factor kappa B (NF-κB)/p65 protein in lung tissue. The results showed that, compared with LPS group, the intervention of synthetic salidroside alleviated the pathological damage in lung tissue, decreased the LIS and lung W/D ratio (P < 0.05), reduced the PMN number, the contents of protein and inflammatory factors in BALF (P < 0.05), reduced the contents of MPO and MDA in lung tissue (P < 0.05), and inhibited the expression of p-NF-κB in lung tissue (P < 0.05). The results suggest that synthetic salidroside has a protective effect on ALI induced by LPS, and its mechanism is related to inhibiting the phosphorylation of NF-κB and reducing the aggregation of PMN in the lung.

  15. Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

    PubMed Central

    Ivarsson, K; Myllymäki, L; Jansner, K; Stenram, U; Tranberg, K-G

    2005-01-01

    Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time–response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6–8 days later (tumour size 0.25–0.40 cm3) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n=8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes. PMID:16091763

  16. Signaling pathways and mediators in LPS-induced lung inflammation in diabetic rats: role of insulin.

    PubMed

    Martins, Joilson O; Ferracini, Matheus; Anger, Denise B C; Martins, Daniel O; Ribeiro, Luciano F; Sannomiya, Paulina; Jancar, Sonia

    2010-01-01

    Diabetic patients are more susceptible to infections, and their inflammatory response is impaired. This is restored by insulin treatment. In the present study, we investigated the effect of insulin on LPS-induced signaling pathways and mediators in the lung of diabetic rats. Diabetic male Wistar rats (alloxan, 42 mg/kg i.v., 10 days) and control rats received intratracheal instillation of LPS (750 microg/0.4 mL) or saline. Some diabetic rats were given neutral protamine Hagedorn insulin (4 IU s.c.) 2 h before LPS. After 6 h, bronchoalveolar lavage was performed for the release of mediators, and lung tissue was homogenized for analysis of LPS-induced signaling pathways. Relative to control rats, diabetic rats exhibited a significant reduction in the LPS-induced phosphorylation of extracellular signal-regulated kinase (64%), p38 (70%), protein kinase B (67%), and protein kinase C alpha (57%) and delta (65%) and in the expression of iNOS (32%) and cyclooxygenase 2 (67%) in the lung homogenates. The bronchoalveolar lavage fluid concentrations of NO (47%) and IL-6 (49%) were also reduced in diabetic rats, whereas the cytokine-induced neutrophil chemoattractant 2 (CINC-2) levels were increased 23%, and CINC-1 was not different from control animals. Treatment of diabetic rats with insulin completely or partially restored all these parameters. In conclusion, data presented show that insulin regulates mitogen-activated protein kinase, phosphatidylinositol 3'-kinase, protein kinase C pathways, expression of the inducible enzymes, cyclooxygenase 2 and iNOS, and levels of IL-6 and CINC-2 in LPS-induced lung inflammation in diabetic rats. These results suggest that the protective effect of insulin in sepsis could be due to modulation of cellular signal transduction factors.

  17. Lung response to ultrafine Kevlar aramid synthetic fibrils following 2-year inhalation exposure in rats.

    PubMed

    Lee, K P; Kelly, D P; O'Neal, F O; Stadler, J C; Kennedy, G L

    1988-07-01

    Four groups of 100 male and 100 female rats were exposed to ultrafine Kevlar fibrils at concentrations of 0, 2.5, 25, and 100 fibrils/cc for 6 hr/day, 5 days/week for 2 years. One group was exposed to 400 fibrils/cc for 1 year and allowed to recover for 1 year. At 2.5 fibrils/cc, the lungs had normal alveolar architecture with a few dust-laden macrophages (dust cell response) in the alveolar airspaces. At 25 fibrils/cc, the lungs showed a dust cell response, slight Type II pneumocyte hyperplasia, alveolar bronchiolarization, and a negligible amount of collagenized fibrosis in the alveolar duct region. At 100 fibrils/cc, the same pulmonary responses were seen as at 25 fibrils/cc. In addition, cystic keratinizing squamous cell carcinoma (CKSCC) was found in 4 female rats, but not in male rats. Female rats had more prominent foamy alveolar macrophages, cholesterol granulomas, and alveolar bronchiolarization. These pulmonary lesions were related to the development of CKSCC. The lung tumors were derived from metaplastic squamous cells in areas of alveolar bronchiolarization. At 400 fibrils/cc following 1 year of recovery, the lung dust content, average fiber length, and the pulmonary lesions were markedly reduced, but slight centriacinar emphysema and minimal collagenized fibrosis were found in the alveolar duct region. One male and 6 female rats developed CKSCC. The lung tumors were a unique type of experimentally induced tumors in the rats and have not been seen as spontaneous tumors in man or animals. Therefore, the relevance of this type of lung tumor to the human situation is minimal.

  18. Transcriptomics analysis of lungs and peripheral blood of crystalline silica-exposed rats.

    PubMed

    Sellamuthu, Rajendran; Umbright, Christina; Roberts, Jenny R; Chapman, Rebecca; Young, Shih-Houng; Richardson, Diana; Cumpston, Jared; McKinney, Walter; Chen, Bean T; Frazer, David; Li, Shengqiao; Kashon, Michael; Joseph, Pius

    2012-08-01

    Minimally invasive approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. The potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity was investigated. Rats were exposed by inhalation to crystalline silica (15 mg/m(3), 6 h/day, 5 days) and pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined at 32 weeks following termination of exposure. A significant elevation in bronchoalveolar lavage fluid lactate dehydrogenase activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 levels in the lungs showed pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression [>1.5-fold change and false discovery rate (FDR) p < 0.01] of 520 and 537 genes, respectively, in the lungs and blood of the exposed rats. Bioinformatics analysis of the differentially expressed genes demonstrated significant similarity in the biological processes, molecular networks, and canonical pathways enriched by silica exposure in the lungs and blood of the rats. Several genes involved in functions relevant to silica-induced pulmonary toxicity such as inflammation, respiratory diseases, cancer, cellular movement, fibrosis, etc, were found significantly differentially expressed in the lungs and blood of the silica-exposed rats. The results of this study suggested the potential application of peripheral blood gene expression profiling as a toxicologically relevant and minimally invasive surrogate approach to study the mechanisms underlying silica-induced pulmonary toxicity.

  19. Modification of the 31P magnetic resonance spectra of a rat tumour using vasodilators and its relationship to hypotension.

    PubMed Central

    Tozer, G. M.; Maxwell, R. J.; Griffiths, J. R.; Pham, P.

    1990-01-01

    The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS1 fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an increase in inorganic phosphate, a reduction in nucleotide triphosphates and a reduction in pH) were consistent with nutrient deprivation. These changes were dose dependent. Changes in MABP and heart rate were consistent with vasodilatation in normal tissues. However, for the same fall in MABP, hydralazine produced a greater rise in tumour inorganic phosphate (Pi) and a greater fall in tumour pH than did prostacyclin. Controlled bleeding was effective in reducing MABP. It also reduced tumour pH but had no significant effect on tumour Pi. The clinical application of the two drugs for reducing tumour blood flow and pH for therapy is likely to be limited by the large degree of hypotension necessary to produce an effect. The differential effect of the two drugs for the same fall in MABP may be related to different degrees of direct tumour vasodilatation or to a direct effect of hydralazine on tumour energy metabolism. The observation that controlled bleeding does not change tumour Pi is further evidence indicating that the degree of arterial hypotension is not the sole factor in determining tumour energy status. PMID:2223572

  20. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    PubMed Central

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  1. Lymphoreticular response to a syngeneic rat tumour: gravimetric and histological studies.

    PubMed Central

    Flannery, G. R.; Muller, H. K.; Nairn, R. C.

    1975-01-01

    Gravimetric and histological studies of lymphoreticular tissues during growth of a syngeneic squamous cell carcinoma in Wistar rats show that the regional lymph node anergy reported previously in this system is associated with replacement of paracortical small lymphocytes by large blastoid cells. The regional node continued to gain weight throughout the period of anergy and showed no atrophy and minimal necrosis. Over the same period the spleen increased in both weight and cytotoxicity. Images Fig. 4 Fig. 5 PMID:1174441

  2. Hypothalamic energy metabolism is impaired by doxorubicin independently of inflammation in non-tumour-bearing rats.

    PubMed

    Antunes, Barbara M M; Lira, Fabio Santos; Pimentel, Gustavo Duarte; Rosa Neto, José Cesar; Esteves, Andrea Maculano; Oyama, Lila Missae; de Souza, Cláudio Teodoro; Gonçalves, Cinara Ludvig; Streck, Emilio Luiz; Rodrigues, Bruno; dos Santos, Ronaldo Vagner; de Mello, Marco Túlio

    2015-08-01

    We sought to explore the effects of doxorubicin on inflammatory profiles and energy metabolism in the hypothalamus of rats. To investigate these effects, we formed two groups: a control (C) group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control (C) or DOXO groups. The hypothalamus was collected. The levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α and energy metabolism (malate dehydrogenase, complex I and III activities) were analysed in the hypothalamus. The DOXO group exhibited a decreased body weight (p < 0.01). Hypothalamic malate dehydrogenase activity was reduced when compared with control (p < 0.05). In addition, pro-inflammatory cytokine levels were unchanged. Therefore, our results demonstrate that doxorubicin leads to an impairment of \\hypothalamic energy metabolism, but do not affect the inflammatory pathway. SIGNIFICANCE PARAGRAPH: The hypothalamus is a central organ that regulates a great number of functions, such as food intake, temperature and energy expenditure, among others. Doxorubicin can lead to deep anorexia and metabolic chaos; thus, we observed the effect of this chemotherapeutic drug on the inflammation and metabolism in rats after the administration of doxorubicin in order to understand the central effect in the hypothalamus. Drug treatment by doxorubicin is used as a cancer therapy; however the use of this drug may cause harmful alterations to the metabolism. Thus, further investigations are needed on the impact of drug therapy over the long term. Copyright © 2015 John Wiley & Sons, Ltd.

  3. Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats.

    PubMed

    Tillie-Leblond, I; Gosset, P; Le Berre, R; Janin, A; Prangère, T; Tonnel, A B; Guery, B P H

    2007-07-01

    Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma. KGF (1 mg x kg(-1)) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed. Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins beta-catenin and zonula occludens protein-1. In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.

  4. The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats.

    PubMed

    Sun, Yingxin; Zhang, Juan; Yan, Yongjian; Chi, Mingfeng; Chen, Wenwen; Sun, Peng; Qin, Song

    2011-09-01

    To investigate the potential protective effect of C-phycocyanin (PC) on paraquat (PQ)-induced acute lung injury, rats were divided into control, PQ-treated and PQ+PC-treated groups. Rats in PQ-treated group were orally administered with 50mg/kg PQ, and rats in PQ+PC-treated group were intraperitoneally injected with 50mg/kg PC after administration of PQ. At 8, 24, 48 and 72h after treatments, GSH-Px and SOD activities, MDA levels in plasma and BALF, HYP, NF-κB, IκB-α and TNF-α contents in lung tissues were measured. The pathological changes in lung were observed. After treatment with PC, the levels of MDA and the relative contents of NF-κB and TNF-α were significantly decreased, the activities of GSH-Px and SOD and the relative contents of IκB-α were significantly increased. The degree of rat lung damage was obviously reduced in PQ+PC-treated group. The results suggested that PC treatment significantly attenuated PQ-induced acute lung injury.

  5. Extraction and Quantification of Carbon Nanotubes in Biological Matrices with Application to Rat Lung Tissue

    PubMed Central

    Doudrick, Kyle; Corson, Nancy; Oberdörster, Günter; Elder, Alison; Herckes, Pierre; Halden, Rolf U.; Westerhoff, Paul

    2013-01-01

    Extraction of carbon nanotubes (CNTs) from biological matrices such as rat lung tissue is integral to developing a quantification method for evaluating the environmental and human health exposure and toxicity of CNTs. The ability of various chemical treatment methods, including Solvable (2.5% sodium hydroxide/surfactant mixture), ammonium hydroxide, nitric acid, sulfuric acid, hydrochloric acid, hydrofluoric acid, hydrogen peroxide, and proteinase K, to extract CNTs from rat lung tissue was evaluated. CNTs were quantified using programmed thermal analysis (PTA). Two CNTs were used to represent the lower (500°C) and upper (800°C) PTA limit of CNT thermal stability. The recovery efficiency of each of the eight chemical reagents evaluated was found to depend on the ability to (1) minimize oxidation of CNTs, (2) remove interfering background carbon from the rat lung tissue, and (3) separate the solid-phase CNTs from the liquid-phase dissolved tissue via centrifugation. A two-step extraction method using Solvable and proteinase K emerged as the optimal approach, enabling a recovery of 98 ± 15% of a 2.9 ± 0.19 µg CNT loading that was spiked into whole rat lungs. Due to its high yield and applicability to low organ burdens of nanomaterials, this extraction method is particularly well suited for in vivo studies to quantify clearance rates and retained CNTs in lungs and other organs. PMID:23992048

  6. The ultrastructure of radiation injury in rat lung: modification by D-penicillamine. [/sup 60/Co

    SciTech Connect

    Port, C.D.; Ward, W.F.

    1982-10-01

    The present study compared the ultrastructure of radiation injury in the lungs of penicillamine-treated and untreated male rats sacrificed 3, 6, 9, or 12 months after a single exposure of 25 Gy of /sup 60/Co ..gamma..-rays to the right hemithorax. All morphological components of the irradiated lungs exhibited injury typical of pneumonitis progressing to interstitial fibrosis. In addition to these well-documented responses, several less common ultrastructural changes were noted, including capillary recanalization; focal disappearance of interstitial collagen fibers, initially perivascularly, then throughout some septa; and a low-grade but significant cellular reaction in the shielded left lung. Radiation reactions in the lungs of penicillamine-treated rats were qualitatively similar to those of untreated animals, but differed in the degree of change: collagen deposition was less extensive and less highly organized into fibers, capillary recanalization and disappearance of interstitial collagen were more common, and arterial wall thickening was reduced in the drug-treated rats. Thus the beneficial effect of penicillamine on the histopathology of irradiated rat lung does not appear to be attributable to unique ultrastructural phenomena. Rather, penicillamine treatment produces a generalized inhibition of pathologic events such as collagen accumulation and arterial wall thickening, and acceleration of restorative processes such as revascularization and collagen degradation.

  7. Tumour necrosis factor-α and its receptors in the beneficial effects of vagal stimulation after myocardial infarction in rats.

    PubMed

    Kong, Shan-Shan; Liu, Jin-Jun; Hwang, Tyzh-Chang; Yu, Xiao-Jiang; Lu, Yi; Zang, Wei-Jin

    2011-05-01

    1. Acute myocardial infarction (AMI) often activates the sympathetic system and inhibits the vagal system. Long-term vagal nerve stimulation (VNS) exerts several beneficial effects on the ischaemic heart, including an anti-inflammatory effect. The aim of the present study was to investigate whether short-term VNS during AMI could inhibit tumour necrosis factor (TNF)-α expression and the effect of TNF receptor (TNFR), key components in inflammatory responses to AMI, in a rodent model. 2. Adult male Sprague-Dawley rats were divided into four groups, namely a control (C), VNS (S), AMI (M) and an AMI group subjected to prior VNS (MS). In the S and MS groups, the right vagus nerve was stimulated electrically for 4 h; in the M and MS groups, AMI was induced by occlusion of the left anterior descending coronary artery. Haemodynamic data were monitored continuously using a multichannel physiological recorder. Lactate dehydrogenase (LDH) leakage, creatine kinase (CK) leakage and infarct size were determined. The expression of TNF-α and its receptors were analysed by reverse transcription-polymerase chain reaction, western blotting and ELISA. 3. Compared with the control group, rats in the M group had low blood pressure, high left ventricular (LV) end-diastolic pressure, a depressed maximum dP/dt of LV pressure, higher LDH and CK leakage, a larger infarct size, increased TNF-α levels and an increased TNFR1/TNFR2 ratio. However, these presumably harmful effects of AMI were all significantly ameliorated by VNS during AMI (MS group). 4. In conclusion, VNS can rectify ischaemia-induced cardiac dysfunction partly via inhibition of a TNF-α-mediated signalling pathway.

  8. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    PubMed

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  9. Atelectasis Induced by Thoracotomy Causes Lung Injury during Mechanical Ventilation in Endotoxemic Rats

    PubMed Central

    Kwon, Kun Young; Kim, Jin Mo; Quinn, Deborah A.; Hales, Charles A.; Seo, Jeong Wook

    2008-01-01

    Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression. PMID:18583875

  10. Atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats.

    PubMed

    Choi, Won-Il; Kwon, Kun Young; Kim, Jin Mo; Quinn, Deborah A; Hales, Charles A; Seo, Jeong Wook

    2008-06-01

    Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.

  11. Induction of HSP70 is associated with vincristine resistance in heat-shocked 9L rat brain tumour cells.

    PubMed Central

    Lee, W. C.; Lin, K. Y.; Chen, K. D.; Lai, Y. K.

    1992-01-01

    The most prominent cellular changes in heat-shock response are induction of HSPs synthesis and reorganisation of cytoskeleton. Vincristine was used as a tool to evaluate the integrity of microtubules in 9L rat brain tumour cells recovering from heat-shock treatment. Cells treated at 45 degrees C for 15 min and recovered under normal growing condition became resistant to vincristine-inflicted cytotoxicity and microtubule destruction. Among all HSPs, the level of HSP70 and the degree of vincristine resistance are best correlated. HSP70 and tubulin were found to be associated with each other as they were co-immunoprecipitated by either anti-HSP70 or anti-beta-tubulin monoclonal antibody. The current studies establish for the first time that HSP70 can complex with tubulin in cells and this association may stabilise the organisation of microtubules thus protect the heat-treated cells from vincristine damage. These findings are noteworthy in combining hyperthermia and chemotherapy in the management of malignant diseases. Images Figure 2 Figure 3 Figure 5 Figure 6 PMID:1419602

  12. Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats.

    PubMed

    Ibrahim, Shaimaa S; Osman, Rihab; Mortada, Nahed D; Geneidy, Ahmed-Shawky; Awad, Gehanne A S

    2017-11-01

    Pulmonary bed can retain microparticles (MP) larger than their capillaries' diameter, hence we offer a promising way for lung passive targeting following intravenous (IV) administration. In this study, enoxaparin (Enox)-albumin microspheres (Enox-Alb MS) were, optimally, developed as lung targeted sustained release MP for IV use. Lung tolerability and targeting efficiency of Enox-Alb MS were tested, and the pharmacokinetic profile following IV administration to albino rats was constructed. In vivo studies confirmed high lung targeting efficiency of Enox-Alb MS with lack of potential tissue toxicity. The anticoagulant activity of the selected Alb MS was significantly sustained for up to 38 h compared to 5 h for the market product. Alb MS are promising delivery carriers for controlled and targeted delivery of Enox to the lungs for prophylaxis and treatment of pulmonary embolism.

  13. Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats.

    PubMed

    Bakkal, B H; Gultekin, F A; Guven, B; Turkcu, U O; Bektas, S; Can, M

    2013-09-01

    Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

  14. Abnormal Sonic hedgehog signaling in the lung of rats with esophageal atresia induced by adriamycin.

    PubMed

    Fragoso, Ana Catarina; Martinez, Leopoldo; Estevão-Costa, José; Tovar, Juan A

    2014-10-01

    Abnormal lung development was recently described in the rat model of esophageal atresia and tracheoesophageal fistula (EA-TEF). Since in this condition the ventral-to-dorsal switch of Shh expression in the foregut is disturbed, the present study tested the hypothesis that this abnormal expression at the emergence of the tracheobronchial bud might be translated into the developing lung. Pregnant rats received either 1.75 mg/kg i.p. adriamycin or vehicle from E7 to E9. Three groups were studied: control and adriamycin-exposed with and without EA-TEF. Embryos were recovered and the lungs were harvested and processed for reverse transcription polymerase chain reaction and immunofluorescence analysis of the Shh signaling cascade. Shh signaling was downregulated at the late embryonic stage of lung development (E13) in embryos with EA-TEF. Throughout the subsequent stages of development, the expression of both Shh and its downstream components increased significantly and remained upregulated throughout gestation. Immunofluorescent localization was consistent with these findings. Defective Shh signaling environment in the foregut is present beyond the emergence of lung buds and probably impairs lung development. Later in gestation, lungs exhibited a remarkable ability to upregulate the Shh cascade, suggesting a compensatory response. These findings may be relevant to understand pulmonary disease suffered by children with EA-TEF.

  15. Supplementary catechins attenuate cooking-oil-fumes-induced oxidative stress in rat lung.

    PubMed

    Yang, Chao-Huei; Lin, Chun-Yao; Yang, Joan-Hwa; Liou, Shaw-Yih; Li, Ping-Chia; Chien, Chiang-Ting

    2009-06-30

    Cooking-oil-fumes containing toxic components may induce reactive oxygen species (ROS) to oxidize macromolecules and lead to acute lung injury. Our previous study showed that a decaffineated green tea extract containing (+)-catechin, (-)-epicatechin, (+)-gallocatechin, (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epigallocatechin gallate can inhibit oxidation, inflammation, and apoptosis. We determined whether the catechins supplement may reduce cooking-oil-fumes-induced acute lung injury in rat. In the urethane-anesthetized Wistar rat subjected to 30-120 min of cooking-oil-fumes exposure, blood ROS significantly increased in the recovery stage. After 30-min cooking-oil-fumes exposure, the enhanced blood ROS level further increased in a time-dependent manner during the recovery stage (321 +/- 69 counts/10 s after 1 h, 540 +/- 89 counts/10 s after 2 h, and 873 +/- 112 counts/10 s after 4 h). Four hours after 30-min cooking-oil-fumes exposure, lung lavage neutrophils and ROS as well as lung tissue dityrosine and 4-hydroxy-2-nonenal increased significantly. Two weeks of catechins supplememnt significantly reduced the enhanced lavage ROS, lung dityrosine and 4-hydroxy-2-nonenal level. Cooking-oil-fumes-induced oxidative stress decreased lung Bcl-2/Bax ratio and HSP70 expression, but catechins treatment preserved the downregulation of Bcl-2/Bax ratio and HSP70 expression. We conclude that catechins supplement attenuates cooking-oil-fumes-induced acute lung injury via the preservation of oil-smoke induced downregulation of antioxidant, antiapoptosis, and chaperone protein expression.

  16. Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats.

    PubMed

    Tsujiuchi, Toshifumi; Nakae, Dai; Konishi, Yoichi

    2014-03-01

    N-Nitrosobis(2-hydroxypropyl)amine (BHP) was first synthesized by Krüger et al. (1974), and has been shown to primarily induce pancreatic duct adenocarcinomas by a subcutaneous injection in Syrian hamsters. By contrast, the carcinogenic effect of BHP has been indicated at the different target organs in rats, namely the lung. When rats are received by an oral administration of BHP in drinking water for 25 weeks, a high incidence of lung carcinomas are induced, which include adenocarcinomas, squamous cell carcinomas and combined squamous cell and adenocarcinomas. So many similarities are observed in terms of not only histological appearances but also gene alterations between human and BHP-induced rat lung cancers. Moreover, the step by step development of lung lesions, from preneoplastic lesions to cancers in rat lung carcinogenesis by BHP offers a good model to investigate the mechanisms underlying the pathogenesis of lung cancers. Because data for genetic and epigenetic alterations have indeed been accumulated during the BHP-induced rat lung carcinogenesis, we will introduce them in this review and hence demonstrate that this lung carcinogenesis model provides a useful opportunity for the research on the pathogenesis of lung cancers of both humans and rats.

  17. Leukemia Inhibitory Factor in Rat Fetal Lung Development: Expression and Functional Studies

    PubMed Central

    Nogueira-Silva, Cristina; Piairo, Paulina; Carvalho-Dias, Emanuel; Peixoto, Francisca O.; Moura, Rute S.; Correia-Pinto, Jorge

    2012-01-01

    Background Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are members of the family of the glycoprotein 130 (gp130)-type cytokines. These cytokines share gp130 as a common signal transducer, which explains why they show some functional redundancy. Recently, it was demonstrated that IL-6 promotes fetal lung branching. Additionally, LIF has been implicated in developmental processes of some branching organs. Thus, in this study LIF expression pattern and its effects on fetal rat lung morphogenesis were assessed. Methodology/Principal Findings LIF and its subunit receptor LIFRα expression levels were evaluated by immunohistochemistry and western blot in fetal rat lungs of different gestational ages, ranging from 13.5 to 21.5 days post-conception. Throughout all gestational ages studied, LIF was constitutively expressed in pulmonary epithelium, whereas LIFRα was first mainly expressed in the mesenchyme, but after pseudoglandular stage it was also observed in epithelial cells. These results point to a LIF epithelium-mesenchyme cross-talk, which is known to be important for lung branching process. Regarding functional studies, fetal lung explants were cultured with increasing doses of LIF or LIF neutralizing antibodies during 4 days. MAPK, AKT, and STAT3 phosphorylation in the treated lung explants was analyzed. LIF supplementation significantly inhibited lung growth in spite of an increase in p44/42 phosphorylation. On the other hand, LIF inhibition significantly stimulated lung growth via p38 and Akt pathways. Conclusions/Significance The present study describes that LIF and its subunit receptor LIFRα are constitutively expressed during fetal lung development and that they have an inhibitory physiological role on fetal lung branching. PMID:22291973

  18. Inverse relationship of tumors and mononuclear cell leukemia infiltration in the lungs of F344 rats

    SciTech Connect

    Lundgren, D.L.; Griffith, W.C.; Hahn, F.F.

    1995-12-01

    In 1970 and F344 rat, along with the B6C3F{sub 1} mouse, were selected as the standard rodents for the National Cancer Institute Carcinogenic Bioassay program for studies of potentially carcinogenic chemicals. The F344 rat has also been used in a variety of other carcinogenesis studies, including numerous studies at ITRI. A major concern to be considered in evaluating carcinogenic bioassay studies using the F344 rat is the relatively high background incidence of mononuclear cell leukemia (MCL) (also referred to as large granular lymphocytic leukemia, Fischer rat leukemia, or monocytic leukemia). Incidences of MCL ranging from 10 to 72% in male F344 rats to 6 to 31% in female F344 rats have been reported. Gaining the understanding of the mechanisms involved in the negative correlations noted should enhance our understanding of the mechanisms involved in the development of lung cancer.

  19. Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues.

    PubMed Central

    Vago, T.; Bevilacqua, M.; Conci, F.; Baldi, G.; Ongini, E.; Chebat, E.; Monopoli, A.; Norbiato, G.

    1992-01-01

    1. Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase which catalyzes the final activation step in the formation of angiotensin II, was identified by radioligand studies in rat heart and lung. In this work we identified ACE binding sites in human left ventricle and lung by radioligand binding using the ACE inhibitor [3H]-ramiprilat in all tissues tested was saturable, temperature and zinc-dependent, and inhibited by EDTA. In human left ventricle homogenate we found a density of binding sites of 121 +/- 15 fmol mg-1 protein (n = 4) with an affinity (Kd) of 850 +/- 55 pM, whereas in rat left ventricle the same values were 23 +/- 4 fmol mg-1 protein and 315 +/- 30 pM, (n = 4), respectively. 3. [3H]-ramiprilat binding to rat (n = 4) and human lung (n = 4) showed a binding site density of 2132 +/- 155 and 1085 +/- 51 fmol mg-1 protein respectively with an affinity of 639 +/- 54 and 325 +/- 22 pM. The lung:heart ratio of ACE binding site density was about 9:1 in man and 100:1 in rat. 4. The binding affinities of 13 ACE inhibitors were evaluated on human heart and lung: the drugs tested showed a wide range of affinities for the ACE binding sites in both tissues, and the affinity for lung was significantly greater than for heart for most of the drugs. 5. The greater potency of some ACE inhibitors in displacing [3H]-ramiprilat in human lung compared with the heart indicates differences between ACE binding sites in these tissues and suggests the possibility of a selective organ-targeted therapeutic approach. PMID:1335341

  20. Tumor necrosis factor-alpha in ischemia and reperfusion injury in rat lungs.

    PubMed

    Khimenko, P L; Bagby, G J; Fuseler, J; Taylor, A E

    1998-12-01

    The effects of both recombinant rat tumor necrosis factor-alpha (TNF-alpha) and an anti-TNF-alpha antibody were studied in isolated buffer-perfused rat lungs subjected to either 45 min of nonventilated [ischemia-reperfusion (I/R)] or air-ventilated (V/R) ischemia followed by 90 min of reperfusion and ventilation. In the I/R group, the vascular permeability, as measured by the filtration coefficient (Kfc), increased three- and fivefold above baseline after 30 and 90 min of reperfusion, respectively (P < 0.001). Over the same time intervals, the Kfc for the V/R group increased five- and tenfold above baseline values, respectively (P < 0.001). TNF-alpha measured in the perfusates of both ischemic models significantly increased after 30 min of reperfusion. Recombinant rat TNF-alpha (50,000 U), placed into perfusate after baseline measurements, produced no measurable change in microvascular permeability in control lungs perfused over the same time period (135 min), but I/R injury was significantly enhanced in the presence of TNF-alpha. An anti-TNF-alpha antibody (10 mg/rat) injected intraperitoneally into rats 2 h before the lung was isolated prevented the microvascular damage in lungs exposed to both I/R and V/R (P < 0.001). These results indicate that TNF-alpha is an essential component at the cascade of events that cause lung endothelial injury in short-term I/R and V/R models of lung ischemia.

  1. Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects

    PubMed Central

    Song, Ruiping; Kubo, Masatoshi; Morse, Danielle; Zhou, Zhihong; Zhang, Xuchen; Dauber, James H.; Fabisiak, James; Alber, Sean M.; Watkins, Simon C.; Zuckerbraun, Brian S.; Otterbein, Leo E.; Ning, Wen; Oury, Tim D.; Lee, Patty J.; McCurry, Kenneth R.; Choi, Augustine M.K.

    2003-01-01

    Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1α and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation. PMID:12819027

  2. Effects of food restriction and hyperoxia on rat survival and lung polyamine metabolism.

    PubMed

    Elsayed, N M; Tierney, D F; Hacker, A D

    1988-05-01

    We fed Sprague-Dawley rats either freely or by restricting them to 20% of their usual diet for 21 days. In one experiment, we refed half of the food-restricted rats for 12 h, then exposed the three groups to air or 85% O2 for 5 days. The mortalities in 85% O2 were 100, 33, and 0% for the food-restricted, restricted-refed, and freely fed groups, respectively. In air lung polyamine contents and glucose 6-phosphate dehydrogenase and NADP-dependent isocitrate dehydrogenase activities were significantly lower with food restriction. After hyperoxia, lung polyamine and protein contents and enzyme activities were increased in the two surviving groups, but spermine and DNA contents of refed rats did not increase. In a second experiment, we exposed rats to 60% O2 and found that DNA synthesis of food-restricted rats was lower than the freely fed rats in air and remained low after hyperoxia. We conclude that food restriction increases the mortality from 85% O2 and is associated with lower DNA synthesis and polyamine content. We speculate that food-restricted animals may accumulate greater lung injury partly because of a compromised repair process.

  3. Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha.

    PubMed

    Jawaid, Talha; Shakya, Ashok K; Siddiqui, Hefazat Hussain; Kamal, Mehnaz

    2014-01-01

    Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.

  4. Two-layer method (UW solution/perfluorochemical plus O2) for lung preservation in rat lung transplantation.

    PubMed

    Liu, C-C; Hsu, P-K; Huang, W-C; Huang, M-H; Hsu, H-S

    2007-12-01

    A new preservation method using perfluorochemicals (PFC) with oxygen administered continuously was developed for lung preservation and compared with traditional cold preservation methods for rat lung transplantation. Male Sprague-Dawley rats underwent orthotopic left lung transplantations of grafts preserved in lactiated Ringers solution (LR), University of Wisconsin solution (UW), Celsior solution, or a two-layer (PFC plus O2) solution for 6 hours. One hour after reperfusion, the right pulmonary artery and bronchus were clamped and 5 minutes later we recorded peak airway pressure and PaO2 level. The isograft was excised for measurement of myeloperoxidase activity, wet-to-dry ratio, and histologic examination to evaluate isograft function. The mean peak airway pressure was 29.80+/-6.72 mm H2O in the LR group, 28.80+/-5.76 mm H2O in the UW group, 33.60+/-5.17 mm H2O in the Celsior group, and 32.40+/-2.60 in the two-layer group. The mean PaO2 level was 99.78+/-76.09 mm Hg in the LR group, 87.84+/-33.58 mm Hg in the UW group, 104.50+/-72.93 mm Hg in the Celsior group, and 62.08+/-31.34 mm Hg in PFC and UW solution plus O2 group (two layers). The mean net myeloperoxidase activity OD level was 0.110+/-0.104 in the LR group, 0.392+/-0.328 in the UW group, 0.351+/-0.620 in the Celsior group, and 0.532+/-0.616 in the two-layer group. The mean wet-to-dry ratio was 7.47+/-1.60 in the LR group, 6.56+/-0.62 in the UW group, 7.54+/-2.19 in the Celsior group, and 5.32+/-2.20 in the two-layer group. The differences between groups in these parameters were not significant. Upon histologic examination, more inflammatory cell aggregates were seen in the two-layer group, less in the LR and the Celsior groups. The function of the lung graft after 6 hours of storage was not better using this two-layer method for preservation than traditional preservation methods in rat lung transplantation. Histologic examination revealed more inflammatory cell aggregates in the lung graft preserved

  5. Ultrahigh resolution optical coherence tomography imaging of diseased rat lung using Gaussian shaped super continuum sources

    NASA Astrophysics Data System (ADS)

    Nishizawa, N.; Ishida, S.; Kitatsuji, M.; Ohshima, H.; Hasegawa, Y.; Matsushima, M.; Kawabe, T.

    2012-02-01

    We have been investigating ultrahigh resolution optical coherence tomography (UHR-OCT) imaging of lung tissues using fiber super continuum sources. The high power, low-noise, Gaussian shaped supercontinuum generated with ultrashort pulses and optical fibers at several wavelengths were used as the broadband light sources for UHR-OCT. For the 800 nm wavelength region, the axial resolution was 3.0 um in air and 2.0 um in tissue. Since the lung consists of tiny alveoli which are separated by thin wall, the UHR-OCT is supposed to be effective for lung imaging. The clear images of alveoli of rat were observed with and without index matching effects by saline. In this work, we investigated the UHR-OCT imaging of lung disease model. The lipopolysaccharide (LPS) induced acute lung injury / acute respiratory distress syndrome (ALI/ARDS) model of rat was prepared as the sample with disease and the UHR-OCT imaging of the disease part was demonstrated. The increment of signal intensity by pleural thickening was observed. The accumulation of exudative fluid in alveoli was also observed for two samples. By the comparison with normal lung images, we can obviously show the difference in the ALI/ARDS models. Since the lung consists of alveolar surrounded by capillary vessels, the effect of red-blood cells (RBC) is considered to be important. In this work, ex-vivo UHR-OCT imaging of RBC was demonstrated. Each RBC was able to be observed individually using UHR-OCT. The effect of RBC was estimated with the rat lung perfused with PBS.

  6. [Protective effect of melatonin in rats with phosgene-induced lung injury].

    PubMed

    Zhang, Lin; Shen, Jie; Gan, Zheng-yi; He, Dai-kun; Zhong, Zhi-yue

    2012-11-01

    To investigate the antioxidant effect of melatonin (MT) in the rats with phosgene-induced lung injury and its possible mechanism. Fifty male SD rats were equally randomized into phosgene exposure group, air control group, MT treatment group, dexamethasone (DX) treatment group, and negative control group. All groups except the air control group were exposed to 8.33 mg/L phosgene for 5 min, and the MT treatment group, DX treatment group, and negative control group were injected with MT (10 mg/kg), DX (2.5 mg/kg), and 1% ethanol saline (1 ml/kg), respectively, via the caudal vein 1 hour after exposure. The rats were sacrificed 6h later. Then, the wet/dry ratio of the lung, the total protein content and neutrophil count in bronchoalveolar lavage fluid (BALF), and the malonaldehyde (MDA) content and superoxide dismutase (SOD) and myeloperoxidase (MPO) activities in lung homogenate were measured; pathological observation was made on the lung tissue under an optical microscope; the protein expression of inducible nitric oxide synthase (iNOS) and NF-κB in the lung tissue was measured by Western blot. Compared with the air control group, the phosgene exposure group showed significantly increased wet/dry ratio of the lung and total protein content and neutrophil count in BALF (P < 0.01) as well as significantly increased MDA content and MPO activity in the lung tissue (P < 0.05). Compared with the phosgene exposure group, the MT treatment group showed significantly decreased MDA content and MPO activity and significantly increased SOD activity (P < 0.01), and the MT treatment group and DX treatment group showed significantly decreased protein expression of iNOS and NF-κB (P < 0.01). MT has protective effect in phosgene-induced lung injury, and its protective mechanism may be associated with scavenging free radicals and inhibiting expression of iNOS and NF-κB.

  7. Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone.

    PubMed

    Bernhard, Wolfgang; Gesche, Jens; Raith, Marco; Poets, Christian F

    2016-05-15

    Surfactant, synthesized by type II pneumocytes (PN-II), mainly comprises phosphatidylcholine (PC) and is essential to prevent neonatal respiratory distress. Furthermore, PC is essential to lung tissue growth and maintenance as a membrane component. Recent findings suggest that the lung contributes to systemic lipid homeostasis via PC export through ABC-A1 transporter expression. Hence it is important to consider pharmacological interventions in neonatal lung PC metabolism with respect to such export. Five-day-old rats were treated with carrier (control), intraperitoneal betamethasone, subcutaneous recombinant human keratinocyte growth factor (rhuKGF), or their combination for 48 h. Animals were intraperitoneally injected with 50 mg/kg [D9-methyl]choline chloride 1.5, 3.0, and 6.0 h before death at day 7, and lung lavage fluid (LLF) and tissue were harvested. Endogenous PC, D9-labeled PC species, and their water-soluble precursors (D9-)choline and (D9-)phosphocholine were determined by tandem mass spectrometry. Treatment increased secreted and tissue PC pools but did not change equilibrium composition of PC species in LLF. However, all treatments increased specific surfactant components in tissue. In control rats, peak D9-PC in lavaged lung was reached after 3 h and was decreased at 6 h. Only 13% of this net loss in lavaged lung was found in LLF. Such decrease was not present in lungs treated with betamethasone and/or with rhuKGF. D9-PC loss at 3-6 h and PC synthesis calculated from D9 enrichment of phosphocholine indicated that daily synthesis rate is higher than total pool size. We conclude that lung tissue contributes to systemic PC homeostasis in neonatal rats, which is altered by glucocorticoid and rhuKGF treatment.

  8. Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

    SciTech Connect

    Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir; Richardson, Jason R.; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2014-08-15

    The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage.

  9. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    PubMed Central

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  10. N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro.

    PubMed

    Liao, Zhengchang; Zhou, Xiaocheng; Luo, Ziqiang; Huo, Huiyi; Wang, Mingjie; Yu, Xiaohe; Cao, Chuanding; Ding, Ying; Xiong, Zeng; Yue, Shaojie

    2016-01-01

    Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR's expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801's influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA's direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development.

  11. N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro

    PubMed Central

    Liao, Zhengchang; Zhou, Xiaocheng; Luo, Ziqiang; Huo, Huiyi; Wang, Mingjie; Yu, Xiaohe; Cao, Chuanding; Ding, Ying; Xiong, Zeng

    2016-01-01

    Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR's expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801's influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA's direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development. PMID:27478831

  12. Active Oxygen Metabolites and Thromboxane in Phorbol Myristate Acetate Toxicity to the Isolated, Perfused Rat Lung.

    NASA Astrophysics Data System (ADS)

    Carpenter, Laurie Jean

    When administered intravenously or intratracheally to rats, rabbits and sheep, phorbol myristate acetate (PMA) produces changes in lung morphology and function are similar to those seen in humans with the adult respiratory distress syndrome (ARDS). Therefore, it is thought that information about the mechanism of ARDS development can be gained from experiments using PMA-treated animals. Currently, the mechanisms by which PMA causes pneumotoxicity are unknown. Results from other studies in rabbits and in isolated, perfused rabbit lungs suggest that PMA-induced lung injury is mediated by active oxygen species from neutrophils (PMN), whereas studies in sheep and rats suggest that PMN are not required for the toxic response. The role of PMN, active oxygen metabolites and thromboxane (TxA_2) in PMA-induced injury to isolated, perfused rat lungs (IPLs) was examined in this thesis. To determine whether PMN were required for PMA to produce toxicity to the IPL, lungs were perfused for 30 min with buffer containing various concentrations of PMA (in the presence or absence of PMN). When concentrations >=q57 ng/ml were added to medium devoid of added PMN, perfusion pressure and lung weight increased. When a concentration of PMA (14-28 ng/ml) that did not by itself cause lungs to accumulate fluid was added to the perfusion medium containing PMN (1 x 10 ^8), perfusion pressure increased, and lungs accumulated fluid. These results indicate that high concentrations of PMA produce lung injury which is independent of PMN, whereas injury induced by lower concentrations is PMN-dependent. To examine whether active oxygen species were involved in mediating lung injury induced by PMA and PMN, lungs were coperfused with the oxygen radical scavengers SOD and/or catalase. Coperfusion with either or both of these enzymes totally protected lungs against injury caused by PMN and PMA. These results suggest that active oxygen species (the hydroxyl radical in particular), mediate lung injury in

  13. The multiple forms and kinetic properties of the N-acetyl-beta-D-hexosaminidases from colonic tumours and mucosa of rats treated with 1,2-dimethylhydrazine.

    PubMed Central

    Mian, N; Herries, D G; Cowen, D M; Batte, E A

    1979-01-01

    The separation and purification of the N-acetyl-beta-D-hexosaminidase activities from tumours induced by 1,2-dimethylhydrazine in the rat colon and from colonic mucosa of tumour-bearing animals are reported. Mucosa contained N-acetylhexosaminidases A and B, as well as a third form whose properties with regard to electrophoretic mobility and thermostability lay between those of A and B. Tumours contained only N-acetylhexosaminidase A and B activities. Each form possessed both N-acetylglucosaminidase (EC 3.2.1.30) and N-acetylgalactosaminidase (EC 3.2.1.53) activities, which could not be separated by a variety of techniques. The alteration of the ratio of the two specific activities in each form during purification, together with differences in the kinetic inhibition constants and behaviour during inactivation by various reagents or a temperature of 50 degrees C, supported the belief that each form contains the two enzyme activities, glucosaminidase and galactosaminidase, at separate active sites. This model is in contrast with that reported for these activities from a number of other sources. A variety of treatments reported to cause the conversion of form A into a form resembling B failed to produce such an effect on the rat colonic hexosaminidases. PMID:34391

  14. Developmental expression of heme oxygenase in the rat lung.

    PubMed

    Dennery, Phyllis A; Lee, Christen S; Ford, Berendera S; Weng, Yi-Hao; Yang, Guang; Rodgers, Pamela A

    2003-01-01

    Heme oxygenase (HO), the rate-limiting enzyme in the formation of bilirubin, is expressed in the lung and may serve as an antioxidant. This enzyme results in the formation of antioxidant bile pigments and the degradation of pro-oxidant heme. We wanted to evaluate the differences in expression of HO-1, the inducible form, and HO-2, the constitutive isoenzyme, during lung maturation and document whether lung HO expression was similar to that of other antioxidant enzymes. Lung total HO activity and HO-1 and HO-2 proteins as well as HO-1 and HO-2 mRNA were evaluated in animals from 16 d of gestation (e(16.5)) to 2 mo of age. Heme content was also evaluated because heme is the substrate of the reaction. HO-1 mRNA was maximal at e(19.5) and e(20.5), whereas HO-2 mRNA was not changed throughout maturation. Lung HO-1 protein was highest on the first days of life and lowest in adults, whereas HO-2 protein was maximally expressed at postnatal d 5 and then declined to reach adult values. As to HO activity, there was a prenatal peak at e(20.5), a second lesser peak at d 5, and thereafter a decline to adult values. Lung heme content was inversely correlated with HO activity or protein as the highest heme values were seen in adults with the lowest HO activity. In response to hyperoxia, HO-1 mRNA was induced only in the adult lungs. A better understanding of the maturational regulation of lung HO will define a role for HO in newborns at risk for oxygen toxicity.

  15. Neonatal developmental pattern of superoxide dismutase and aniline hydroxylase in rat lung

    SciTech Connect

    Kakkar, P.; Jaffery, F.N.; Viswanathan, P.N.

    1986-10-01

    The developmental biology of superoxide dismutase and aniline hydroxylase was followed in rat lungs from prenatal stage to 3 months old. Total superoxide dismutase activity as determined by spectrophotometry as well as electrophoresis was high in the prenatal rat lung, decreased in the first 24 hr postpartum, increased within 7 days, and then decreased gradually to adult levels. On polyacrylamide gel electrophoresis only two isozymic forms of superoxide dismutase were located as achromatic zones in the fetal lung. In the adult rat lung, there were three molecular forms of superoxide dismutase, two in the postmitochondrial supernatant and one in the mitochondrial fraction. Unlike superoxide dismutase, aniline hydroxylase was detectable only after 5 days of age and the activity exhibited a gradual increase afterward up to 1 month of age. The developmental pattern of superoxide dismutase and aniline hydroxylase activities in lung may be significant in understanding the mechanism of body defenses and their regulatory modulations in response to toxic air pollutants and environmental stress.

  16. Inhibition of acid-induced lung injury by hyperosmolar sucrose in rats.

    PubMed

    Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

    2005-10-15

    Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration.

  17. Dynamic ventilation 3He MRI for the quantification of disease in the rat lung.

    PubMed

    Kyriazis, Angelos; Rodriguez, I; Nin, N; Izquierdo-Garcia, J L; Lorente, J A; Perez-Sanchez, J M; Pesic, J; Olsson, L E; Ruiz-Cabello, J

    2012-03-01

    Pulmonary diseases are known to be largely inhomogeneous. To evaluate such inhomogeneities, we are testing an image-based method to measure gas flow in the lung regionally. Dynamic, spin-density-weighted hyperpolarized (3)He MR images performed during slow inhalation of this gas were analyzed to quantify regional inflation rate. This parameter was measured in regions of interest (ROIs) that were defined by a rectangular grid that covered the entire rat lung and grew dynamically with it during its inflation. We used regional inflation rate to quantify elastase-induced emphysema and to differentiate healthy (n = 8) from elastase-treated (n = 9) rat lungs as well as healthy from elastase-treated areas of one rat unilaterally treated with elastase in the left lung. Emphysema was also assessed by gold standard morphological and well-established hyperpolarized (3)He MRI diffusion measurements. Mean values of regional inflation rates were significantly different for healthy and elastase-treated animals and correlated well with the apparent diffusion coefficient of (3)He and morphological measurements. The image-based biomarker inflation rate may be useful for the assessment of regional lung ventilation.

  18. A role for platelet-derived growth factor-BB in rat postpneumonectomy compensatory lung growth.

    PubMed

    Yuan, Shizeng; Hannam, Vicky; Belcastro, Rosetta; Cartel, Nicholas; Cabacungan, Judy; Wang, Jinxia; Diambomba, Yenge; Johnstone, Leslie; Post, Martin; Tanswell, A Keith

    2002-07-01

    Unilateral pneumonectomy leads to compensatory growth in the residual lung, the mediators of which are largely unknown. We hypothesized, based on its other known roles in lung cell growth, that platelet-derived growth factor (PDGF)-BB would be an essential mediator of postpneumonectomy compensatory lung growth. Left-sided pneumonectomies were performed on 21-d-old rats, for comparison with sham-operated or unoperated control animals. Body weights were not different between groups. Right lung weights and DNA content were significantly increased (p < 0.05), compared with controls, by 10 d after pneumonectomy. The rate of DNA synthesis was maximal on d 5 postpneumonectomy. Total right lung PDGF-B mRNA and PDGF-BB protein increased after pneumonectomy, but were apparently tightly regulated, relative to total right lung beta-actin mRNA and protein content, respectively. However, PDGF-BB expression after pneumonectomy was apparently not purely constitutive, in that daily i.p. injections of a truncated soluble PDGF beta-receptor both reduced activation of the native PDGF beta-receptor, and attenuated increased lung DNA synthesis on d 3 after pneumonectomy. These findings are consistent with a critical role for PDGF-BB in postpneumonectomy lung growth.

  19. Grape seed and skin extract protects against bleomycin-induced oxidative stress in rat lung.

    PubMed

    Khazri, Olfa; Charradi, Kamel; Limam, Ferid; El May, Michelle Veronique; Aouani, Ezzedine

    2016-07-01

    Lung fibrosis is a common side effect of the chemotherapeutic agent bleomycin and current evidence suggests that reactive oxygen species play a key role in the development of lung injury. We examined whether grape seed and skin extract (GSSE), a polyphenolic mixture exhibiting antioxidant properties, is able to protect against bleomycin-induced lung oxidative stress and injury. Rats were pre-treated during three weeks either with vehicle (ethanol 10% control) or GSSE (4g/kg), then administered with a single high dose bleomycin (15mg/kg) at the 7th day. Bleomycin increased lung lipoperoxidation, carbonylation and decreased antioxidant enzyme activities as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Bleomycin also induced copper depletion from the lung and iron accumulation within the lung, but had no effect on either zinc nor manganese. Correlatively bleomycin decreased the copper associated enzyme tyrosinase, increased the zinc dependent lactate dehydrogenase (LDH) and did not affect the manganese dependent glutamine synthetase. GSSE efficiently counteracted almost all bleomycin-induced oxidative stress, biochemical and morphological changes of lung tissue. Data suggest that GSSE exerts potent antioxidant properties that could find potential application in the protection against bleomycin-induced lung fibrosis. Copyright © 2016. Published by Elsevier Masson SAS.

  20. A Peptide to Reduce Pulmonary Edema in a Rat Model of Lung Transplantation

    PubMed Central

    Finsterwalder, Richard; Friedl, Heinz P.; Rauscher, Sabine; Gröger, Marion; Kocher, Alfred; Wagner, Christine; Wagner, Stephan N.; Fischer, Gottfried; Schultz, Marcus J.; Wiedemann, Dominik; Petzelbauer, Peter

    2015-01-01

    Background Despite significant advances in organ preservation, surgical techniques and perioperative care, primary graft dysfunction is a serious medical problem in transplantation medicine in general and a specific problem in patients undergoing lung transplantation. As a result, patients develop lung edema, causing reduced tissue oxygenation capacity, reduced lung compliance and increased requirements for mechanical ventilatory support. Yet, there is no effective strategy available to protect the grafted organ from stress reactions induced by ischemia/reperfusion and by the surgical procedure itself. Methods We assessed the effect of a cingulin-derived peptide, XIB13 or a random peptide in an established rat model of allogeneic lung transplantation. Donor lungs and recipients received therapeutic peptide at the time of transplantation and outcome was analyzed 100min and 28 days post grafting. Results XIB13 improved blood oxygenation and reduced vascular leak 100min post grafting. Even after 28 days, lung edema was significantly reduced by XIB13 and lungs had reduced fibrotic or necrotic zones. Moreover, the induction of an allogeneic T cell response was delayed indicating a reduced antigen exchange between the donor and the host. Conclusions In summary, we provide a new tool to strengthen endothelial barrier function thereby improving outcomes in lung transplantation. PMID:26536466

  1. Polymorphonuclear leukocytes are activated during atelectasis before lung reexpansion in rat.

    PubMed

    Minamiya, Yoshihiro; Saito, Hajime; Takahashi, Naoko; Kawai, Hideki; Ito, Manabu; Hosono, Yukiko; Motoyama, Satoru; Ogawa, Jun-ichi

    2008-07-01

    Although reexpansion of a collapsed lung often causes pulmonary edema, the pathogenesis of the condition is not yet fully understood. To determine whether inflammatory changes occur in the pulmonary circulation during atelectasis and study the mechanism underlying the development of reexpansion pulmonary edema, we used a rat model in which the left lung was collapsed by bronchial occlusion for 1 h and then reexpanded and ventilated for an additional 1 h. We evaluated the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and the production of reactive oxygen species (ROS) in the pulmonary circulation using a fluorescent imaging technique. We also used confocal laser scanning microscopy and computerized image analysis to evaluate the membrane translocation of p47-phox, one of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase subunits, in PMNs sequestered in the lung. Polymorphonuclear leukocytes accumulated in the lung during atelectasis, and p47-phox was translocated to the plasma membrane, but no ROS production was observed. Marked PMN ROS production was observed after reexpansion of the collapsed lung with air. Little ROS production was observed when the lung was reexpanded with nitrogen. During atelectasis, PMNs accumulate in the lung, where they are primed for respiratory bursting. After pulmonary reexpansion, oxygen is supplied from the alveoli, and PMN respiratory bursting occurs.

  2. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    PubMed Central

    Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung. PMID:28127418

  3. TYLOXAPOL CONFERS DURABLE PROTECTION AGAINST HYPEROXIC LUNG INJURY IN THE RAT

    EPA Science Inventory

    We tested the hypothesis that the non-lipid components of ExosurfR, tyloxapol (TY) and cetyl alcohol (CA), protect against hyperoxic lung injury by either 1) direct radical scavenging activity or 2) induction of the animals? endogenous anti-oxidant defenses. Adult rats were in...

  4. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats

    USGS Publications Warehouse

    Kim, K.S.; Suh, G.J.; Kwon, W.Y.; Kwak, Y.H.; Lee, Kenneth; Lee, H.J.; Jeong, K.Y.; Lee, M.W.

    2012-01-01

    CONTEXT: Paraquat (PQ) causes lethal intoxication by inducing oxidant injury to the lung. Selenium is a cofactor for glutathione peroxidase (GPx), which is one of the major endogenous antioxidant enzymes. OBJECTIVE: To determine whether selenium post-treatment activates GPx, decreases lung injury, and improves survival in PQ intoxicated rats. MATERIALS AND METHODS: Male Spraque-Dawley rats were categorized into three groups: sham (n = 6), PQ (n = 12), and PQ + Se (n = 12). In the PQ and PQ + Se groups, 50 mg/kg of PQ was administered intraperitoneally. After 10 minutes, 60 μg/kg of Se (PQ + Se) or saline (PQ) was administered via the tail vein. Six rats per group were euthanized 6 hours or 24 hours later. Lung tissues were harvested for the measurement of GPx activity, reduced glutathione (GSH), glutathione disulfide (GSSG) and malondialdehyde (MDA) and for histological analysis. Using separated set of rats, survival of PQ (n = 10) and PQ + Se (n = 10) were observed for 72 hours. RESULTS: GPx activity in the PQ group at the 6-hour and 24-hour time points was lower than in the sham group (p CONCLUSION: Single dose of selenium post-treatment activates GPx and attenuates lipid peroxidation and lung injury early after paraquat intoxication, but does not improve 72 hours of survival.

  5. Ambroxol reduces LPS toxicity mediated by induction of alkaline phosphatases in rat lung.

    PubMed

    Koyama, Iwao; Matsunaga, Toshiyuki; Harada, Tsuyoshi; Kikuno, Akira; Hokari, Shigeru; Komoda, Tsugikazu

    2004-08-01

    Alkaline phosphatases (APs) have been suggested to detoxify lipopolysaccharide (LPS) by dephosphorylation. Ambroxol, a bronchial expectorant, is known to accelerate the secretion of pulmonary surfactant particles including AP molecules as a pharmacological action. In the present study, some beneficial effects of ambroxol on LPS toxicity in the rat lung were investigated. In an experiment using the rat lung organ culture, AP activities were enhanced in a time-dependent manner by incubation with 25 microM of ambroxol in both the tissue and the medium. Western blot analysis indicated that AP activity was elevated by the treatment with ambroxol, due to the induction of surfactant proteins (SPs) and AP molecules. In the in vivo experiment, the serum LPS content was markedly increased after LPS administration to rats by intratracheal instillation of 20 mg/kg. However, when the rats were pretreated with oral ambroxol (1.0 mg/kg) at 1 h before LPS challenge, the area under the concentration--time curve (AUC) of serum LPS was significantly decreased. These results suggest that ambroxol inhibits the translocation of LPS from the lung into the circulation as well as its detoxification effect via the elevation of AP activity. Bromhexine, another expectorant, is less effective than ambroxol as an LPS detoxificant. Maintenance of high AP activity level in the lung suggests APs to have physiological significant