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Sample records for rat lung tumours

  1. Evaluation of tumour vascularisation in two rat sarcoma models for studying isolated lung perfusion. Injection route determines the origin of tumour vessels.

    PubMed

    Pan, Youmin; Krueger, T; Tran, Nam; Yan, Hua; Ris, H-B; McKee, T A

    2005-01-01

    Isolated cytostatic lung perfusion (ILP) is an attractive technique allowing delivery of a high-dose of cytostatic agents to the lungs while limiting systemic toxicity. In developing a rat model of ILP, we have analysed the effect of the route of tumour cell injection on the source of tumour vessels. Pulmonary sarcomas were established by injecting a sarcoma cell suspension either by the intravenous (i.v.) route or directly into the lung parenchyma. Ink perfusion through either pulmonary artery (PA) or bronchial arteries (BA) was performed and the characteristics of the tumour deposits defined. i.v. and direct injection methods induced pulmonary sarcoma nodules, with similar histological features. The intraparenchymal injection of tumour cells resulted in more reliable and reproducible tumour growth and was associated with a longer survival of the animals. i.v. injected tumours developed a PA-derived vascular tree whereas directly injected tumours developed a BA-derived vasculature. PMID:15905614

  2. Tumours of the lung

    PubMed Central

    Stünzi, H.; Head, K. W.; Nielsen, S. W.

    1974-01-01

    Lung tumours are not common in domestic animals; there has not been the increase in epidermoid carcinomas and anaplastic small-cell carcinomas that has occurred in man this century. Adenocarcinoma is the most common type in animals. The biological behaviour of each type of tumour in animals seems to be much the same as in man. The tumours are described histologically, the main categories being: epidermoid carcinoma, anaplastic carcinoma, adenocarcinoma, combined epidermoid and adenocarcinoma, carcinoid tumours, bronchial gland tumours, benign tumours, and sarcomas. ImagesFig. 13Fig. 14Fig. 15Fig. 16Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12 PMID:4371738

  3. Haemangioleiomyomatous tumour of the lung.

    PubMed Central

    Soorae, A S; Bharucha, H

    1980-01-01

    A case of haemangioleiomyomatous tumour of the lung, occurring as a peripheral, solitary nodule in an asymptomatic 54-year-old man is presented. The tumour was well-demarcated and microscopically it was characterised by the presence of vascular spaces with endothelial, pericytic, and, predominantly, smooth muscle proliferation. Islands of cartilage and slit-like spaces lined by bronchial epithelium make this a hamartomatous lesion of a quite distinctive and unusual variety, which does not fit any of the well-recognised patterns of hamartomas previously described. The long-term prognosis after limited excision is considered to be favourable. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7358861

  4. An unusual tumour of the lung.

    PubMed

    Ayadi, L; Abid, N; Makni, S; Bahri, I; Frikha, I; Sellami-Boudawara, T

    2015-03-01

    We report a case of a 51-year-old woman with a solitary mast cell tumour of the lung, a rare neoplasm with only three previously-reported cases reported in the literature. Unlike previous cases, the tumour in the present case was bulky, measuring 14 cm in diameter and budding into the segmental bronchus. Histologically, it showed proliferation of typical metachromatic mast cells intermingled with undifferentiated cells with a ratio of 3:1. The neoplastic mast cells stained strongly with tryptase, CD117, CD68 and CD45, CD14 and CD33; whereas the undifferentiated cells lacked all these markers and expressed EMA and cytokeratin. Histological examination of bone marrow and laboratory data were unremarkable. To our knowledge, this is the fourth case of solitary extracutaneous mastocytoma of the lung. The differentiating features of this neoplasm and a review of literature are presented. PMID:26591626

  5. Premitive neuro-ectodermal tumour of the lung

    PubMed Central

    Patil, Pradeep; Malur, Prakash; Annurshetru, Shivappa

    2015-01-01

    Primitive neuro-ectodermal tumour of the lung is an extremely rare occurrence and we hereby report a case of a neuro-ectodermal tumour of the lung which was proved by immuno-histochemical examination of the resected specimen, and he had a very aggressive pattern of behavior. PMID:26793390

  6. 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

  7. Site-specific volumetric analysis of lung tumour motion

    NASA Astrophysics Data System (ADS)

    Pepin, Eric W.; Wu, Huanmei; Sandison, George A.; Langer, Mark; Shirato, Hiroki

    2010-06-01

    The treatment of lung cancer with radiation therapy is hindered by respiratory motion. Real-time adjustments to compensate for this motion are hampered by mechanical system latencies and imaging-rate restrictions. To better understand tumour motion behaviour for adaptive image-guided radiation therapy of lung cancer, the volume of a tumour's motion space was investigated. Motion data were collected by tracking an implanted fiducial using fluoroscopy at 30 Hz during treatment sessions. A total of 637 treatment fractions from 31 tumours were used in this study. For each fraction, data points collected from three consecutive breathing cycles were used to identify instantaneous tumour location. A convex hull was created over these data points, defining the tumour motion envelope. The study sought a correlation between the tumour location in the lung and the convex hull's volume and shape. It was found that tumours located in the upper apex had smaller motion envelopes (<50 mm3), whereas tumours located near the chest wall or diaphragm had larger envelopes (>70 mm3). Tumours attached to fixed anatomical structures had small motion spaces. Three general shapes described the tumour motion envelopes: 50% of motion envelopes enclosed largely 1D oscillation, 38% enclosed an ellipsoid path, 6% enclosed an arced path and 6% were of hybrid shape. This location-space correlation suggests it may be useful in developing a predictive model, but more work needs to be done to verify it.

  8. 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

  9. Effect of Resection of Lung Tumours on the Steroid Abnormalities in Patients with Lung Cancer

    PubMed Central

    Rao, L. G. S.

    1971-01-01

    The urinary excretion of androsterone, aetiocholanolone, total 17-oxosteroids, and 17-hydroxycorticosteroids (17-OHCS) was measured in 40 patients with lung cancer three days before resection and again 10-15 days after resection of their lung tumours. There was a significant postoperative increase in the excretion of 17-OHCS but a significant decrease in the excretion of androsterone and aetiocholanolone, resulting in an increase of the preoperative abnormalities in steroid excretion in these patients. Since there was no change in steroid excretion towards normal after resection of the lung tumours, it seems that the steroid abnormalities found in lung cancer are not the effect of the presence of the lung tumours. As the excretions of 17-OHCS and 11-deoxy-17-oxosteroids change in opposite directions after resection, it is suggested that a dissociation of factors that control the excretion of these two groups of steroids takes place as a response to surgical stress in patients with lung cancer. PMID:5130212

  10. Towards fluoroscopic respiratory gating for lung tumours without radiopaque markers

    NASA Astrophysics Data System (ADS)

    Berbeco, Ross I.; Mostafavi, Hassan; Sharp, Gregory C.; Jiang, Steve B.

    2005-10-01

    Due to the risk of pneumothorax, many clinicians are reluctant to implant radiopaque markers within patients' lungs for the purpose of radiographic or fluoroscopic tumour localization. We propose a method of gated therapy using fluoroscopic information without the implantation of radiopaque markers. The method presented here does not rely on any external motion signal either. Breathing phase information is found by analysing the fluoroscopic intensity fluctuations in the lung. As the lungs fill/empty, the radiological pathlength through them shortens/lengthens, giving brighter/darker fluoroscopic intensities. The phase information is combined with motion-enhanced template matching to turn the beam on when the tumour is in the desired location. A study based on patient data is presented to demonstrate the feasibility of this procedure. The resulting beam-on pattern is similar to that produced by an external gating system. The only discrepancies occur briefly and at the gate edges.

  11. Metabolic consequences of methotrexate therapy in tumour-bearing rats.

    PubMed

    Rofe, A M; Bourgeois, C S; Washington, J M; Philcox, J C; Coyle, P

    1994-02-01

    The metabolic response of the tumour-bearing host to methotrexate (MTX) therapy was investigated with particular attention to effects resulting from MTX-induced anorexia. Biochemical changes in female Dark Agouti rats bearing mammary adenocarcinomas and treated with MTX (0.5 mg/kg, 2 i.m. injections, 24 h apart) were compared with untreated (CON) tumour-bearing rats, and tumour-bearing rats pair-fed (PF) to the MTX group. MTX treatment halted progression of the tumour (tumour 6% of bodyweight) while the tumour burden doubled in the CON and PF groups. A number of biochemical and haematological changes were specific to MTX treatment and did not result from decreased food intake. MTX treatment was associated with significantly decreased plasma calcium, bilirubin, alkaline phosphatase, aspartate aminotransferase and the total white cell count. Decreases in plasma albumin and total protein concentrations were observed in both MTX and PF rats. Other parameters commonly used to assess renal and liver function were not significantly affected by MTX. MTX reversed the hypoglycaemia, hyperketonaemia and hypertriglyceridaemia induced by tumour-bearing. In contrast, PF rats had an even more pronounced hypoglycaemia and hyperketonaemia than the CON rats. Measurement of glucose uptake in vivo with 2-deoxy[U-14C]-glucose showed that MTX treatment halved the glucose requirement of the tumour (8.2% of bodyweight compared to 12.2% in the control). It is concluded that the potentially adverse effects of MTX treatment on host metabolism are outweighed by the beneficial effects of a reduced metabolic demand resulting from inhibition of tumour progression. PMID:8157287

  12. Tumour ablation: current role in the kidney, lung and bone.

    PubMed

    Gillams, Alice

    2009-01-01

    The last few years have seen a rapid expansion in the use and availability of ablation techniques with hundreds of papers published. Radiofrequency remains the front-runner in terms of cost, ease of set-up, versatility and flexibility but other techniques are catching up. Ablation with cryotherapy and microwave, which were previously only available at open laparotomy due to the large size of the probes, are now readily performed percutaneously, with a predictable reduction in morbidity. Ablation is now accepted as the first line of treatment in patients with limited volume hepatocellular carcinoma who are not candidates for transplantation. There is continuing debate in most other areas but the evidence is increasing for an important role in liver metastases, renal carcinoma, inoperable lung tumours and some bone tumours. PMID:19965298

  13. 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.

  14. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26056045

  16. A soft agar colony assay for Lewis lung tumour and B16 melanoma taken directly from the mouse.

    PubMed Central

    Courtenay, V. D.

    1976-01-01

    A soft agar colony assay has been developed for the B16 mouse melanoma and the Lewis lung tumour. The special features of the technique are the use of a gas phase with 5% O2 instead of air and the addition of rat red blood cells. Single cell suspensions are prepared by trypsinization from the solid tumour and the cells are plated out in 0-3% agar over a layer of 0-5% agar in 30-mm Petri dishes. After 8 to 15 days' incubation in 5% O2, colonies of more than 50 cells are produced. Plating efficiencies of between 30 and 50% are usually obtained. The addition of up to 10(4) heavily irradiated tumour cells gives some further improvement in plating efficiency for the B16 melanoma but not for the Lewis lung tumour. Applications of the technique to measure cell survival in the two tumours after treatment with cytotoxic drugs and radiation are reported. The scatter of experimental points is relatively small, and in comparative experiments good agreement has been obtained with results using in vivo assay techniques. PMID:782495

  17. Synchronized moving aperture radiation therapy (SMART): average tumour trajectory for lung patients

    NASA Astrophysics Data System (ADS)

    Neicu, Toni; Shirato, Hiroki; Seppenwoolde, Yvette; Jiang, Steve B.

    2003-03-01

    Synchronized moving aperture radiation therapy (SMART) is a new technique for treating mobile tumours under development at Massachusetts General Hospital (MGH). The basic idea of SMART is to synchronize the moving radiation beam aperture formed by a dynamic multileaf collimator (DMLC) with the tumour motion induced by respiration. SMART is based on the concept of the average tumour trajectory (ATT) exhibited by a tumour during respiration. During the treatment simulation stage, tumour motion is measured and the ATT is derived. Then, the original IMRT MLC leaf sequence is modified using the ATT to compensate for tumour motion. During treatment, the tumour motion is monitored. The treatment starts when leaf motion and tumour motion are synchronized at a specific breathing phase. The treatment will halt when the tumour drifts away from the ATT and will resume when the synchronization between tumour motion and radiation beam is re-established. In this paper, we present a method to derive the ATT from measured tumour trajectory data. We also investigate the validity of the ATT concept for lung tumours during normal breathing. The lung tumour trajectory data were acquired during actual radiotherapy sessions using a real-time tumour-tracking system. SMART treatment is simulated by assuming that the radiation beam follows the derived ATT and the tumour follows the measured trajectory. In simulation, the treatment starts at exhale phase. The duty cycle of SMART delivery was calculated for various treatment times and gating thresholds, as well as for various exhale phases where the treatment begins. The simulation results show that in the case of free breathing, for 4 out of 11 lung datasets with tumour motion greater than 1 cm from peak to peak, the error in tumour tracking can be controlled to within a couple of millimetres while maintaining a reasonable delivery efficiency. That is to say, without any breath coaching/control, the ATT is a valid concept for some lung

  18. Identification of a common oncofoetal protein in x-ray and chemically induced rat gastrointestinal tumours.

    PubMed Central

    Stevens, R. H.; Cole, D. A.; Cheng, H. F.

    1981-01-01

    An apparently unique circulating common oncofoetal protein has been identified in rat small-bowel, colonic and pancreatic adenocarcinomas. The tumours were induced by ionizing radiation (small bowel), an alkyl hydrocarbon, 1,2-dimethylhydrazine (colon) and a polyaromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene (pancreas). The oncofoetal protein was identified by the use of specific xenogenic antitumour rabbit sera generated to the X-ray-induced neoplasm. In addition, the foetal protein was also found always to occur in the liver and lungs of those animals bearing the chemically induced tumours as well as in their serum. These results suggest the existence of a close relationship at the molecular level in the tumorigenic processes, even though induction is by apparently different mechanisms, for cancers arising in tissue or common embryonic origin. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:6788060

  19. 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

  20. A New Model for Inducing Malignant Ovarian Tumours in Rats*

    PubMed Central

    Hilfrich, J.

    1973-01-01

    After the implantation of ovarian tissue into the spleen of gonadectomized female Sprague-Dawley rats (splenic ovary), luteomata and later benign granulosa or granulosa-theca cell tumours develop. Treatment of these rats with 7,12 dimethylbenz(a)anthracene (DMBA), given intravenously, 2 mg/kg body weight weekly, total dosage 40 mg/kg, immediately and especially 25 weeks after implantation of ovarian tissue into the spleen, led to malignant, partially metastasizing granulosa, and in one case theca cell tumours, 16-46 weeks after beginning the carcinogen treatment. No malignant neoplastic growth was seen when diethylnitrosamine (DEN), 20 mg/kg once weekly for life, was injected subcutaneously immediately or 25 weeks after implanting ovarian tissue. Since the normal, non-implanted rat ovary was not affected by DMBA treatment the malignant transformation of splenic ovaries in the respective experimental groups may be related to the increased stimulation by pituitary gonadotrophins and formation of luteomata or beginning granulosa and theca cell proliferations. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9 PMID:4353388

  1. 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.

  2. Phantom tumour of the lung in a patient with renal failure misdiagnosed as chest infection

    PubMed Central

    Althomali, Sarah Ali; Almalki, Mazen Mohammed; Mohiuddin, Syed Atif

    2014-01-01

    Phantom or vanishing tumour of the lung is a rare finding on chest radiographs that has been reported secondary to heart failure or chronic kidney disease. It has been described as an interlobular effusion of the transverse or oblique fissure of the right lung. Although it is uncommon, it should always be considered as a differential diagnosis for a radiographic opacity of the right-middle lung zone because it can be easily mistaken for a lung mass or infiltration. We herein present a case involving a patient with chronic kidney disease and a radiographic opacity of the right-middle lung that was diagnosed as a chest infection. The patient did not respond to various antibiotics and showed a poor response to diuretics, the standard treatment for phantom tumour. However, the patient markedly improved after dialysis, and the radiographic chest opacity disappeared. PMID:24943144

  3. Phantom tumour of the lung in a patient with renal failure misdiagnosed as chest infection.

    PubMed

    Althomali, Sarah Ali; Almalki, Mazen Mohammed; Mohiuddin, Syed Atif

    2014-01-01

    Phantom or vanishing tumour of the lung is a rare finding on chest radiographs that has been reported secondary to heart failure or chronic kidney disease. It has been described as an interlobular effusion of the transverse or oblique fissure of the right lung. Although it is uncommon, it should always be considered as a differential diagnosis for a radiographic opacity of the right-middle lung zone because it can be easily mistaken for a lung mass or infiltration. We herein present a case involving a patient with chronic kidney disease and a radiographic opacity of the right-middle lung that was diagnosed as a chest infection. The patient did not respond to various antibiotics and showed a poor response to diuretics, the standard treatment for phantom tumour. However, the patient markedly improved after dialysis, and the radiographic chest opacity disappeared. PMID:24943144

  4. 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. PMID:25793737

  5. 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

  6. Lungs and subcutaneous metastases from a solitary fibrous tumour of the pancreas

    PubMed Central

    Tesfom, Meron F.; Caldwell, Carole; Hanasoge, Raveesh; Bramhall, Simon R.

    2015-01-01

    Solitary fibrous tumour is an uncommon mesenchymal neoplasm previously thought to only originate from the pleura; it is seen only rarely in an extra-pleural location. We report the first case of pancreatic solitary fibrous tumour in an 87-year-old woman that has metastasized to the lungs and subcutaneous tissue. We have identified a solitary mass excised from the groin region, which is positive for CD34 and vimentic marker with high proliferative rate, nuclear atypia and cellular necrosis. Imaging studies confirmed a slow-growing solitary mass in the uncinate lobe of the pancreas with evidence of lung metastasis. PMID:26612261

  7. DT-diaphorase and cytochrome B5 reductase in human lung and breast tumours.

    PubMed Central

    Marín, A.; López de Cerain, A.; Hamilton, E.; Lewis, A. D.; Martinez-Peñuela, J. M.; Idoate, M. A.; Bello, J.

    1997-01-01

    The level of expression of enzymes that can activate or detoxify bioreductive agents within tumours has emerged as an important feature in the development of these anti-tumour compounds. The levels of two such reductase enzymes have been determined in 19 human non-small-cell lung tumours and 20 human breast tumours, together with the corresponding normal tissue. DT-diaphorase (DTD) enzyme levels (both expression and activity) were determined in these samples. Cytochrome b5 reductase (Cytb5R) activity was also assessed. With the exception of six patients, the levels of DTD activity were below 45 nmol min(-1) mg(-1) in the normal tissues assayed. DTD tumour activity was extremely variable, distinguishing two different groups of patients, one with DTD activity above 79 nmol min(-1) mg(-1) and the other with levels that were in the same range as found for the normal tissues. In 53% of the lung tumour samples, DTD activity was increased with respect to the normal tissue by a factor of 2.4-90.3 (range 79-965 nmol min[-1] mg[-1]). In 70% of the breast tumour samples, DTD activity was over 80 nmol min(-1) mg(-1) (range 83-267 nmol min[-1] mg[-1]). DTD expression measured by Western blot correlated well with the enzyme activity measured in both tumour and normal tissues. The levels of the other reductase enzyme, Cytb5R, were not as variable as those for DTD, being in the same range in both tumour and normal tissue or slightly higher in the normal tissues. The heterogeneous nature of DTD activity and expression reinforces the need to measure enzyme levels in individual patients before therapy with DTD-activated bioreductive drugs. Images Figure 1 Figure 2 PMID:9328153

  8. NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinoma.

    PubMed

    Rocha, Cláudia M; Barros, António S; Goodfellow, Brian J; Carreira, Isabel M; Gomes, Ana; Sousa, Vitor; Bernardo, João; Carvalho, Lina; Gil, Ana M; Duarte, Iola F

    2015-01-01

    Lung tumour subtyping, particularly the distinction between adenocarcinoma (AdC) and squamous cell carcinoma (SqCC), is a critical diagnostic requirement. In this work, the metabolic signatures of lung carcinomas were investigated through (1)H NMR metabolomics, with a view to provide additional criteria for improved diagnosis and treatment planning. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (NMR) spectroscopy was used to analyse matched tumour and adjacent control tissues from 56 patients undergoing surgical excision of primary lung carcinomas. Multivariate modeling allowed tumour and control tissues to be discriminated with high accuracy (97% classification rate), mainly due to significant differences in the levels of 13 metabolites. Notably, the magnitude of those differences were clearly distinct for AdC and SqCC: major alterations in AdC were related to phospholipid metabolism (increased phosphocholine, glycerophosphocholine and phosphoethanolamine, together with decreased acetate) and protein catabolism (increased peptide moieties), whereas SqCC had stronger glycolytic and glutaminolytic profiles (negatively correlated variations in glucose and lactate and positively correlated increases in glutamate and alanine). Other tumour metabolic features were increased creatine, glutathione, taurine and uridine nucleotides, the first two being especially prominent in SqCC and the latter in AdC. Furthermore, multivariate analysis of AdC and SqCC profiles allowed their discrimination with a 94% classification rate, thus showing great potential for aiding lung tumours subtyping. Overall, this study has provided new, clear evidence of distinct metabolic signatures for lung AdC and SqCC, which can potentially impact on diagnosis and provide important leads for future research on novel therapeutic targets or imaging tracers. PMID:25368033

  9. 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

  10. 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

  11. Modulation of lung liquid clearance by isoproterenol in rat lungs.

    PubMed

    Saldías, F; Lecuona, E; Friedman, E; Barnard, M L; Ridge, K M; Sznajder, J I

    1998-05-01

    beta-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which beta-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10(-4) to 10(-8) M increased lung liquid clearance compared with that of control lungs (P < 0.01). The increase in lung liquid clearance was inhibited by the beta-antagonist propranolol (10(-5) M), the Na(+)-channel blocker amiloride (10(-4) M), and the antagonist of Na-K-ATPase, ouabain (5 x 10(-4) M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase alpha 1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10(-6) M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase alpha 1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of beta-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+ pumps to the plasma membrane participate in beta-adrenergic stimulation of lung liquid clearance in rat lungs. PMID:9612284

  12. Quantifying the effect of respiratory motion on lung tumour dosimetry with the aid of a breathing phantom with deforming lungs

    NASA Astrophysics Data System (ADS)

    Nioutsikou, Elena; Symonds-Tayler, J. Richard N.; Bedford, James L.; Webb, Steve

    2006-07-01

    The contribution of organ and tumour motion to the degradation of planned dose distributions during radiotherapy to the breathing lung has been experimentally investigated and quantified. An anthropomorphic, tissue-equivalent breathing phantom with deformable lungs has been built, in which the lung tumour can be driven in any arbitrary 3D trajectory. The trajectory is programmed into a motion controller connected to a high-precision moving platform that is connected to the tumour. The motion controller is connected to the accelerator's dose counter and the speed of motion is scaled to the dose rate. This ensures consistent delivery despite variation in either the dose rate or inter-segment timing. For this study, the phantom was made to breathe by a set of periodic equations representing respiratory motion by an asymmetric, trigonometric function. Several motion amplitudes were selected to be applied in the primary axis of motion. Five three-dimensional, geometrically conformal (3DCRT) fractions with different starting phases (spaced uniformly in the breathing cycle) were delivered to the phantom and compared to a delivery where the phantom was static at the end-expiration position. A set of intensity-modulated radiotherapy plans (IMRT) was subsequently delivered in the same manner. Bigger amplitudes of motion resulted in a higher degree of dose blurring. Severe underdosages were observed when deliberately selecting the PTV wrongly, their extent being correlated with the degree of margin error. IMRT motion-averaged dose distributions exhibited areas of high dose in the gross tumour volume (GTV) which were not present in the static irradiations, arising from booster segments that the optimizer was creating to achieve planning target volume (PTV) homogeneity during the inverse-planning process. 3DCRT, on the other hand, did not demonstrate such effects. It has been concluded that care should be taken to control the delivered fluence when delivering IMRT to the

  13. Cyclopentenylcytosine does not enhance cisplatin-induced radiosensitization in human lung tumour cells

    PubMed Central

    RODERMOND, HANS M.; CATE, ROSEMARIE TEN; HAVEMAN, JAAP; VAN KUILENBURG, ANDRÉ; MEDEMA, JAN PAUL; VAN BREE, CHRIS; FRANKEN, NICOLAAS A.P.

    2010-01-01

    The search for agents that enhance the effect of ionizing radiation has been an object of study for decades. In this study, the sensitizing properties of cyclopentenylcytosine (CPEC) on radiation and cisplatin-induced radiosensitization in human squamous lung carcinoma cells were investigated. Human lung tumour SW-1573 cells (SWp, parental; SWg, gemcitabine-resistant) were incubated with CPEC and cisplatin and subsequently irradiated with different doses of γ-rays. Clonogenic survival was determined to measure the effectiveness of the treatments. CPEC (1 or 2 μM) treatment for 4 h decreased the plating efficiency to 75 and 50% in SWp and SWg cells, respectively. In the SWg cells, 0.1 and 1 μM CPEC for 4 h enhanced the cell killing effect of cisplatin. However, an increase was not noted in the SWp cells. Due to the moderate toxicity of 1 μM for 4 h, this CPEC dose was used in the radiosensitization experiments. However, CPEC neither radiosensitized the lung tumour cells nor enhanced the radiosensitizing effect of cisplatin. A 2-h incubation with 4 μM cisplatin also decreased the plating efficiency to 75–80% in the two cell lines. Using this cisplatin dose, radiosensitization was obtained in the two cell lines. Although cisplatin treatment clearly radiosensitized the lung tumour cells, CPEC treatment did not. Cisplatin-induced radiosensitization was also not enhanced by CPEC. PMID:22966339

  14. Body protein and lipid deficit in tumour-bearing rats in relation to age.

    PubMed Central

    Oudart, H.; Heitz, A.; Bnouham, M.; Malan, A.; Le Maho, Y.

    1993-01-01

    Cancer cachexia is among the most dramatic situations of depletion in body energy reserves. To ascertain whether the pattern of body composition alteration during tumour development is influenced by aging as in uncomplicated starvation, we compared the difference of body composition between Yoshida sarcoma bearing rats and young (200 g, 7 weeks) and adult (400 g, 13 weeks) control rats. After the same duration of tumour bearing, mass and composition of tumours were similar in adult and young rats, indicating that they are independent of host age. Food intake decreased to a remarkably similar value in both young and adults. Body water content was elevated in hosts of both ages. The relative deficit of body lipid vs controls was similar for both, the absolute lipid deficit being therefore larger in adult than in young tumour-bearing rats (14.3 +/- 4.4 g vs 6.8 +/- 0.9 g; P < 0.01). In contrast, there was a relatively larger deficit of body protein in young rats. Paradoxically, these rats still maintained a positive nitrogen balance whereas this balance was negative in adult tumour-bearing rats. In conclusion, as previously shown in uncomplicated undernutrition, the anorexia induced by Yoshida sarcoma development is still associated with some protein accretion in young rats whereas cachexia develops in adults. PMID:8217604

  15. 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.

  16. Combined Micro-PET/Micro-CT Imaging of Lung Tumours in SPC-raf and SPC-myc Transgenic Mice

    PubMed Central

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

    2012-01-01

    Introduction 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. Material and Methods 14 C57BL/6 mice (4 nontransgenic, 4 SPC-raf transgenic, 6 SPC-myc transgenic) were examined using micro-CT and 18F-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. Results 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. Conclusions 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. PMID:23028537

  17. Acute vascular response to cediranib treatment in human non-small-cell lung cancer xenografts with different tumour stromal architecture

    PubMed Central

    Jiang, Yanyan; Allen, Danny; Kersemans, Veerle; Devery, Aoife M.; Bokobza, Sivan M.; Smart, Sean; Ryan, Anderson J.

    2015-01-01

    Objectives Tumours can be categorised based on their stromal architecture into tumour vessel and stromal vessel phenotypes, and the phenotypes have been suggested to define tumour response to chronic treatment with a VEGFR2 antibody. However, it is unclear whether the vascular phenotypes of tumours associate with acute vascular response to VEGFR tyrosine kinase inhibitors (TKI), or whether the early changes in vascular function are associated with subsequent changes in tumour size. This study was sought to address these questions by using xenograft models of human non-small cell lung cancer (NSCLC) representing stromal vessel phenotype (Calu-3) and tumour vessel phenotype (Calu-6), respectively. Methods For dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), nude mice bearing established Calu-3 or Calu-6 xenografts were treated with a potent pan-VEGFR TKI, cediranib (6 mg/kg), at 0 h and 22 h. DCE-MRI was performed 2 h before the first dose and 2 h after the second dose of cediranib to examine acute changes in tumour vessel perfusion. Tumours were harvested for hypoxia detection by CA9 immunohistochemistry. For tumour growth study, mice carrying established Calu-3 or Calu-6 tumours were treated with cediranib once daily for 5 days. Results Twenty-four hours after cediranib administration, the perfusion of Calu-3 tumours was markedly reduced, with a significant increase in hypoxia. In contrast, neither perfusion nor hypoxia was significantly affected in Calu-6 tumours. Tumour regressions were induced in Calu-3 xenografts, but not in Calu-6 xenografts, although there was a trend towards tumour growth inhibition after 5 days of cediranib treatment. Conclusion These findings suggest that tumour stromal architecture may associate with acute tumour vascular response to VEGFR TKI, and this acute tumour vascular response may be a promising early predictive marker of response to VEGFR TKI in NSCLC. PMID:26323213

  18. Assessment of tumour viability in human lung cancer xenografts with texture-based image analysis

    PubMed Central

    Turkki, Riku; Linder, Nina; Holopainen, Tanja; Wang, Yinhai; Grote, Anne; Lundin, Mikael; Alitalo, Kari; Lundin, Johan

    2015-01-01

    Aims To build and evaluate an automated method for assessing tumour viability in histological tissue samples using texture features and supervised learning. Methods H&E-stained sections (n=56) of human non-small cell lung adenocarcinoma xenografts were digitised with a whole-slide scanner. A novel image analysis method based on local binary patterns and a support vector machine classifier was trained with a set of sample regions (n=177) extracted from the whole-slide images and tested with another set of images (n=494). The extracted regions, or single-tissue entity images, were chosen to represent as pure as possible examples of three morphological tissue entities: viable tumour tissue, non-viable tumour tissue and mouse host tissue. Results An agreement of 94.5% (area under the curve=0.995, kappa=0.90) was achieved to classify the single-tissue entity images in the test set (n=494) into the viable tumour and non-viable tumour tissue categories. The algorithm assigned 250 of the 252 non-viable and 219 of the 242 of viable sample regions to the correct categories, respectively. This corresponds to a sensitivity of 90.5% and specificity of 99.2%. Conclusions The proposed image analysis-based tumour viability assessment resulted in a high agreement with expert annotations. By providing extraction of detailed information of the tumour microenvironment, the automated method can be used in preclinical research settings. The method could also have implications in cancer diagnostics, cancer outcome prognostics and prediction. PMID:26021331

  19. 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.

  20. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat.

    PubMed Central

    Poynter, D; Pick, C R; Harcourt, R A; Selway, S A; Ainge, G; Harman, I W; Spurling, N W; Fluck, P A; Cook, J L

    1985-01-01

    The oral administration of loxtidine, a potent histamine H2-antagonist, to a total of 378 rats at doses of 50, 185, or 685 mg/kg/day for 116 weeks resulted in the late formation of carcinoid tumours of the gastric fundus. The first such tumour was detected after 712 days of treatment. There was no dose related response; 11 rats at the low level of treatment were affected, 12 at the intermediate and 11 at the high. Twenty seven females but only seven males were affected. No gastric tumours were found in the 228 controls. There is no evidence that loxtidine acts as a direct carcinogen and it is suggested that the tumours were the result of prolonged achlorhydria produced by a potent unsurmountable histamine H2 receptor antagonist. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:2867954

  1. 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

  2. Building motion models of lung tumours from cone-beam CT for radiotherapy applications.

    PubMed

    Martin, James; McClelland, Jamie; Yip, Connie; Thomas, Christopher; Hartill, Clare; Ahmad, Shahreen; O'Brien, Richard; Meir, Ivan; Landau, David; Hawkes, David

    2013-03-21

    A method is presented to build a surrogate-driven motion model of a lung tumour from a cone-beam CT scan, which does not require markers. By monitoring an external surrogate in real time, it is envisaged that the motion model be used to drive gated or tracked treatments. The motion model would be built immediately before each fraction of treatment and can account for inter-fraction variation. The method could also provide a better assessment of tumour shape and motion prior to delivery of each fraction of stereotactic ablative radiotherapy. The two-step method involves enhancing the tumour region in the projections, and then fitting the surrogate-driven motion model. On simulated data, the mean absolute error was reduced to 1 mm. For patient data, errors were determined by comparing estimated and clinically identified tumour positions in the projections, scaled to mm at the isocentre. Averaged over all used scans, the mean absolute error was under 2.5 mm in superior-inferior and transverse directions. PMID:23442367

  3. 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

    2011-01-01

    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. PMID:21119223

  4. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study

    PubMed Central

    Morrow, C. J.; Trapani, F.; Metcalf, R. L.; Bertolini, G.; Hodgkinson, C. L.; Khandelwal, G.; Kelly, P.; Galvin, M.; Carter, L.; Simpson, K. L.; Williamson, S.; Wirth, C.; Simms, N.; Frankliln, L.; Frese, K. K.; Rothwell, D. G.; Nonaka, D.; Miller, C. J.; Brady, G.; Blackhall, F. H.; Dive, C.

    2016-01-01

    Background Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ‘liquid biopsies’ such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). Patients and methods CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. Results The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. Conclusions This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM+) does not preclude CDX generation

  5. 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.

  6. Immunological screening of a glycoprotein antigen expressed by Zajdela ascites hepatoma cells on normal rat tissues and tumour cells.

    PubMed

    Nato, F; Goulut, C; Mirshahi, M; Bourrillon, R

    1991-10-01

    Expression of the glycoprotein MII2 antigen originally identified in Zajdela ascites hepatoma cells was investigated in several normal rat tissues and in more or less differentiated tumours using biochemical and immunological approaches. SDS-polyacrylamide gel electrophoresis followed by fluorography or immunoblotting with an antiserum raised against the purified MII2 antigen revealed that this antigen was absent from normal liver cells. ELISA assays, indirect immunofluorescence and immunoprecipitation experiments using the same antiserum showed that this glycoprotein was not expressed in various normal tissues such as liver, spleen, lung, pancreas, intestine and stomach, but it was unexpectedly detected in kidney and thymic tissues. However, the molecular weight of the antigens immunoprecipitated from kidney and thymus was lower than the one of MII2 (Mr of 60,000 versus 110,000-160,000 for purified MII2). No staining was observed in embryonic rat liver at 10 and 20 days of development. Moreover, this antigen was present on the surface of Morris hepatoma 7777, another rapidly proliferating and poorly differentiated hepatocellular carcinoma. In contrast, this antigen was not detected on the surface of in vitro Zajdela hepatoma cells (ZHC) or of partially differentiated hepatomas (Faza) which have recovered some hepatic functions. In addition, the MII2 antigen was found on the human non-hepatic HT-29 tumour cell line, under its undifferentiated form (HT-29 G+ subline). The possible relationships between the expression of this antigen and both the malignant transformation process and the differentiation process are discussed. PMID:1656518

  7. 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

  8. 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

    2016-01-01

    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

  9. 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

  10. Endotoxin-induced acute lung injury is enhanced in rats with spontaneous hypertension.

    PubMed

    Liu, Demeral D; Hsu, Yung Hsiang; Chen, Hsing I

    2007-01-01

    1. Acute lung injury (ALI), or acute respiratory distress syndrome, is a major cause of mortality in endotoxaemia. The present study tested whether the endotoxaemia-induced changes and associated ALI were enhanced in rats with established hypertension and to examine the possible mechanisms involved. 2. Fifty spontaneously hypertensive rats (SHR) and the same number of normotensive Wistar Kyoto (WKY) rats, aged 12-15 weeks, were used. The experiments were performed in conscious, unanaesthetized rats. Endotoxaemia was produced by intravenous lipopolysaccharide (LPS; 10 mg/kg). N(G)-Nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, i.v.), L-N(6)-(1-iminoethyl)-lysine (L-Nil; 5 mg/kg, i.v.) and 3-morpholinosydnonimine (SIN-1; 5 mg/kg, i.v.) were given 5 min before LPS to observe the effects of nitric oxide synthase (NOS) inhibition and nitric oxide (NO) donation. 3. We monitored arterial pressure and heart rate and evaluated ALI by determining the lung weight/bodyweight ratio, lung weight gain, leakage of Evans blue dye, the protein concentration in bronchoalveolar lavage and histopathological examination. Plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, and lung tissue cGMP were determined. Expression of mRNA for inducible and endothelial NOS was examined using reverse transcription-polymerase chain reaction. 4. Lipopolysaccharide caused systemic hypotension, ALI and increases in plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines and lung cGMP content. The LPS-induced changes were greater in SHR than in WKY rats. Pretreatment with L-NAME or L-Nil attenuated, whereas the NO donor SIN-1 aggravated, the endotoxin-induced changes. 5. In conclusion, rats with genetic hypertension are more susceptible to endotoxaemia and this results in a greater extent of ALI compared with normotensive WKY rats. PMID:17201737

  11. 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

  12. FATE OF INHALED NITROGEN DIOXIDE IN ISOLATED PERFUSED RAT LUNG

    EPA Science Inventory

    The fate of inhaled NO2 was studied with isolated perfused rat lungs. The isolated lungs were exposed to 5 ppm NO2 for 90 min at a ventilation rate of 45 ml/min. The NO2 exposure had no adverse effects on the lungs as judged from their weights, glucose uptake, or lactate producti...

  13. The Presence of Tumour Specific Membrane Antigen in the Serum of Rats with Chemically Induced Sarcomata

    PubMed Central

    Thomson, D. M. P.; Steele, K.; Alexander, P.

    1973-01-01

    Antibodies to the tumour-specific transplantation type antigen (TSTA) of a transplanted methylcholanthrene-induced sarcoma (MC-1) in syngeneic rats were studied using the techniques of indirect membrane immunofluorescence and mixed haemadsorption with a 51Cr-labelled indicator cell. After tumour excision, anti-TSTA antibody was readily measurable in both serum and lymph. In contrast, the tumour-bearing animal had no measurable anti-TSTA antibody in the serum but low titres in the lymph. Consequently, we formed the hypothesis that in the presence of a growing tumour the serum contained antigen-antibody complexes with antigen in excess. To test this hypothesis, tumour-bearing serum was examined for the presence of free antigen and antigen-antibody complexes by 2 different methods. In the first method, tumour-bearing serum was cross-linked with glutaraldehyde and was found to absorb specifically the anti-TSTA antibody, indicating free circulating TSTA. Next, antigen-antibody complexes were split with salt or acid and separated into a low molecular weight (or “antigen”) fraction (<100,000) and a high molecular weight (or “antibody”) fraction (>100,000). The low M.W. fraction specifically inhibited the anti-TSTA antibody when tested by either membrane immunofluorescence or mixed haemadsorption, indicating the presence of antigen from antigen-antibody complexes in the tumour-bearing circulation. The possible effect on the host's immune response of circulating free tumour antigen and antigen-antibody complexes are discussed. PMID:4568460

  14. Characterization of (+/-)-methadone uptake by rat lung.

    PubMed Central

    Chi, C H; Dixit, B N

    1977-01-01

    1. By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (+/-)-methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (+/-)-methadone against a concentration gradient. 2. This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3. The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (+/-)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (+/-)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.5; (iii) When the concentration of (+/-)-methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4. These results suggested that at low concentrations, (+/-)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5. At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (+/-)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (approximately 100 degrees C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6. Kinetic analysis of data showed that the diffusion constant

  15. Postoperative intrapleural BCG in lung cancer: lack of efficacy and possible enhancement of tumour growth.

    PubMed Central

    Bakker, W; Nijhuis-Heddes, J M; Wever, A M; Brutel de la Rivière, A; van der Velde, E A; Dijkman, J H

    1981-01-01

    Fifty-six patients out of a group of 99 with lung cancer received postoperative intrapleural BCG (Pasteur strain) in three different dosages (16 X 10(6) culturable particles (cp), 32 X 10(6) cp, and 64 X 10(6) cp). When comparing the whole group of 99 patients with a historical control group of 126 patients no statistically significant differences were found in survival and disease-free interval. The two groups were well matched in respect of age, sex, histology, stage of disease, and type of operation. Patients with epidermoid carcinoma stage I receiving BCG, however, did significantly worse than those who had not received BCG in terms of disease-free interval. This unfavourable trend was caused by earlier local recurrences rather than metastases. The possible phenomenon of enhanced tumour growth noted in or patients with epidermoid carcinoma stage I might be related to the dosages used in this study, but the different BCG strain used hinders comparison with other studies. We conclude that BCG has no beneficial effect on survival or on disease-free interval; possible enhancement of tumour growth in stage I epidermoid carcinoma was found. PMID:7330812

  16. The seventh tumour-node-metastasis staging system for lung cancer: Sequel or prequel?

    PubMed

    van Meerbeeck, Jan P; Janssens, Annelies

    2013-09-01

    Anatomical cancer extent is an important predictor of prognosis and determines treatment choices. In non-small-cell lung cancer (NSCLC) the tumour-node-metastasis (TNM) classification developed by Pierre Denoix replaced in 1968 the Veterans Administration Lung cancer Group (VALG) classification, which was still in use for small-cell lung cancer (SCLC). Clifton Mountain suggested several improvements based on a database of mostly surgically treated United States (US) patients from a limited number of centres. This database was pivotal for a uniform reporting of lung cancer extent by the American Joint Committee of Cancer (AJCC) and the International Union against Cancer (IUCC), but it suffered increasingly from obsolete diagnostic and staging procedures and did not reflect new treatment modalities. Moreover, its findings were not externally validated in large Japanese and European databases, resulting in persisting controversies which could not be solved with the available database. The use of different mediastinal lymph-node maps in Japan, the (US) and Europe facilitated neither the exchange nor the comparison of treatment results. Peter Goldstraw, a United Kingdom (UK) thoracic surgeon, started the process of updating the sixth version in 1996 and brought it to a good end 10 years later. His goals were to improve the TNM system in lung cancer by addressing the ongoing controversies, to validate the modifications and additional descriptors, to validate the TNM for use in staging SCLC and carcinoid tumours, to propose a new uniform lymph-node map and to investigate the prognostic value of non-anatomical factors. A staging committee was formed within the International Association for the Study of Lung Cancer (IASLC) - which supervised the collection of the retrospective data from >100,000 patients with lung cancer - treated throughout the world between 1990 and 2000, analyse them with the help of solid statistics and validate externally with the Surveillance

  17. Validation of dose painting of lung tumours using alanine/EPR dosimetry.

    PubMed

    Knudtsen, Ingerid Skjei; Svestad, Jørund Graadal; Skaug Sande, Erlend Peter; Rekstad, Bernt Louni; Rødal, Jan; van Elmpt, Wouter; Öllers, Michel; Hole, Eli Olaug; Malinen, Eirik

    2016-03-21

    Biologic image guided radiotherapy (RT) with escalated doses to tumour sub volumes challenges today's RT dose planning and delivery systems. In this phantom study, we verify the capability of a clinical dose planning and delivery system to deliver an 18F-FDG-PET based dose painted treatment plan to a lung tumour. Furthermore, we estimate the uncertainties of the dose painted treatment compared to conventional RT plans. An anthropomorphic thorax phantom of polystyrene and polyurethane was constructed based on CT images of a lung cancer patient. 101 EPR/alanine dosimeters were placed in separate cavities within the phantom. IMRT and VMAT plans were generated in Eclipse (version 10.0, Analytical Anisotropic Algorithm version 10.2.28, Varian Medical Systems, Inc.) for 6 and 15 MV photons, based on 18F-FDG-PET/CT images of the patient. A boost dose of 3.8 Gy/fraction was given to the 18F-FDG-avid region (biological planning volume; BTV), whereas 3.1 Gy/fraction was planned to the planning target volume (PTV, excluding the BTV). For the homogenous plans, 3.2 Gy/fraction was given to the PTV. Irradiation of the phantom was carried out at a Varian Trilogy linear accelerator (Varian Medical Systems, Inc.). Uncertainties involved in treatment planning and delivery were estimated from portal dosimetry gamma evaluation. Measured and calculated doses were compared by Bland-Altmann analysis. For all treatment plans, all dose-volume objectives could be achieved in the treatment planning system. The mean absolute differences between calculated and measured doses were small (<0.1 Gy) for BTV, PTV-BTV, lung and soft tissue. The estimated uncertainty of the planned doses was less than 3% for all plans, whereas the estimated uncertainty in the measured doses was less 2.3%. Our results show that planning and delivery of dose escalated lung cancer treatment on a clinical dose planning and delivery system has high dosimetric accuracy. The uncertainties associated with the dose escalated

  18. 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

  19. Montelukast reduces sepsis-induced lung and renal injury in rats.

    PubMed

    Khodir, Ahmed E; Ghoneim, Hamdy A; Rahim, Mona Abdel; Suddek, Ghada M

    2014-10-01

    This study was undertaken to examine the effects of montelukast (MNT) on lung and kidney injury in lipopolysaccharide (LPS) induced systemic inflammatory response. Rats were randomized into 5 groups (n = 8 rats/group): (i) Control; (ii) LPS treated (10 mg/kg body mass, by intraperitoneal (i.p.) injection); (iii) LPS + MNT (10 mg/kg, per oral (p.o.)); (iv) LPS + MNT (20 mg/kg, p.o); (v) LPS + dexamethasone (DEX; 1 mg/kg, i.p.). Twenty-four hours after sepsis was induced, the lung or kidney:body mass ratio and percent survival of rats were determined. Creatinine, blood urea nitrogen (BUN), albumin, total protein, and LDH activity were measured. Lung and kidney samples were taken for histological assessment and for determination of their malondialdehyde (MDA) and glutathione (GSH) contents. The expression of tumour necrosis factor α (TNF-α) in tissue was evaluated immunohistochemically. LPS significantly increased the organ:body mass ratio, serum creatinine, BUN, and LDH, and decreased serum albumin and total protein levels. MDA levels increased in lung and kidney tissues after treatment with LPS, and there was a concomitant reduction in GSH levels. Immunohistochemical staining of lung and kidney specimens from LPS-treated rats revealed high expression levels of TNF-α. MNT suppresses the release of inflammatory and oxidative stress markers. Additionally, MNT effectively preserved tissue morphology as evidenced by histological evaluation. These results demonstrate that MNT could have lung and renoprotective effects against the inflammatory process during endotoxemia. This effect can be attributed to its antioxidant and (or) anti-inflammatory properties. PMID:25243774

  20. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer

    PubMed Central

    Tsai, Meng-Feng; Wang, Chi-Chung; Chen, Jeremy JW

    2014-01-01

    Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC. PMID:25493224

  1. A new tumour associated antigen of non-small cell lung cancer: tumour liberated proteins (TLP)--a possible new tumor marker.

    PubMed

    Garaci, E; Sinibaldi, P; Rasi, G

    1996-01-01

    TLP (Tumour Liberated Proteins) is a 214 kDa protein, isolated from lung cancer tissue and synthetic nonapeptide CSH-275 is a major epitope identified on a 100 kDa TLP fragment and used to create antibodies in rabbit (antiserum termed CSH-419). CSH-419 antiserum, labelled or conjugated as necessary, was used to detect TLP on sera from NSCLC patients by a new ELISA test set up as a 1 step sandwich format test. This ELISA was performed on sera from 534 individuals. TLP was detected in 53.1% of NSCLC patients, with a 0% response in patients with cancers other than NSCLC, 7.6% response in unknown blood donors, and 17.4% response in patients with chronic lung diseases correlated with an elevated risk for lung cancer. TLP was particularly present in early stages of disease: 75% in stage I, 56% in stage II and III and 45% in stage IV. The presence of TLP antigen in sera from NSCLC patients indicates that TLP could represent an useful tumour marker. PMID:8694552

  2. HIFU and Chemotherapy Synergistic Inhibitory Effect on Dunning AT2 Tumour-Bearing Rats

    NASA Astrophysics Data System (ADS)

    Curiel, Laura; Paparel, Philipe; Chesnais, Sabrina; Gelet, Albert; Chapelon, Jean-Yves

    2005-03-01

    Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty-one Dunning AT2 tumour-bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU-chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control group volumes were significantly greater than those of the chemotherapy-only (p = 0.006) or HIFU-only group (p = 0.006). The greatest difference was observed between the chemotherapy plus HIFU combined group and the control group. Additionally, tumour-doubling times were 7.7 days for the control group, 13.2 days for the HIFU-only group, and 31.2 days for the chemotherapy plus HIFU group. The differences in tumour growth rates between the chemotherapy plus HIFU combined group and a chemotherapy-only + HIFU-only grouping was 3.8% (p = 0.0020). Thus, the combined chemotherapy plus HIFU treatment was clearly more effective in reducing the tumour size than HIFU only or chemotherapy only, which indicates a synergy between the two types of treatment. Our results suggest that this combined therapy could be useful for the treatment of high-risk prostate cancer.

  3. Localized hypothermia: impact on oxygenation, microregional perfusion, metabolic and bioenergetic status of subcutaneous rat tumours.

    PubMed Central

    Kelleher, D. K.; Nauth, C.; Thews, O.; Krueger, W.; Vaupel, P.

    1998-01-01

    The effect of localized hypothermia on microcirculatory and metabolic parameters in s.c. DS sarcomas on the hind foot dorsum of Sprague-Dawley rats was investigated. Tumours were cooled by superfusion of the tumour surface with cooled saline solution to 25 degrees C or 15 degrees C. Control tumours remained at 35 degrees C. These temperatures were maintained for 30 min. In tumour oxygenation measurements, hypothermia at 25 degrees C and 15 degrees C caused progressive decreases in the size of the fraction of pO2 measurements between 0 and 2.5 mmHg together with a reduction in pO2 variability. No significant changes in median or mean pO2 or in the fraction of pO2 measurements between 0 and 5 mmHg, and 0 and 10 mmHg were observed. Using laser Doppler flowmetry, red blood cell flux was found to decrease significantly upon 25 degrees C or 15 degrees C hypothermia treatment to 67% and 37% of starting values respectively, whereas no significant changes were seen in control tumours over the whole observation period. Viscosity was measured in blood and plasma samples over a range of temperatures and was found to increase with decreasing temperature. Assessment of tumour glucose levels showed an increased concentration of glucose following 15 degrees C hypothermia, an observation consistent with a 'slowing down' of glycolysis. No changes in lactate or adenylate phosphate levels were observed. As a way of improving tumour oxygenation, localized hypothermia may therefore be a useful means of radiosensitization. PMID:9662251

  4. Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock.

    PubMed Central

    Thiemermann, C.; Wu, C. C.; Szabó, C.; Perretti, M.; Vane, J. R.

    1993-01-01

    1. This study investigates the role of tumour necrosis factor (TNF) in the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in a rat model of endotoxin shock. 2. In anaesthetized rats, pretreatment with a monoclonal antibody for TNF (TNFab; 20 mg kg-1, s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg-1, i.v.). For instance, endotoxaemia for 180 min resulted in a fall in MAP from 114 +/- 6 (control) to 84 +/- 5 mmHg (P < 0.01; n = 7). In contrast, animals pretreated with TNFab prior to LPS injection maintained significantly higher MAP when compared to LPS-control (MAP at 180 min; 118 +/- 3 mmHg; P < 0.01, n = 5). 3. Three hours of endotoxaemia was also associated with a significant reduction of the contractile effects of noradrenaline (NA) (10(-8)-10(-6) M) on the thoracic aorta ex vivo. This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with NG-nitro-L-arginine methyl ester (L-NAME, 20 min, 3 x 10(-4) M). Pretreatment of rats with TNFab (20 mg kg-1; at 16 h prior to LPS) significantly (P < 0.05) attenuated the LPS-induced hyporeactivity of rat aortic rings ex vivo. L-NAME did not enhance the contractions of aortic rings obtained from TNFab pretreated LPS-rats. 4. At 180 min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 +/- 0.57 pmol citrulline mg-1 min-1, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7693276

  5. 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. PMID:26655996

  6. 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.

  7. 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

    2015-01-01

    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. PMID:25765541

  8. Cold ischemia-induced autophagy in rat lung tissue

    PubMed Central

    CHEN, XU; WU, JING-XIANG; YOU, XING-JI; ZHU, HONG-WEI; WEI, JIONG-LIN; XU, MEI-YING

    2015-01-01

    Autophagy is a highly conserved pathway that permits recycling of nutrients within the cell and is rapidly upregulated during starvation or cell stress. Autophagy has been implicated in the pathophysiological process of warm ischemia-reperfusion injury in the rat lung. Cold ischemia (CI) preservation for lung transplantation also exhibits cell stress and nutrient deprivation, however, little is known with regard to the involvement of autophagy in this process. In the present study, CI preservation-induced autophagy and apoptosis was investigated in the lungs of Sprague Dawley rats. Sprague Dawley rat lungs were flushed and preserved at 4°C (i.e. CI) for various durations (0, 3, 6, 12 and 24 h). The levels of autophagy, autophagic cell death and apoptosis were measured at each time point following CI. The results revealed that autophagy was induced by CI preservation, which was initiated at 3 h, peaked at 6 h after CI and declined thereafter. Additionally, a coexistence of autophagic cell death and apoptosis was observed in rat lung tissues following prolonged CI. These findings demonstrate that autophagy is involved in the pathophysiological process of lung CI. Furthermore, autophagic cell death in addition to necrosis and apoptosis occurs following CI in the lung. CI preservation may therefore be a potential mechanism of lung injury during organ preservation prior to lung transplantation. PMID:25435100

  9. 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.

  10. Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model

    PubMed Central

    Orendáš, Peter; Kubatka, Peter; Bojková, Bianka; Kassayová, Monika; Kajo, Karol; Výbohová, Desanka; Kružliak, Peter; Péč, Martin; Adamkov, Marián; Kapinová, Andrea; Adamicová, Katarína; Sadloňová, Vladimíra; Chmelová, Martina; Stollárová, Nadežda

    2014-01-01

    Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea-induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 μg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties. PMID:25270735

  11. 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.

  12. 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. PMID:14680076

  13. FACTORS DETERMINING DEGREE OF INFLATION IN INTRATRACHEALLY FIXED RAT LUNGS

    EPA Science Inventory

    The total lung capacity (TLC) of rats was measured in vivo and was compared to the displacement volume of the lungs following intratracheal fixation with glutaraldehyde or formaldehyde solution. When glutaraldehyde was used the speed of infusion of the fixative was an important f...

  14. Thyroid tumours in rats and hepatomas in mice after griseofulvin treatment.

    PubMed Central

    Rustia, M.; Shubik, P.

    1978-01-01

    Griseofulvin, an antibiotic used to treat dermatophystosis, was tested for carcinogenicity in mice, rats and hamsters. Three groups of mice and rats were given the drug in powdered diet in alternating 5-week periods for life, at dose levels of 3.0%, 1.5% and 0.3% (mice) and 2.0%, 1.0% and 0.2% (rats). A group of mice and 3 groups of hamsters received continuous daily treatment for life with griseofulvin at 3.0%, 1.5%, 0.3% and 0.1% dose levels respectively. A significant incidence of hepatic tumours was observed at the 2 higher treatment levels in mice. Also, statistically significant rates (P less than or equal to 0.001 and/or P less than or equal to 0.020) of thyroid tumours, indicating a dose-response, were recorded in male rats at the 2.0%, 1.0%, and 0.2% dose levels, and in females at the 2.0% and 1.0% dose levels. Hamsters did not develop neoplasms in response to treatment at any level. Images Figs. 2-5 Figs. 6-9 PMID:698038

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

    PubMed Central

    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

    2016-01-01

    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. PMID:27161380

  16. 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

    2016-01-01

    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. PMID:27161380

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

    PubMed

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

    2015-09-01

    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 (V600) (E)BRAF-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

  18. Cell Population Kinetics of a Spontaneous Rat Tumour During Serial Transplantation

    PubMed Central

    Steel, G. G.; Adams, K.; Hodgett, J.; Janik, P.

    1971-01-01

    Studies have been made on the growth and cell population kinetics of a spontaneous rat mammary fibroadenoma and of 10 successive transplantation passages. The volume doubling time decreased from about 30 days in the primary tumour and first two transplants to 1·7 days in the tenth transplant. This acceleration was accompanied by a considerable shortening of the mitotic cycle and of its S and G1 phases but without change in the proportion of time spent in S. There was also a reduction in the apparent extent of cell loss and a considerable increase in the growth fraction. Histological changes were noted and studies by feulgen densitometry indicated a considerable shift in ploidy from hyperdiploid to hypertetraploid. The results constitute a detailed example of the effect on tumour growth kinetics of serial transplantation. ImagesFig. 5 PMID:5144541

  19. 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. PMID:24978211

  20. Boron absorption imaging in rat lung colon adenocarcinoma metastases

    NASA Astrophysics Data System (ADS)

    Altieri, S.; Bortolussi, S.; Bruschi, P.; Fossati, F.; Vittor, K.; Nano, R.; Facoetti, A.; Chiari, P.; Bakeine, J.; Clerici, A.; Ferrari, C.; Salvucci, O.

    2006-05-01

    Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher 10B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of 10B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.

  1. 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

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

    PubMed Central

    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. PMID:26889245

  3. Metabolism of N-methylcarbazole by rat lung microsomes.

    PubMed

    Ibe, B O; Raj, J U

    1994-01-01

    N-methylcarbazole (NMC) is a procarcinogenic component of tobacco smoke particulate matter. It is metabolized by liver microsomes into some hydroxylated metabolites such as the potent mutagen N-hydroxymethylcarbazole (NHMC). Lung metabolism and toxicity of NMC is not known. Since the lung is the primary organ of inhalation of tobacco smoke, NMC metabolism by lung microsomes was studied in comparison with the metabolism by liver microsomes. Liver or lung microsomes (1 mg/mL) were incubated with 0.5 mM NMC for 30 min at 37 degrees C. NMC metabolites were extracted with ethyl acetate and analyzed by reversed-phase high-performance liquid chromatography. Rat lung microsomes metabolized NMC with a similar profile to liver microsomes, although lung microsomes produced greater number of metabolites. The potent mutagen NHMC was also the major NMC metabolite produced by lung microsomes, as confirmed by particle beam mass spectrometry. However, lung microsomes produced only 10% of NHMC produced by liver microsomes. Metabolism of NMC by lung microsomes also led to depletion of the endogenous antioxidant glutathione by 34% compared to controls, indicating a significant generation of some reactive intermediates during NMC metabolism by lung microsomes. The data show that the lung participates directly in producing the potent mutagen NHMC from NMC present in tobacco smoke. PMID:7925139

  4. 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.

  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

    2014-01-01

    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

  6. 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

  7. 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.

  8. Assessment of texture measures susceptibility to noise in conventional and contrast enhanced computed tomography lung tumour images.

    PubMed

    Al-Kadi, Omar Sultan

    2010-09-01

    Noise is one of the major problems that hinder an effective texture analysis of disease in medical images, which may cause variability in the reported diagnosis. In this paper seven texture measurement methods (two wavelet, two model and three statistical based) were applied to investigate their susceptibility to subtle noise caused by acquisition and reconstruction deficiencies in computed tomography (CT) images. Features of lung tumours were extracted from two different conventional and contrast enhanced CT image data-sets under filtered and noisy conditions. When measuring the noise in the background open-air region of the analysed CT images, noise of Gaussian and Rayleigh distributions with varying mean and variance was encountered, and Fishers' distance was used to differentiate between an original extracted lung tumour region of interest (ROI) with the filtered and noisy reconstructed versions. It was determined that the wavelet packet (WP) and fractal dimension measures were the least affected, while the Gaussian Markov random field, run-length and co-occurrence matrices were the most affected by noise. Depending on the selected ROI size, it was concluded that texture measures with fewer extracted features can decrease susceptibility to noise, with the WP and the Gabor filter having a stable performance in both filtered and noisy CT versions and for both data-sets. Knowing how robust each texture measure under noise presence is can assist physicians using an automated lung texture classification system in choosing the appropriate feature extraction algorithm for a more accurate diagnosis. PMID:20060263

  9. Photodynamic therapy using intravenous delta-aminolaevulinic acid-induced protoporphyrin IX sensitisation in experimental hepatic tumours in rats.

    PubMed Central

    Svanberg, K.; Liu, D. L.; Wang, I.; Andersson-Engels, S.; Stenram, U.; Svanberg, S.

    1996-01-01

    The efficacy of photodynamic therapy (PDT) using delta-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) sensitisation and laser light at 635 nm was investigated in the treatment of experimental hepatic tumours. The model of liver tumours was induced either by local inoculation or by administration of tumour cells through the portal vein in rats. ALA at a dose of 60 mg kg(-1) b.w. was intravenously administered 60 min before PDT. PpIX accumulation in tumour, normal liver and abdominal wall muscle was detected by means of laser-induced fluorescence (LIF). Laser Doppler imaging (LDI) was used to determine changes in the superficial blood flow in connection with PDT. Histopathological examinations were performed to evaluate the PDT effects on the tumour and the surrounding liver tissue, including pathological features in the microvascular system. The accumulation of PpIX, as monitored by LIF, showed high fluorescence intensities at about 635 nm in both the hepatic tumour tissue and normal liver and low values in the abdominal wall. LDI demonstrated that the blood flow in the treated tumour and its surrounding normal liver tissue decreased immediately after the PDT, indicating an effect on the vascular system. A large number of thrombi in the irradiated tumour were found microscopically 3 h after the PDT. The tumour growth rate showed a marked decrease when evaluated 3 and 6 days after the treatment. These results show that the ALA-PDT is effective in the inhibition of growth of experimental hepatic tumours. Images Figure 4 Figure 5 Figure 7 Figure 9 PMID:8932330

  10. Circadian variations in 32P uptake of DMBA-induced mammary tumour and Walker carcinosarcoma in rats.

    PubMed Central

    Møoller, U.; Bojsen, J.

    1976-01-01

    The 32P uptake in a mammary tumour induced by DMBA and in the Walker 256 carcinosarcoma was measured by external GM -tubes. The uptake was significantly higher than in the skin. During exposure to a synchronized light regime a circadian variation was present in the 32P uptake of the hormone-dependent DMBA-induced tumour. The maximal 32P uptake was in the dark period, in which the highest temperature in the tumour has also been found (Møoller and Bojsen, 1975). In the hormone-independent Walker 256 carcinosarcoma there was no periodicity in 32P uptake. No variation in 32P uptake was registered in the skin of normal controls or in tumour-bearing rats. PMID:820364

  11. Antioxidant enzyme expression in rat lungs during hyperoxia.

    PubMed

    Ho, Y S; Dey, M S; Crapo, J D

    1996-05-01

    To understand the molecular mechanisms that upregulate the activities of pulmonary antioxidant enzymes in adult rats during exposure to 85% oxygen, the relative contents of corresponding mRNA in normal and hyperoxic lungs were determined. Hyperoxic exposure drastically induced the expression of lung manganese-containing superoxide dismutase (MnSOD) mRNA. Maximal induction of MnSOD mRNA occurred at days 3 and 5 of exposure to hyperoxia, reaching a 600 and a 340% increase over the levels of air-exposed rats, respectively. In addition, hyperoxia induced lung mRNA for glucose-6-phosphate dehydrogenase, glutathione peroxidase, glyceraldehyde-3-phosphate dehydrogenase, alpha-tubulin, and gamma-actin to different extends at various days of exposure. Hyperoxia had little or no effect on the levels of mRNA for copper/zinc-containing superoxide dismutase (CuZnSOD), catalase, heat shock protein (HSP70), and creatine kinase. Nuclear run-on experiments showed that the transcriptional rate of the MnSOD gene is enhanced in hyperoxic rat lungs by approximately 400% at day 3 of exposure compared with that of controls. The specific activities of CuZnSOD and MnSOD in these lung samples per unit of lung protein or DNA were also determined. The activity of CuZnSOD in hyperoxic lungs was found to be unchanged compared with controls, except a 20% decrease at day 7 of exposure when standardized against protein content of lung homogenate. Changes of CuZnSOD activity were more dramatic in hyperoxic lungs (a 40% increase at days 3, 5, 7, and 14 of exposure) when enzyme activity was normalized using lung DNA content. Surprisingly, no proportional increase of lung MnSOD enzyme activity was observed at days 3 and 5 of oxygen exposure. The increase of MnSOD activity per unit of lung protein also did not parallel the increase in MnSOD protein content at days 5, 7, and 14 of exposure. These data suggest that, in addition to transcriptional activation, translational and/or posttranslational

  12. Lipopolysaccharide induces expression of collagen VI in the rat lung.

    PubMed

    Okawa, Sayuri; Unuma, Kana; Yamada, Atsushi; Aki, Toshihiko; Uemura, Koichi

    2015-01-01

    The involvement of the lung during the septic systemic inflammatory response elicited by administration of lipopolysaccharide (LPS) was investigated. Eight-week-old male Sprague-Dawley rats were injected i.p. with 15 mg/kg LPS. After 24 h, the lungs were excised to evaluate the cellular responses to LPS. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) analysis revealed that type VI collagen (ColVI) was extremely upregulated during sepsis in the rat lung within the first 24 h of LPS administration. Upregulation of ColVI protein and its mRNA was demonstrated by Western blot analysis, real time PCR, and immunohistochemistry. To the best of our knowledge, this is the first report demonstrating the activation of ColVI in the rat lung at the early stage of systemic inflammation. Activation of ColVI might be involved in sepsis-mediated lung fibrosis at an early stage. PMID:26023260

  13. NEUROGENIC RESPONSES OF RAT LUNG TO DIESEL EXHAUST

    EPA Science Inventory

    The investigators are among the first researchers to investigate neurogenic inflammation in the lungs of rats exposed to whole diesel exhaust. After exposure to both concentrations of diesel exhaust, consistently higher levels of plasma leakage and lower activity of the enz...

  14. Prostaglandin synthesis by chicken and rat lung microsomes

    SciTech Connect

    Craig-Schmidt, M.C.; Faircloth, S.A.; Wu-Wang, C.Y.

    1986-03-01

    A comparison between chicken and rat lung was made for microsomal prostaglandin (PG) synthesis from 1-/sup 14/C-arachidonic acid. Microsomal protein (2.0 mg) from chicken or rat lung was incubated in the presence of 20 ..mu..g of 1-/sup 14/C-arachidonic acid (specific activity = 3 x 10/sup 6/ dpm/..mu..mol for chicken; 6 x 10/sup 6/ dpm/..mu..mol for rat), 0.05 M Tris-HCl buffer (pH = 8.0), 0.5 mM epinephrine, and 1 mM reduced glutathione in a total volume of 0.5 ml in a 37/sup 0/C water bath with shaking for 15 min. After acidification with 1 M HCl to pH 3, prostaglandins were extracted with ethyl acetate. The products of the reactions were separated by reversed phase chromatography, and the radioactivity of each prostanoid fraction was determined. The predominant prostanoid synthesized by chicken lung microsomes was PGE/sub 2/, followed by much lower amounts of thromboxane B/sub 2/ (TXB/sub 2/), PGF/sub 2//sub ..cap alpha../ and PGD/sub 2/. In at lung, 6-keto-PGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGE/sub 1/, TXB/sub 2/, PGF/sub 2//sub ..cap alpha../ and PGD/sub 2/. In rat lung, 6-keto-FGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGE/sub 1/, TXB/sub 2/, PGF/sub 2//sub ..cap alpha../, PGE/sub 2/ and PGD/sub 2/ being formed. Enzyme specific activity (pmol of PG produced per mg microsomal protein per min) was 11.9 for PGE/sub 2/ produced by chicken lung and 16. 7 for 6-keto-P/sub 1//sub ..cap alpha../ produced by rat lung. Thus, there appears to be a species variation in chicken compared to rat for the lung prostanoids which are known to cause bronchial dilation.

  15. 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

  16. 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.

  17. 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. PMID:26991519

  18. 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.

  19. 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

  20. 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

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

    PubMed

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

    2011-01-01

    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

  2. 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.

  3. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression

    PubMed Central

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  4. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression.

    PubMed

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

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

    PubMed Central

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

    2016-01-01

    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. PMID:26804196

  6. Hyperbaric oxygen treatment ameliorates lung injury in paraquat intoxicated rats.

    PubMed

    Akcılar, Raziye; Akcılar, Aydın; Şimşek, Hasan; Koçak, Fatma Emel; Koçak, Cengiz; Yümün, Gündüz; Bayat, Zeynep

    2015-01-01

    Paraquat (PQ) is an agrochemical agent commonly used worldwide, which can cause acute lung injury (ALI) and death. Hyperbaric oxygen treatment (HBOT) is a therapeutic method, but the mechanisms of the protective effect of HBOT on ALI remain elusive. The purpose of this study was to evaluate the effect of HBOT on acute lung injury induced by PQ in rats. Wistar Albino rats (n=21) were separated into three groups of seven animals each: control (C), PQ, and PQ + HBOT groups. 20 mg/kg PQ was administered intraperitoneally in PQ and PQ + HBOT groups to induce experimental lung injury. Three days after PQ treatment, PQ + HBOT group was administered 100% O2 at 2.0 ATA for 1 hour per day, for five consecutive days. At the end of the study, lung tissue was obtained for determining total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and histopathological determination. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-β1 mRNA levels were assessed by quantitative reverse transcription-polymerase chain reaction. In addition, the inducible nitric oxide synthase (iNOS) level in the plasma was determined. Plasma iNOS, OSI, tissue TNF-α, TGF-β1 and bFGF mRNA levels, and histological injury scores in PQ + HBOT group were significantly lower than PQ group. TAS level in PQ + HBOT group was significantly higher than PQ group. The findings suggest that HBOT could effectively ameliorate PQ-induced lung injury in rats. PMID:26722498

  7. Hyperbaric oxygen treatment ameliorates lung injury in paraquat intoxicated rats

    PubMed Central

    Akcılar, Raziye; Akcılar, Aydın; Şimşek, Hasan; Koçak, Fatma Emel; Koçak, Cengiz; Yümün, Gündüz; Bayat, Zeynep

    2015-01-01

    Paraquat (PQ) is an agrochemical agent commonly used worldwide, which can cause acute lung injury (ALI) and death. Hyperbaric oxygen treatment (HBOT) is a therapeutic method, but the mechanisms of the protective effect of HBOT on ALI remain elusive. The purpose of this study was to evaluate the effect of HBOT on acute lung injury induced by PQ in rats. Wistar Albino rats (n=21) were separated into three groups of seven animals each: control (C), PQ, and PQ + HBOT groups. 20 mg/kg PQ was administered intraperitoneally in PQ and PQ + HBOT groups to induce experimental lung injury. Three days after PQ treatment, PQ + HBOT group was administered 100% O2 at 2.0 ATA for 1 hour per day, for five consecutive days. At the end of the study, lung tissue was obtained for determining total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and histopathological determination. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-β1 mRNA levels were assessed by quantitative reverse transcription-polymerase chain reaction. In addition, the inducible nitric oxide synthase (iNOS) level in the plasma was determined. Plasma iNOS, OSI, tissue TNF-α, TGF-β1 and bFGF mRNA levels, and histological injury scores in PQ + HBOT group were significantly lower than PQ group. TAS level in PQ + HBOT group was significantly higher than PQ group. The findings suggest that HBOT could effectively ameliorate PQ-induced lung injury in rats. PMID:26722498

  8. Anti-tumour efficacy of calusterone against DMBA-induced rat mammary adenocarcinoma in vivo and in organ culture.

    PubMed Central

    Horn, H.; Erlichman, I.; Levij, I. S.

    1976-01-01

    The effect of calusterone (7beta,17alpha-dimethyltestosterone) on rat mammary DMBA-induced adenocarcinoma was studied both in vivo and in organ culture. In vivo all 8 tumours with a diameter of less than 30 mm regressed following calusterone injection (10 mg/day for 2-3 weeks). In organ culture calusterone (20 mug/ml medium) inhibited the synthesis of DNA and RNA in all 7 cases examined. Testosterone also inhibited the synthesis of DNA and RNA in organ culture in 12 out of 14 and 10 out of 14 tumours respectively. Oestradiol-17beta on the other hand had no effect on DNA and RNA synthesis in organ culture although 70% of the tumours examined were ovarian dependent, i.e. regressed following castration. This could be explained by the direct effect of calusterone on rat adenocarcinoma compared with the indirect effect of oestradiol-17beta which probably exerts its action by activating the secretion of prolactin which acts on the tumour. PMID:131571

  9. 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.

  10. Fluorescence distribution and photodynamic effect of ALA-induced PP IX in the DMH rat colonic tumour model.

    PubMed Central

    Bedwell, J.; MacRobert, A. J.; Phillips, D.; Bown, S. G.

    1992-01-01

    Aminolaevulinic acid (ALA) is the first committed step in haem synthesis. In the presence of excess ALA the natural regulatory feedback system is disrupted allowing accumulation of protoporphyrin IX (PP IX) the last intermediate product before haem, and an effective sensitiser. This method of endogenous photosensitisation of cells has been exploited for photodynamic therapy (PDT). We have studied the fluorescence distribution and biological effect of induced PP IX in normal and tumour tissue in the rat colon. Fluorescence in normal colonic tissue was at a peak of 4 h with a rapid fall off by 6 h. The fluorescence had returned to background levels by 24 h. All normal tissue layers followed the same fluorescence profile but the mucosa showed fluorescent levels six times higher than the submucosa, with muscle barely above background values. At 6 h the ratio of fluorescence levels between normal mucosa and viable tumour was approximately 1:6. At this time laser treatment showed necrosis of normal mucosa and tumour with sparing of normal muscle. There was good correlation between the fluorescence distribution and the biological effect of ALA-induced photosensitisation on exposure to red light. ALA may be superior to conventional sensitisers for tumours that produce haem as the PP IX is synthesised in malignant cells while the other sensitisers mainly localise to the vascular stroma of tumours. There is also a greater concentration difference between the PP IX levels in tumours and in normal mucosa and normal muscle than with the other photosensitisers raising the possibility of more selective necrosis in tumours. Images p820-a Figure 2 Figure 3 Figure 4 Figure 7 Figure 8 PMID:1616853

  11. Enhanced Re-Endothelialization of Decellularized Rat Lungs.

    PubMed

    Stabler, Collin T; Caires, Luiz C; Mondrinos, Mark J; Marcinkiewicz, Cezary; Lazarovici, Philip; Wolfson, Marla R; Lelkes, Peter I

    2016-05-01

    Decellularized lung tissue has been recognized as a potential platform to engineer whole lung organs suitable for transplantation or for modeling a variety of lung diseases. However, many technical hurdles remain before this potential may be fully realized. Inability to efficiently re-endothelialize the pulmonary vasculature with a functional endothelium appears to be the primary cause of failure of recellularized lung scaffolds in early transplant studies. Here, we present an optimized approach for enhanced re-endothelialization of decellularized rodent lung scaffolds with rat lung microvascular endothelial cells (ECs). This was achieved by adjusting the posture of the lung to a supine position during cell seeding through the pulmonary artery. The supine position allowed for significantly more homogeneous seeding and better cell retention in the apex regions of all lobes than the traditional upright position, especially in the right upper and left lobes. Additionally, the supine position allowed for greater cell retention within large diameter vessels (proximal 100-5000 μm) than the upright position, with little to no difference in the small diameter distal vessels. EC adhesion in the proximal regions of the pulmonary vasculature in the decellularized lung was dependent on the binding of EC integrins, specifically α1β1, α2β1, and α5β1 integrins to, respectively, collagen type-I, type-IV, and fibronectin in the residual extracellular matrix. Following in vitro maturation of the seeded constructs under perfusion culture, the seeded ECs spread along the vascular wall, leading to a partial reestablishment of endothelial barrier function as inferred from a custom-designed leakage assay. Our results suggest that attention to cellular distribution within the whole organ is of paramount importance for restoring proper vascular function. PMID:26935764

  12. Radiation pneumonitis in patients with lung and mediastinal tumours: a retrospective study of risk factors focused on pulmonary emphysema

    PubMed Central

    Kimura, T; Togami, T; Takashima, H; Nishiyama, Y; Ohkawa, M; Nagata, Y

    2012-01-01

    Objectives To evaluate the impact of pulmonary emphysema (PE) on the incidence and severity of radiation pneumonitis (RP) in patients with lung and mediastinal tumours. Methods 92 patients were enrolled. Involved-field radiation therapy (non-small cell carcinoma or mediastinal tumours in 69 patients; median 70 Gy) and accelerated hyperfractionation (limited disease small cell carcinoma in 23 patients; median 45 Gy) were performed. Common Terminology Criteria for Adverse Events v.3.0 was used to evaluate RP and the relationship with the percentage of pulmonary volume irradiated to >20 Gy (V20) and PE. PE was diagnosed by the presence of low-attenuation areas (LAAs) on CT scans and was classified into Grades 0–4 according to the extent of the LAAs. Results The median follow-up time was 16 months. The 6-month cumulative incidence of RP at Grade 3 or greater was 7.7% and 34.1% in patients with a V20 of <25% and ≥25%, respectively (p=0.017). In patients with PE Grades 0, 1, 2 and 3 or greater, the incidence of RP was 16.5%, 9.1%, 8.6% and 54.0%, respectively. As the PE Grade increased, the incidence of RP also increased significantly. Conclusion The incidence and severity of RP are significantly higher in patients with a high V20 value as well as in those with severe PE. PMID:21385918

  13. 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.

  14. A dosimetric phantom study of dose accuracy and build-up effects using IMRT and RapidArc in stereotactic irradiation of lung tumours

    PubMed Central

    2012-01-01

    Background and purpose Stereotactic lung radiotherapy (SLRT) has emerged as a curative treatment for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC) and the use of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc treatments (VMAT) have been proposed as the best practical approaches for the delivery of SLRT. However, a large number of narrow field shapes are needed in the dose delivery of intensity-modulated techniques and the probability of underdosing the tumour periphery increases as the effective field size is decreased. The purpose of this study was to evaluate small lung tumour doses irradiated by intensity-modulated techniques to understand the risk for dose calculation errors in precision radiotherapy such as SLRT. Materials and methods The study was executed with two heterogeneous phantoms with targets of Ø1.5 and Ø4.0 cm. Dose distributions in the simulated tumours delivered by small sliding window apertures (SWAs), IMRT and RapidArc treatment plans were measured with radiochromic film. Calculation algorithms of pencil beam convolution (PBC) and anisotropic analytic algorithm (AAA) were used to calculate the corresponding dose distributions. Results Peripheral doses of the tumours were decreased as SWA decreased, which was not modelled by the calculation algorithms. The smallest SWA studied was 2 mm, which reduced the 90% isodose line width by 4.2 mm with the Ø4.0 cm tumour as compared to open field irradiation. PBC was not able to predict the dose accurately as the gamma evaluation failed to meet the criteria of ±3%/±1 mm on average in 61% of the defined volume with the smaller tumour. With AAA the corresponding value was 16%. The dosimetric inaccuracy of AAA was within ±3% with the optimized treatment plans of IMRT and RapidArc. The exception was the clinical RapidArc plan with dose overestimation of 4%. Conclusions Overall, the peripheral doses of the simulated lung tumours were

  15. Production of Histamine-like and Prostaglandin-Like Substances from Serum Incubated with Rat, Dog, Mouse or Human Tumours

    PubMed Central

    Apps, M. C. P.; Cater, D. B.

    1973-01-01

    When diluted serum was incubated at 37° with finely minced tumour tissue (from rat, dog, mouse or man) there was a fall of haemolytic complement titre (0-30 minutes), the production of a “histamine-like” material (30-90 minutes) and a prostaglandin-like “active lipid” (90-150 minutes). This latter was extracted with ethyl acetate at pH 3 and produced contraction of a rat stomach-fundus-strip preparation. Production of both types of activity was approximately proportional to the quantity of serum in the incubation mixture and to the fall in the haemolytic complement titre. With a constant amount of serum there was an optimum quantity of tumour, above which no further increase of active material was obtained. Aspirin or indomethacin added to the serum abolished the production of the “active lipid” but did not affect the “histamine-like” material. Inhibition of C′1 activity had a similar effect, but inhibition of C′3 abolished the production of both “histamine-like” and “prostaglandin-like” activity. When tumour was incubated with Tyrode's solution, both active fractions were present but their amount did not increase with time. When serum was incubated with liver or muscle from rat or guinea-pig, there was no “production” of either “histamine-like” or “prostaglandin-like” material. PMID:4349540

  16. Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: improvement of tumour uptake by internalisation.

    PubMed

    Kwa, H B; Wesseling, J; Verhoeven, A H; van Zandwijk, N; Hilkens, J

    1996-02-01

    The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLS) xenografts was studied in a Balb/c nu/nu mouse model. These Mabs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 125I, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after the administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. Mab 123C3 is internalised into tumour cells, whereas both other anti-NCAM Mabs are not. Internalisation into NCI H69 cells was demonstrated in vitro by radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabeled Mabs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results immunoscintigraphy. PMID:8595157

  17. Segmental hemodynamics during partial liquid ventilation in isolated rat lungs

    PubMed Central

    Ko, Angela C.; Hirsh, Emily; Wong, Andrew C.; Moore, Timothy M.; Taylor, Aubrey E.; Hirschl, Ronald B.; Younger, John G.

    2011-01-01

    Partial liquid ventilation (PLV) is a means of ventilatory support in which gas ventilation is carried out in a lung partially filled with a perfluorocarbon liquid capable of supporting gas exchange. Recently, this technique has been proposed as an adjunctive therapy for cardiac arrest, during which PLV with cold perfluorocarbons might rapidly cool the intrathoracic contents and promote cerebral protective hypothermia while not interfering with gas exchange. A concern during such therapy will be the effect of PLV on pulmonary hemodynamics during very low blood flow conditions. In the current study, segmental (i.e. precapillary, capillary, and postcapillary) hemodynamics were studied in the rat lung using a standard isolated lung perfusion system at a flow rate of 6 ml/min ( ~5% normal cardiac output). Lungs received either gas ventilation or 5 or 10 ml/kg PLV. Segmental pressures and vascular resistances were determined, as was transcapillary fluid flux. The relationship between individual hemodynamic parameters and PLV dose was examined using linear regression, with n = 5 in each study group. PLV at both the 5 and 10 ml/kg dose produced no detectable changes in pulmonary blood flow or in transcapillary fluid flux (all R2 values < 0.20). Conclusion: In an isolated perfused lung model of low flow conditions, normal segmental hemodynamic behavior was preserved during liquid ventilation. These data support further investigation of this technique as an adjunct to cardiopulmonary resuscitation. PMID:12668304

  18. 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.

  19. 4D radiobiological modelling of the interplay effect in conventionally and hypofractionated lung tumour IMRT

    PubMed Central

    Uzan, J; Baker, C; Nahum, A

    2015-01-01

    Objective: To study the impact of the interplay between respiration-induced tumour motion and multileaf collimator leaf movements in intensity-modulated radiotherapy (IMRT) as a function of number of fractions, dose rate on population mean tumour control probability () using an in-house developed dose model. Methods: Delivered dose was accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and was studied for conventionally and hypofractionated treatments using digital imaging and communications in medicine data sets. Moreover, the effect of dose rate on interplay was also studied for single-fraction treatments. Simulations were repeated several times to obtain for each plan. Results: The average variation observed in mean dose to the target volumes were −0.76% ± 0.36% for the 20-fraction treatment and −0.26% ± 0.68% and −1.05% ± 0.98% for the three- and single-fraction treatments, respectively. For the 20-fraction treatment, the drop in was −1.05% ± 0.39%, whereas for the three- and single-fraction treatments, it was −2.80% ± 1.68% and −4.00% ± 2.84%, respectively. By reducing the dose rate from 600 to 300 MU min−1 for the single-fraction treatments, the drop in was reduced by approximately 1.5%. Conclusion: The effect of interplay on is negligible for conventionally fractionated treatments, whereas considerable drop in is observed for the three- and single-fraction treatments. Reduced dose rate could be used in hypofractionated treatments to reduce the interplay effect. Advances in knowledge: A novel in silico dose model is presented to determine the impact of interplay effect in IMRT treatments on . PMID:25251400

  20. 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

  1. Sensitivity of locally recurrent rat mammary tumour cell lines to syngeneic polymorphonuclear cell, macrophage and natural killer cell cytolysis.

    PubMed

    Aeed, P A; Welch, D R

    1988-12-01

    Using a recently developed model for studying the biology of locally recurrent (LR) mammary tumours in the 13762NF rat mammary adenocarcinoma system, we examined the sensitivity to polymorphonuclear cell, macrophage and natural killer cell cytolysis. The parental MTF7(T20) cell line; the 'primary' tumours which arose following subcutaneous inoculation into the mammary fat pad, sc1 and sc3; and the local recurrences (following surgical excision) LR1 and LR1a from sc1, and LR3 from sc3 were all cells generally resistant to specific PMN cytolysis. LPS-activated macrophages caused 25.1%, 38.7% and 58.8% specific cytolysis in MTF7, sc1 and LR1 cells, respectively at E:T of 20:1 and 72 h co-incubation. LR1a, sc3 and LR3 lysis ranged from 0-4.4% under the same conditions. Non-activated macrophages did not lyse any of the cell lines. Locally recurrent and 'primary' tumour cell lines were also not lysed by naive NK cells (range 0.5-4.0% cytolysis). NK cells activated with bropirimine, a potent immunomodulator currently being studied in clinical trials, and/or interleukin-2 were mildly more effective at killing LR cells. Our results show that locally recurrent tumours exhibit heterogeneous sensitivities and are different from 'primary' tumour cells in sensitivities to immune cell killing, but they are not necessarily more or less sensitive. Results with bropirimine-activated or IL-2-activated NK cells emphasize that nonspecific activation is insufficient to eliminate all tumour subpopulations. PMID:3224080

  2. Analysis of lung tumor risks in rats exposed to radon.

    PubMed

    Gilbert, E S; Cross, F T; Dagle, G E

    1996-03-01

    Using data on 3117 rats exposed by inhalation to radon, radon progeny and uranium ore dust, the hazard function (or age-specific risk) for lung tumor incidence was modeled as a function of exposure, exposure rate and other factors. The overall estimate of lifetime risk was 237 cases per 10(6) rats per WLM (237 per 10(6) WLM), reasonably comparable to estimates obtained from data for humans. The data below 1000 WLM (20-640 WLM) were consistent with linearity with positive excess risks at all levels; however, evidence of statistically significant excess risk was limited to exposures of 80 WLM or greater. Evidence for an inverse exposure-rate effect was limited primarily to cumulative exposures exceeding 1000 WLM (1280-10,240 WLM) and to comparison of results at 100 and 1000 WL. Even at these levels, the possibility that the effect might be explained by time since last exposure or by heterogeneity across experiments could not be entirely excluded. The inverse exposure-rate effect was strongest for epidermoid and adenosquamous tumors, and the only indication of such an effect at exposures below 1000 WLM was modest evidence (P=0.024) in analyses limited to these tumors. When all lung tumors, or all malignant lung tumors, were included, there was no evidence of such an effect below 1000 WLM. These data support the viewpoint that the inverse exposure-rate effect is primarily a high-dose phenomenon. PMID:8927704

  3. Ultrastructural alterations during embryonic rats' lung development caused by ozone.

    PubMed

    López, Irma; Sánchez, Ivonne; Bizarro, Patricia; Acevedo, Sandra; Ustarroz, Martha; Fortoul, Teresa

    2008-01-01

    Ozone (O3) is an oxidizing agent that acts on phospholipids, proteins and sugars of cellular membranes producing free radicals, which cause oxidative damages. The O3 exposure has been used as a model to study oxidative stress, in which the respiratory airways represent the entrance to the organism. In this study, ultrastructural alterations were identified at the bronchiolar level during the intra-uterine lung development, using an O3 exposure model in pregnant rats during 18, 20 and 21 days of gestation. Twelve pregnant Wistar rats, six controls and six exposed to 1 ppm O3 inhalation during 12 h per day, were used. The rats were sacrificed at gestational days 18, 20 and 21; the fetuses were obtained and their lungs dissected. The ultrastructural analysis evidenced swollen mitochondria, cytoplasmic vacuolization of the epithelial cells and structural disorder caused by the oxidative stress. At gestation day 20, flake-off epithelial cells and laminar bodies in the bronchiolar lumen were observed. In the 21-gestation-day group, the mitochondria were edematous and their cristae were disrupted by the damage caused in mitochondrial membranes. PMID:18083976

  4. 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.

  5. 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. PMID:24378995

  6. Interleukin-33 enhances programmed oncosis of ST2L-positive low-metastatic cells in the tumour microenvironment of lung cancer

    PubMed Central

    Akimoto, M; Hayashi, J-I; Nakae, S; Saito, H; Takenaga, K

    2016-01-01

    The proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L on the surface of immune cells and stimulates the production of Th2 cytokines; however, the effects of IL-33 on tumour cells are poorly understood. Here we show that ST2 was significantly downregulated in human lung cancer tissues and cells compared with normal lung tissues and cells. IL-33 expression was also inversely correlated with the stages of human lung cancers. In accordance with this finding, low-metastatic cells but not high-metastatic cells derived from Lewis lung carcinoma expressed functional ST2L. IL-33 was abundantly present in the tumours established by the low-metastatic cells compared with those formed by the high-metastatic cells. Although the low-metastatic cells scarcely expressed IL-33 in vitro, these cells did expry 6ess this molecule in vivo, likely due to stimulation by intratumoural IL-1β and IL-33. Importantly, IL-33 enhanced the cell death of ST2L-positive low-metastatic cells, but not of ST2L-negative high-metastatic cells, under glucose-depleted, glutamine-depleted and hypoxic conditions through p38 MAPK and mTOR activation, and in a mitochondria-dependent manner. The cell death was characterised by cytoplasmic blisters and karyolysis, which are unique morphological features of oncosis. Inevitably, the low-metastatic cells, but not of the high-metastatic cells, grew faster in IL-33−/− mice than in wild-type mice. Furthermore, IL-33 selected for the ST2L-positive, oncosis-resistant high-metastatic cells under conditions mimicking the tumour microenvironment. These data suggest that IL-33 enhances lung cancer progression by selecting for more malignant cells in the tumour microenvironment. PMID:26775708

  7. 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. PMID:24456333

  8. Removal of albumin microinjected in rat lung perimicrovascular space.

    PubMed

    Ying, X; Qiao, R; Ishikawa, S; Bhattacharya, J

    1994-09-01

    We used a microinjection approach to assess hydraulic properties of lung perimicrovascular adventitia (interstitial cuff surrounding microvessels). Isolated blood-perfused rat lungs held at constant airway pressure were microscopically viewed to identify subpleural venules (20 microns diam). Venular adventitia were microinjected with 20 nl of fluorescent albumin (4 g/dl), and then adventitial fluorescence was quantified at the injection site by either photometery or imaging. Nonlinear decay of adventitial fluorescence indicated liquid flux from the injection site into normal interstitium. In some experiments, we determined that the adventitial fluorescence flowed longitudinally along the venule length and filled single lymphatics. The fluorescence decay at the injection site was best described by equations of convective but not diffusive transport. The decay time constant (time to 37% initial), which relates inversely to hydraulic conductivity, increased 10-fold above baseline on lung expansion with airway pressure from 5 to 15 cmH2O (P < 0.05). However, presence or absence of blood flow, increase in filtration pressure, and tissue edema were all without effect on the time constant. Our estimate of the lower limit of baseline adventitial hydraulic conductivity was 5 x 10(-6) ml.cm-2.s-1.cmH2O-1. We conclude that hydraulic conductivity of perimicrovascular adventitia is not augmented by edema but that it is decreased by lung expansion. PMID:7836133

  9. Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy.

    PubMed

    Zhang, Zhang; Wodzak, Michelle; Belzile, Olivier; Zhou, Heling; Sishc, Brock; Yan, Hao; Stojadinovic, Strahinja; Mason, Ralph P; Brekken, Rolf A; Chopra, Rajiv; Story, Michael D; Timmerman, Robert; Saha, Debabrata

    2016-06-01

    Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer. PMID:27223828

  10. 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

  11. 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.

  12. Vascular response to radiation injury in the rat lung.

    PubMed

    Peterson, L M; Evans, M L; Graham, M M; Eary, J F; Dahlen, D D

    1992-02-01

    Changes in relative left-to-right lung blood flow ratios were followed as an index of vascular radiation injury in left-hemithorax-irradiated Sprague-Dawley rats. Single doses of 11 to 21 Gy gamma radiation resulted in a dose-dependent decrease in relative blood flow to the irradiated lung from 3 to 5 weeks after exposure during the development of pneumonitis. Blood flow returned to near normal by 5 weeks after lower doses (11-13.5 Gy). After a single dose of 15 Gy the left-to-right blood flow ratio recovered to 75% of normal at 12 weeks and leveled off. Following 18 Gy irradiation a second period of reduced flow began 16 weeks after exposure. After 21 Gy irradiation flow to the irradiated side remained low for 1 year after exposure. Rats that received a single dose of 18 Gy to the left hemithorax were also treated with one or two of the following drugs: captopril, cyproheptadine, dexamethasone, diethylcarbamazine, penicillamine, or theophylline. Dexamethasone was most effective at preventing the decrease in blood flow to the irradiated lung when treatment was continued through the pneumonitis period and dose was not tapered until 8 weeks after radiation exposure. All other drugs and drug combinations were, for the most part, virtually ineffective after the pneumonitis period. There was a relatively poor correlation with earlier vascular permeability surface area product studies. This suggests that endothelial damage, as well as damage to other cell types, contributes to the development of post-irradiation fibrosis in the lung. PMID:1734443

  13. 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

  14. Severe psychosis due to Cushing's syndrome in a patient with a carcinoid tumour in the lung: a case report and review of the current management.

    PubMed

    Baba, Mohamad; Ray, Debamalya

    2015-01-01

    Severe psychosis in patients with Cushing's syndrome is a rare occurrence and can be extremely resistant to medical therapy. We describe a case of a 51-year-old Afro-Caribbean female patient, with refractory severe hypertension (initially resistant to polypharmacy) and gradual development of severe psychosis secondary to ectopic Cushing's syndrome, who was subsequently diagnosed to have a carcinoid tumour in her lung. Her psychotic episodes - secondary to hypercortisolism and initially refractory to the medical therapy - subsided only after the resection of the carcinoid tumour in her right lower pulmonary lobe. Early localization and appropriate surgical resection of the ectopic ACTH-secreting tumour can be of immense value to the successful alleviation of the psychotic episodes of the patients with ectopic Cushing's syndrome. PMID:25926160

  15. 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. PMID:22264098

  16. Is there a standard of care for the radical management of non-small cell lung cancer involving the apical chest wall (Pancoast tumours)?

    PubMed

    Peedell, C; Dunning, J; Bapusamy, A

    2010-06-01

    The term Pancoast tumour encompasses a wide range of tumours that invade the apical chest wall. Although less than 5% of non-small cell lung cancers are Pancoast tumours, they still account for most cases. They often pose a formidable challenge to the multidisciplinary lung cancer team due to their relative rarity, anatomical proximity to vital structures, differing stages of presentation, and their association with smoking-related illnesses. A lack of clinical trials makes comparisons between different treatment modalities very difficult and the management of Pancoast tumours has been largely based on the published retrospective experience of large single institutions. The bimodality approach of induction radiotherapy followed by surgical resection has been the accepted standard of care for the last 50 years, with reported 5-year survival rates of 30% in selected patients. However, two recent prospective multicentre phase II studies using a trimodality approach of induction concurrent chemoradiotherapy followed by surgical resection (followed by two further cycles of adjuvant chemotherapy in one of the studies), have reported 5-year survival rates of 44-56%. This has led to some authorities advocating the trimodality approach as the new standard of care for the management of Pancoast tumours. In this overview, the historical evolution of the management of Pancoast tumours and recent published studies on the trimodality approach are discussed. This is followed by a discussion of whether the trimodality approach should be seen as a new standard of care. Finally, other potential treatment options and the possibilities for future research are deliberated. PMID:20347280

  17. 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.

  18. Lung transplantation in the rat. III. Functional studies in iso- and allografts

    SciTech Connect

    Marck, K.W.; Prop, J.; Wildevuur, C.R.

    1983-08-01

    Recently a microsurgical technique for orthotopic left lung transplantation in the rat was developed. The aim of this study was to investigate the influence of the operation itself and of an unmodified rejection reaction on the function of the transplanted rat lung. Orthotopic left lung transplantation was performed in 59 rats (34 isografts and 25 allografts). Isografts demonstrated a mean left lung perfusion of 23.1% in the first two postoperative weeks. Seven out of the 10 animals, subjected to a repeated scintigraphy 5-10 weeks later, had an increased graft perfusion, resulting in an almost normal mean left lung perfusion of 34.8%. At that time chest roentgenography revealed a good aeration of the grafts, that at autopsy had a normal aspect. Allografts showed an initial mean left lung perfusion (24.6%) similar to the isografts, which, however, declined sharply a few days later (4.3%). At that time chest roentgenography revealed totally opalescent grafts that at autopsy had the hepatized aspect characteristic of lung allograft rejection. These results of isogeneic and allogeneic lung transplantation in the rat were comparable with those of canine auto- and allotransplantation. For immunogenetic and economical reasons lung transplantation in the rat is a good alternative animal model in lung transplantation research.

  19. 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

  20. Lung eicosanoids in perinatal rats with congenital diaphragmatic hernia

    PubMed Central

    Ijsselstijn, H.; Zijlstra, F. J.; Van Dijk, J. P. M.; De Jongste, J. C.

    1997-01-01

    Abnormal levels of pulmonary eicosanoids have been reported in infants with persistent pulmonary hypertension (PPH) and congenital diaphragmatic hernia (CDH). We hypothesized that a dysbalance of vasoconstrictive and vasodilatory eicosanoids is involved in PPH in CDH patients. The levels of several eicosanoids in lung homogenates and in bronchoalveolar lavage fluid of controls and rats with CDH were measured after caesarean section or spontaneous birth. In controls the concentration of the stable metabolite of prostacyclin (6-keto-PGF1α), thromboxane A2 (TxB2), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) decreased after spontaneous birth. CDH pups showed respiratory insufficiency directly after birth. Their lungs had higher levels of 6- keto-PGF1α, reflecting the pulmonary vasodilator prostacyclin (PGI2), than those of controls. We conclude that in CDH abnormal lung eicosanoid levels are present perinatally. The elevated levels of 6-keto-PGF1α in CDH may reflect a compensation mechanism for increased vascular resistance. PMID:18472832

  1. 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. PMID:25008149

  2. Inhibition of Neutrophil Exocytosis Ameliorates Acute Lung Injury in Rats

    PubMed Central

    Uriarte, Silvia M.; Rane, Madhavi J.; Merchant, Michael L.; Jin, Shunying; Lentsch, Alex B.; Ward, Richard A.; McLeish, Kenneth R.

    2013-01-01

    Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALf). Administration of TAT-SNAP-23, but not TAT-Control, significantly reduced albumin leakage, total protein levels in the BALf, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALf neutrophils and a decrease in neutrophil granule proteins in BALf. Similar degree of neutrophil accumulation in the lungs and/or BALf suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALf revealed that components of the complement and coagulation pathways were significantly reduced in BALf from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT-fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI. PMID:23364427

  3. 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.

  4. Overexpression of WDR79 in non-small cell lung cancer is linked to tumour progression.

    PubMed

    Sun, Yang; Yang, Chao; Chen, Jieying; Song, Xin; Li, Zhen; Duan, Minlan; Li, Jianglin; Hu, Xiaoxiao; Wu, Kuangpei; Yan, Guobei; Yang, Cai; Liu, Jing; Tan, Weihong; Ye, Mao

    2016-04-01

    WD-repeat protein 79 (WDR79), a member of the WD-repeat protein family, acts as a scaffold protein, participating in telomerase assembly, Cajal body formation and DNA double-strand break repair. Here, we first report that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC). Knockdown of WDR79 significantly inhibited the proliferation of NSCLC cells in vitro and in vivo by inducing cell cycle arrest and apoptosis. WD-repeat protein 79 -induced cell cycle arrest at the G0/G1 phase was associated with the expression of G0/G1-related cyclins and cyclin-dependent kinase complexes. We also provide evidence that WDR79 knockdown induces apoptosis via a mitochondrial pathway. Collectively, these results suggest that WDR79 is involved in the tumorigenesis of NSCLC and is a potential novel diagnostic marker and therapeutic target for NSCLC. PMID:26849396

  5. Ras gene mutation-independent tumours in the intestine of the rat by a single dose of N-methyl-N-nitrosourea.

    PubMed Central

    Waldmann, V.; Rabes, H. M.

    1992-01-01

    Aiming at a sequential analysis of the role of ras gene point mutations during intestinal carcinogenesis, we established an experimental rat tumour model using N-methyl-N-nitrosourea (MNU) as an initiating agent as this carcinogen has been found to induce rat mammary carcinomas with a high prevalence of ras gene mutations. MNU treatment of a total of 249 rats (25 or 50 mg/kg i.p.) in various combinations with partial hepatectomy, hydroxyurea infusion and/or phenobarbital exposure resulted in a high incidence of intestinal adenomas and carcinomas of different histological types, besides liver, soft tissue and auditory sebaceous gland tumours. With PCR-amplified DNA the prevalence of mutations of codon 12 and 61 of H-, K- and N-ras was determined in dot blots by hybridization with 32P-labelled allele-specific oligonucleotides. Ras gene point mutations were not observed in any of the 41 intestinal rat tumours randomly selected from various experimental groups. Considering the high prevalence of ras mutations in MNU-induced mammary carcinomas of the rat the observed complete lack of ras mutations in intestinal tumours induced in the rat by the same carcinogen suggests that organ-specific intraspecies differences in the mechanism of malignant transformation exist even for a heterolytically decomposing, direct acting carcinogen like MNU. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:1390191

  6. 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

  7. Brain and spinal tumour.

    PubMed

    Goh, C H; Lu, Y Y; Lau, B L; Oy, J; Lee, H K; Liew, D; Wong, A

    2014-12-01

    This study reviewed the epidemiology of brain and spinal tumours in Sarawak from January 2009 till December 2012. The crude incidence of brain tumour in Sarawak was 4.6 per 100,000 population/year with cumulative rate 0.5%. Meningioma was the most common brain tumour (32.3%) and followed by astrocytoma (19.4%). Only brain metastases showed a rising trend and cases were doubled in 4 years. This accounted for 15.4% and lung carcinoma was the commonest primary. Others tumour load were consistent. Primitive neuroectodermal tumour (PNET) and astrocytoma were common in paediatrics (60%). We encountered more primary spinal tumour rather than spinal metastases. Intradural schwannoma was the commonest and frequently located at thoracic level. The current healthcare system in Sarawak enables a more consolidate data collection to reflect accurate brain tumours incidence. This advantage allows subsequent future survival outcome research and benchmarking for healthcare resource planning. PMID:25934956

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

    PubMed

    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 (Delta[HbO(2)]) within tumours and oxygen tension (pO(2)) maps were achieved using (19)F MRI of the reporter molecule hexafluorobenzene. Multiple correlations were examined between rates and magnitudes of vascular (Delta[HbO(2)]) and tissue (pO(2)) 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 pO(2) values (R(2) > 0.7). The initial rates of increase of Delta[HbO(2)] and the slope of dynamic pO(2) response, d(pO(2))/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 pO(2) response to oxygen is primarily dependent upon the well perfused rather than poorly perfused vasculature. PMID:16357430

  9. Studies on acetyl-CoA carboxylase and fatty acid synthase from rat mammary gland and mammary tumours.

    PubMed Central

    Ahmad, P M; Feltman, D S; Ahmad, F

    1982-01-01

    The activities of two lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase, were determined in two transplantable mammary adenocarcinomas (13762 and R3230AC) carried by non-pregnant, pregnant and lactating rats, and in mammary tissue of control animals (non-tumour-carrying) of comparable physiological states. During mammary-gland differentiation of control or tumour-carrying animals, the activities of acetyl-CoA carboxylase and fatty acid synthase in the lactating gland increased by about 40--50-fold over the values found in non-pregnant animals. On the other hand, in tumours carried by lactating dams there were only modest increases (1.5--2-fold) in acetyl-CoA carboxylase and fatty acid synthase compared with the neoplasms carried by non-pregnant animals. On the basis of the Km values for different substrates and immunodiffusion and immunotitration data, the fatty acid synthase of neoplastic tissues appeared to be indistinguishable from the control mammary-gland enzyme. However, a comparison of the immunotitration and immunodiffusion experiments indicated that the mammary-gland acetyl-CoA carboxylase might differ from the enzyme present in mammary neoplasms. Images Fig. 1. Fig. 2. PMID:6130760

  10. Long term effects of maternal protein restriction on postnatal lung alveoli development of rat offspring.

    PubMed

    Farid, S A; Mahmoud, O M; Salem, N A; Abdel-Alrahman, G; Hafez, G A

    2015-01-01

    Poor nutrition of women during pregnancy causes reduction in foetal growth and can adversely affect the development of the foetal lungs. The purpose of the present study was to assess the effects of maternal protein restriction on the postnatal lung development in neonatal period, and on lung structure in adult rat offspring. Female virgin Sprague-Dawley albino rats (more than 200 g) were used. One male rat was introduced into a cage with one female for matting. Once the pregnancy was confirmed, pregnant rats were divided into two main groups; each consists of 6 female as follow: 1 - normally nourished group; 2 - protein deficient group. After delivery, offspring were subdivided into three groups: 1 day after delivery, 2 weeks and 2 months postnatal. Rat body and lung weight were recorded and ratio of lung weight to body weight was assessed. Total plasma protein and serum albumin were assessed for all groups. Lung tissue stained with H&E for histological and morphometric analysis. Immunohistochemistry was performed to evaluate the number of cells positive for pulmonary surfactant protein A. Our results showed that protein restriction interfere with neonatal and postnatal lung development resulting in morphological and morphometric changes of normal lung development. We concluded that protein deficiency lead to developmental retardation of lung. PMID:26620509

  11. 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)

  12. 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

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

    PubMed

    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

    2016-06-01

    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

  14. 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

  15. Cobalt iontophoresis of sensory nerves in the rat lung.

    PubMed

    El-Bermani, A W; Chang, T L

    1979-02-01

    By iontophoretically introducing, first, cobalt and, subsequently, sulfide ions into the vagus nerve, it is possible to trace sensory nerves to their endings in the rat lung. Nerve fibers and terminals are found predominantly in the adventitia of the airways and blood vessels. Some nerves are found in the submucosa of the bronchi and bronchioles. Some are found in the cardiac muscle on the periphery of pulmonary veins, and a few nerves are seen to end among smooth muslces of the blood vessels and the airways. At least three types of nerve endings can be identified at the light microscopic level: (1) free nerve endings; (2) brush-like endings; (3) knob-like terminals. PMID:760496

  16. Glucose-induced thermogenesis in patients with small cell lung carcinoma. Before and after inhibition of tumour growth by chemotherapy.

    PubMed

    Simonsen, L; Bülow, J; Sengeløv, H; Madsen, J; Ovesen, L

    1993-07-01

    Seven weight-losing patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g before and at least 3 weeks after the end of chemotherapy to examine the effect of glucose on whole body and skeletal muscle thermogenesis before and after reduction of tumour. Whole body energy expenditure was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous-occlusion strain-gauge plethysmography. The uptake of oxygen in skeletal muscle was calculated as the product of the forearm blood flow and the difference in a-v oxygen concentration. Whole body resting energy expenditure (REE) did not increase, it was 4.4 +/- 0.3 kJ min-1 (mean +/- SE) before chemotherapy and 4.4 +/- 0.2 kJ min-1 after chemotherapy. The glucose-induced thermogenesis in the 180 min following the glucose load was 93.6 +/- 9.9 kJ 180 min-1 before chemotherapy. This is significantly increased compared to that found in a healthy control group (74.7 +/- 4.8 kJ 180 min-1, P < 0.02). The glucose-induced thermogenesis was significantly reduced to 47.7 +/- 10.2 kJ 180 min-1 (P < 0.05) after chemotherapy. The oxygen uptake in resting skeletal muscles was 6.9 +/- 0.3 mumol 100 g-1 min-1 before chemotherapy and 7.0 +/- 0.7 mumol 100 g-1 min-1 after chemotherapy. This did not increase during the first 90 min following the glucose load in either investigations. In the period 90-180 min following the glucose load, the oxygen uptake was significantly increased before chemotherapy as compared to after chemotherapy, which suggests that the reduced whole body thermogenesis after chemotherapy in part was due to reduced skeletal muscle thermogenesis. PMID:8396523

  17. Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

    PubMed Central

    Shanmugam, Srinivasan; Im, Ho Taek; Sohn, Young Taek; Kim, Kyung Soo; Kim, Yong- Il; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon; Woo, Jong Soo

    2013-01-01

    The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol®, sodium cholate, sodium caprate, hydroxypropyl β-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and Papp of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC0-24 h of ZMR in the lungs following oral administration of PO-SC was 125.22 ± 27.25 ng hr ml-1 with a Cmax of 156.00 ± 24.00 ng/ml reached at 0.50±0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC50 concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect. PMID:24009875

  18. 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

  19. Method of isolated ex vivo lung perfusion in a rat model: lessons learned from developing a rat EVLP program.

    PubMed

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes, Don; Black, Sylvester M; Ghadiali, Samir; Whitson, Bryan A

    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

  20. Pyrrolidine Dithiocarbamate Attenuates Paraquat-Induced Lung Injury in Rats

    PubMed Central

    Chang, Xiuli; Shao, Chunfeng; Wu, Qing; Wu, Qiangen; Huang, Min; Zhou, Zhijun

    2009-01-01

    Paraquat (PQ) has been demonstrated that the main target organ for the toxicity is the lung. This study aimed to investigate the potential protective effect of PDTC on the PQ-induced pulmonary damage. Fifty-four rats were divided into control, PQ-treated and PQ+PDTC-treated groups. Rats in the PQ group were administrated 40 mg/kg PQ by gastric gavage, and PDTC group with 40 mg/kg PQ followed by injection of 120 mg/kg PDTC (IP). On the days 3, 7, 14 and 21 after treatments, the activities of GSH-Px, SOD, MDA level and the content of HYP were measured. TGF-β1 mRNA and protein were assayed by RT-PCR and ELISA. MDA level in plasma and BALF was increased and the activities of GSH-Px and SOD were decreased significantly in the PQ-treated groups (P < .05) compared with control group. While the activities of GSH-Px and SOD in the PQ+PDTC-treated groups was markedly higher than that of PQ-treated groups (P < .05), and in contrast, MDA level was lower. TGF-β1 mRNA and protein were significantly lower in the PQ+PDTC-treated groups than that of PQ-treated groups (P < .05). The histopathological changes in the PQ+PDTC-treated groups were milder than those of PQ groups. Our results suggested that PDTC treatment significantly attenuated paraquat-induced pulmonary damage. PMID:19639047

  1. 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. PMID:16337418

  2. 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

  3. The stereochemical configuration of lysobisphosphatidic acid from rat liver, rabbit lung and pig lung.

    PubMed

    Joutti, A; Brotherus, J; Renkonen, O; Laine, R; Fischer, W

    1976-11-19

    Lysobisphosphatidic acid known also as bis(monoacyl-glycerol)phosphate, was isolated from liver of rats treated with Triton WR1339, and from rabbit and pig lung. Alkaline hydrolysates of all these samples of lysobisphosphatidic acid were essentially similar and contained phosphorus, total glycerol, free glycerol, total glycerophosphates, beta-glycerophosphate, total alpha-glycerophosphates, sn-glycero-1-phosphate and sn-glycero-3-phosphate in a molar ratio of 1.0 : 2.0 : 1.0 : 1.0 :0.6 : 0.4 : 0.38 : 0.04. This proves that the backbone of the principal lysobisphosphatidic acid from all three sources has the structure of 1-sn-glycerophospho-1-sn-glycerol. PMID:990300

  4. 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.

  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. 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

  7. 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

  8. Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats.

    PubMed

    Zhao, Hailin; Ning, Jiaolin; Lemaire, Alexandre; Koumpa, Foteini-Stefania; Sun, James J; Fung, Anthony; Gu, Jianteng; Yi, Bin; Lu, Kaizhi; Ma, Daqing

    2015-04-01

    Early renal graft injury could result in remote pulmonary injury due to kidney-lung cross talk. Here we studied the possible role of regulated necrosis in remote lung injury in a rat allogeneic transplantation model. In vitro, human lung epithelial cell A549 was challenged with TNF-α and conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. In vivo, the Brown-Norway rat renal grafts were extracted and stored in 4 °C Soltran preserving solution for up to 24 h and transplanted into Lewis rat recipients, and the lungs were harvested on day 1 and day 4 after grafting for further analysis. Ischemia-reperfusion injury in the renal allograft caused pulmonary injury following engraftment. PARP-1 (marker for parthanatos) and receptor interacting protein kinase 1 (Rip1) and Rip3 (markers for necroptosis) expression was significantly enhanced in the lung. TUNEL assays showed increased cell death of lung cells. This was significantly reduced after treatment with necrostatin-1 (nec-1) or/and 3-aminobenzamide (3-AB). Acute immune rejection exacerbated the remote lung injury and 3-AB or/and Nec-1 combined with cyclosporine A conferred optimal lung protection. Thus, renal graft injury triggered remote lung injury, likely through regulated necrosis. This study could provide the molecular basis for combination therapy targeting both pathways of regulated necrosis to treat such complications after renal transplantation. PMID:25517913

  9. Inhaled cigarette smoke induces the formation of DNA adducts in lungs of rats

    SciTech Connect

    Bond, J.A.; Chen, B.T.; Griffith, W.C.; Mauderly, J.L.

    1989-06-01

    Cigarette smoking causes a variety of adverse human health effects, including lung cancer. The molecular events associated with smoke-induced carcinogenesis are thought to be related in part to the genotoxic activities of the chemicals associated with smoke. The purpose of this investigation was to determine the molecular dosimetry of compounds in cigarette smoke in lungs of rats exposed by inhalation. These studies investigated the effects of exposure mode, sex, and time (adduct persistence) on the level of DNA adducts. Male and female F344/N rats were exposed 6 hr/day, 5 days/week for 22 days to cigarette smoke by nose-only intermittent (NOI), nose-only continuous (NOC), or whole-body continuous (WBC) exposures. Separate groups of rats were sham-exposed nose-only (NOS) or whole-body (WBS) to filtered air. All smoke exposure modes yielded daily smoke exposure concentration X time products of 600 mg particulate.hr/m3 for the first week and 1200 mg particulate.hour/m3 thereafter. Groups of rats were killed at 18 hr and 3 weeks after the 22-day exposure period and DNA adducts in lung tissues were quantified by the /sup 32/P-postlabeling method. There were significant (p less than 0.05) increases in levels of clearly resolved lung DNA adducts in male and female rats exposed to smoke compared to sham-exposed rats. There were no significant effects of exposure mode or sex on lung DNA adducts. Mean levels (+/- SE) of clearly resolved lung DNA adducts for both sexes combined in NOI, NOC, WBC, NOS, and WBS groups were 50 +/- 4, 52 +/- 6, 52 +/- 7, 21 +/- 6, and 22 +/- 4 adducts per 10(9) bases, respectively. Levels of clearly resolved DNA adducts were significantly less in lungs of rats killed 3 weeks after exposure and had declined to near control levels, suggesting that smoke-induced adducts are repaired by lung DNA repair enzymes.

  10. Attenuation of bleomycin-induced lung fibrosis in rats by mesna.

    PubMed

    El-Medany, Azza; Hagar, Hanan H; Moursi, Mahmoud; At Muhammed, Raeesa; El-Rakhawy, Fatma I; El-Medany, Gamila

    2005-02-10

    Lung fibrosis is a common side effect of the chemotherapeutic agent, bleomycin. Current evidence suggests that reactive oxygen species may play a key role in the development of lung fibrosis. The present study examined the effect of mesna on bleomycin-induced lung fibrosis in rats. Animals were divided into three groups: (1) saline control group; (2) Bleomycin group in which rats were injected with bleomycin (15 mg/kg, i.p.) three times a week for four weeks; (3) Bleomycin and mesna group, in which mesna was given to rats (180 mg/kg/day, i.p.) a week prior to bleomycin and daily during bleomycin injections for 4 weeks until the end of the treatment. Bleomycin treatment resulted in a pronounced fall in the average body weight of animals. Bleomycin-induced pulmonary injury and lung fibrosis was indicated by increased lung hydroxyproline content, and elevated nitric oxide synthase, myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. On the other hand, bleomycin induced a reduction in reduced glutathione concentration and angiotensin converting enzyme activity in lung tissues. Moreover, bleomycin-induced severe histological changes in lung tissues revealed as lymphocytes and neutrophils infiltration, increased collagen deposition and fibrosis. Co-administration of bleomycin and mesna reduced bleomycin-induced weight loss and attenuated lung injury as evaluated by the significant reduction in hydroxyproline content, nitric oxide synthase activity, and concentrations of myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. Furthermore, mesna ameliorated bleomycin-induced reduction in reduced glutathione concentration and angiotensin activity in lung tissues. Finally, histological evidence supported the ability of mesna to attenuate bleomycin-induced lung fibrosis and consolidation. Thus, the findings of the present study provide evidence that mesna may serve as a novel target for

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

    PubMed

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

    2012-04-01

    Ventilation with enhanced fractions of O(2) (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% O(2)) 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

  12. 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.

  13. Protective Effects of Lycopene on Furan-treated Diabetic and Non-diabetic Rat Lung.

    PubMed

    Baş, Hatice; Pandir, Dilek

    2016-02-01

    We assessed the effects of furan and lycopene on the histopathological and biochemical changes on lungs, body and lung weights, and food consumption of rats. Furan and diabetes caused histopathological changes, increment in malondialdehyde levels, and decrease in antioxidant enzyme activities. Lycopene showed a protective effect against these damages, except for glutathione-S-transferase and glutathione peroxidase activities. Consequently, furan and diabetes resulted in lung toxicity. Our findings demonstrate that furan treatment resulted in more alterations in histology and biochemical parameters in diabetic rats and lycopene showed protective effects against these alterations. PMID:27003172

  14. Effects of Hypothyroidism and Progesterone on Mammary Tumours Induced by 7,12-Dimethylbenz(a)anthracene in Sprague-Dawley Rats

    PubMed Central

    Jabara, Anne G.; Maritz, J. S.

    1973-01-01

    Hypothyroidism, alone or combined with progesterone, significantly decreased 7,12-dimethylbenz(a)anthracene (DMBA) mammary tumorigenesis relative to controls. However, the decrease was less in the progesterone-treated group, and statistical analysis showed that progesterone enhanced tumorigenesis to the same extent in hypothyroid animals as in the controls. Most tumours in hypothyroid progesterone-treated rats were adenocarcinomata; in the absence of the hormone most tumours were benign. However, the difference between the tumour types in the 2 groups was not statistically significant. The morphological changes observed in the endocrine glands, genital tracts and non-neoplastic mammary tissue, considered in relation to previously reported data, suggest that hypothyroidism reduced the tumour yield mainly by secondarily inhibiting somatotrophin production and secretion, although the effect of decreased food intake could not be excluded completely. The higher tumour yield in the hypothyroid progesterone-treated rats may have been due to higher circulating levels of prolactin in this group compared with those in the hypothyroid group which received no hormone. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8 PMID:4738218

  15. 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. PMID:27098557

  16. Respiratory mechanics and lung histology in normal rats anesthetized with sevoflurane.

    PubMed

    Correa, F C; Ciminelli, P B; Falcão, H; Alcântara, B J; Contador, R S; Medeiros, A S; Zin, W A; Rocco, P R

    2001-08-01

    Respiratory system, lung, and chest wall mechanical properties were subdivided into their resistive, elastic, and viscoelastic/inhomogeneous components in normal rats, to define the sites of action of sevoflurane. In addition, we aimed to determine the extent to which pretreatment with atropine modified these parameters. Twenty-four rats were divided into four groups of six animals each: in the P group, rats were sedated (diazepam) and anesthetized with pentobarbital sodium; in the S group, sevoflurane was administered; in the AP and AS groups, atropine was injected 20 min before sedation/anesthesia with pentobarbital and sevoflurane, respectively. Sevoflurane increased lung viscoelastic/inhomogeneous pressures and static elastance compared with rats belonging to the P group. In AS rats, lung static elastance increased in relation to the AP group. In conclusion, sevoflurane anesthesia acted not at the airway level but at the lung periphery, stiffening lung tissues and increasing mechanical inhomogeneities. These findings were supported by the histological demonstration of increased areas of alveolar collapse and hyperinflation. The pretreatment with atropine reduced central and peripheral airway secretion, thus lessening lung inhomogeneities. PMID:11457797

  17. 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. PMID:14643171

  18. 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.

  19. Mechanical properties and reactivity of vessels in isolated perfused lungs of chronically hypoxic rats.

    PubMed

    Emery, C J; Bee, D; Barer, G R

    1981-11-01

    1. Chronically hypoxic rats kept in 10% (v/v) O2 for 3--6 weeks, were compared with littermate control rats. Pulmonary vascular resistance, measured from the slope of the pressure-flow relationship in isolated lungs perfused with blood of normal packed cell volume was higher in chronically hypoxic than control rats even during normoxia. 2. Chronically hypoxic rats weighed less than control rats but their pulmonary vascular volume, measured with labelled albumin was similar to control rats. This, together with evidence that the number of precapillary vessels is not reduced, does not suggest a large reduction in the vascular bed in chronic hypoxia. 3. A greater vasodilator action of isoprenaline and adenosine in chronically hypoxic than control lungs suggested a higher normoxic vascular tone. This higher tone was not the sole cause of increased resistance in chronically hypoxic lungs, since maximal vasodilatation did not reduce resistance to control levels. The chief cause was probably encroachment of new muscle on the vascular lumen of small vessels. 4. Pulmonary arterial compliance was reduced in chronically hypoxic lungs. 5. Reactivity of vessels to ventilation hypoxia, over a wide range of oxygen tension, to angiotensin II (ANG II) and to adenosine 5'-triphosphate (ATP) was significantly greater in chronically hypoxic than control lungs, but thresholds to these stimuli were not reduced. PMID:7285503

  20. Irradiation of Varying Volumes of Rat Lung to Same Mean Lung Dose: a Little to a Lot or a Lot to a Little?

    SciTech Connect

    Semenenko, Vladimir A. Molthen, Robert C.; Li Chunrong; Morrow, Natalya V.; Li Rongshan; Ghosh, Swarajit N.; Medhora, Meetha M.; Li, X. Allen

    2008-07-01

    Purpose: To investigate whether irradiating small lung volumes with a large dose or irradiating large lung volumes with a small dose, given the same mean lung dose (MLD), has a different effect on pulmonary function in laboratory animals. Methods and Materials: WAG/Rij/MCW male rats were exposed to single fractions of 300 kVp X-rays. Four treatments, in decreasing order of irradiated lung volume, were administered: (1) whole lung irradiation, (2) right lung irradiation, (3) left lung irradiation, and (4) irradiation of a small lung volume with four narrow beams. The irradiation times were chosen to accumulate the same MLD of 10, 12.5, or 15 Gy with each irradiated lung volume. The development of radiation-induced lung injury for {<=}20 weeks was evaluated as increased breathing frequency, mortality, and histopathologic changes in the irradiated and control rats. Results: A significant elevation of respiratory rate, which correlated with the lung volume exposed to single small doses ({>=}5 Gy), but not with the MLD, was observed. The survival of the rats in the whole-lung-irradiated group was MLD dependent, with all events occurring between 4.5 and 9 weeks after irradiation. No mortality was observed in the partial-volume irradiated rats. Conclusions: The lung volume irradiated to small doses might be the dominant factor influencing the loss of pulmonary function in the rat model of radiation-induced lung injury. Caution should be used when new radiotherapy techniques that result in irradiation of large volumes of normal tissue are used for the treatment of lung cancer and other tumors in the thorax.

  1. 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

  2. Asbestos-induced changes in rat lung parenchyma.

    PubMed

    Johnson, N F

    1987-01-01

    Fischer 344 rats have been exposed to UICC crocidolite by whole-body inhalation procedures for periods of 1 d to 12 mo. Material was obtained from the same location in the left lung, and the numbers of cells in the parenchyma were identified and determined by transmission electron microscopy. An immediate increase (1 d of exposure) was evident in the number of type II cells, suggesting a direct action of the dust on these cells. The number of interstitial and alveolar macrophages showed a significant increase after 3 mo of exposure. The number of alveolar macrophages containing dust particles after a 1-d exposure was 49%, and the corresponding value after 12 mo of exposure was 92%. The longer periods of exposure were associated with an increase in the number of particles per macrophage. Polymorphs appeared in the interstitium at airway bifurcations, prior to their appearance in the alveolar space. These bifurcations were also the initial sites where evidence of cell damage and collagen deposition was seen. In this experiment crocidolite appears to be weakly fibrogenic, and other factors may be needed to produce the marked lesions seen in human asbestosis. PMID:3033254

  3. Asbestos-induced changes in rat lung parenchyma

    SciTech Connect

    Johnson, N.F.

    1987-01-01

    Fischer 344 rats have been exposed to UICC crocidolite by whole-body inhalation procedures for periods of 1 d to 12 mo. Material was obtained from the same location in the left lung, and the numbers of cells in the parenchyma were identified and determined by transmission electron microscopy. An immediate increase (1 d of exposure) was evident in the number of type II cells, suggesting a direct action of the dust on these cells. The number of interstitial and alveolar, macrophages showed a significant increase after 3 mo of exposure. The number of alveolar macrophages containing dust particles after a 1-d exposure was 49%, and the corresponding value after 12 mo of exposure was 92%. The longer periods of exposure were associated with an increase in the number of particles per macrophage. Polymorphs appeared in the interstitium at airway bifurcations, prior to their appearance in the alveolar space. These bifurcations were also the initial sites where evidence of cell damage and collagen deposition was seen. In this experiment crocidolite appears to be weakly fibrogenic, and other factors may be needed to produce the marked lesions seen in human asbestosis.

  4. 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.

  5. Differential diagnosis of malignant tumours in the abdominal cavity of rats after intraperitoneal injection of crocidolite or benzo[a]pyrene.

    PubMed

    Friemann, J; Varnai, M; Sutter, C; Hohr, B; Behrens, A; Althoff, G H; Schilpkoter, H W

    1996-01-01

    In our investigation (i.p. test), crocidolite and benzo[a]pyrene, both caused a progression from initially reactive, then autonomously transformed proliferation of myofibroblasts and undifferentiated mesenchymal cells to malignant, multidirectionally differentiated (desmin and ED-1 positive) fibro-histiocytic tumours. Immunohistochemically these tumours showed no morphological characteristics (for example co-expression of vimentin and keratin in spindle-shaped tumour cells) of human asbestos-associated malignant mesotheliomas. On the other hand many tumour cells induced by crocidolite and benzo[a]pyrene had an ultrastructural appearance resembling fibroblasts and myofibroblasts. These have been demonstrated in only a few desmoplastic and sarcomatous mesotheliomas in human beings. None of the tumours revealed the typical ultrastructural features of epitheloid or transitional mesotheliomas. Apparently, both carcinogenic substances induce the transformation of undifferentiated pluripotent mesenchymal cells in rat peritoneum, regardless of their localization in the submesothelial compartment or perivascular connective tissue (preferentially after crocidolite application) or in the connective tissue pseudocapsule of major benzo[a]pyrene containing beeswax/tricaprylin depots in the mesometrium and mesenterial fatty tissue. In this way asbestos fibres in this animal experiment do not seem to induce an arrest in differentiation of intermediate or immature mesothelial cells as supposed formerly, but rather affect undifferentiated mesenchyme cells and myofibroblasts. This is an explanation for the immunohistochemical expression of markers of muscular differentiation in these tumour cells, which is known to occur in human malignant fibro-histiocytic tumours. If supplementary immunohistochemical investigations with different keratin antibodies also fail to confirm the mesothelial differentiation of the tumours induced in our i.p. test, the decision to call them "mesotheliomas

  6. 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.

  7. 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. PMID:18001810

  8. Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi.

    PubMed

    Kennel, S J; Boll, R; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-04-01

    A model system has been used to test the efficacy of vascular targeting of alpha-particle emitter 213Bi for therapy of small, 'artificial' metastases in mouse lung. Specific monoclonal antibody (mAb) 201 B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific 213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6-6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours--epidermoid carcinoma A431 and lung carcinoma A549--growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control 213Bi MAb or EDTA complexed 213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived alpha-particle emitter 213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from alpha-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two. PMID:10389994

  9. Radioimmunotherapy of micrometastases in lung with vascular targeted213Bi

    PubMed Central

    Kennel, S J; Boll, R; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-01-01

    A model system has been used to test the efficacy of vascular targeting of α-particle emitter213Bi for therapy of small, ‘artificial’ metastases in mouse lung. Specific monoclonal antibody (mAb) 201B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6–6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours – epidermoid carcinoma A431 and lung carcinoma A549 – growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control213Bi MAb or EDTA complexed213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived α-particle emitter213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from α-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two. © 1999 Cancer Research Campaign PMID:10389994

  10. 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.

  11. Induction of Lipocalin2 in a Rat Model of Lung Irradiation.

    PubMed

    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

  12. Ginsenoside Rg3 attenuated omethoate-induced lung injury in rats.

    PubMed

    Wang, J; Yu, X F; Zhao, J J; Shi, S M; Fu, L; Sui, D Y

    2016-06-01

    Organophosphorus exposure affects different organs such as the lung, gastrointestinal tract, liver, and brain. The present experiment aimed to evaluate the effect of ginsenoside Rg3 on lung injury induced by acute omethoate poisoning. Rats were administered with omethoate subcutaneously at a single dose of 60 mg/kg, followed by ginsenoside Rg3 (5, 10, or 20 mg/kg) treatment. Histopathological examination of the lung was performed at 24 h after the omethoate exposure. The antioxidative parameters in the lung were also assayed. Moreover, the activities of acetylcholinesterase, myeloperoxidase, and the content of tumor necrosis factor α (TNF-α) in the lung were determined. The results showed that ginsenoside Rg3 attenuated omethoate-induced lung injury. Ginsenoside Rg3 increased the level of glutathione in the lung (p < 0.05 or p < 0.01). The altered activities of superoxide dismutase and catalase in the lung were also ameliorated by ginsenoside Rg3 treatment (p < 0.05 or p < 0.01). Ginsenoside Rg3 caused significant reductions in the contents of malondialdehyde, TNF-α, and the activity of myeloperoxidase (p < 0.05 or p < 0.01). The present study demonstrated that ginsenoside Rg3 had a protective effect against omethoate-induced lung injury in rats, and the mechanisms were related to its antioxidant potential and anti-inflammatory effect. PMID:26240163

  13. Radiation injury in rat lung: II. Angiotensin-converting enzyme activity

    SciTech Connect

    Ward, W.F.; Solliday, N.H.; Molteni, A.; Port, C.D.

    1983-11-01

    To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of /sup 60/Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90 to 150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.

  14. 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

  15. 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.

  16. 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

  17. Stress adaptation and low-frequency impedance of rat lungs.

    PubMed

    Peslin, R; Duvivier, C; Bekkari, H; Reichart, E; Gallina, C

    1990-09-01

    At transpulmonary pressures (Ptp) of 7-12 cmH2O, pressure-volume hysteresis of isolated cat lungs has been found to be 20-50% larger than predicted from their amount of stress adaptation (J. Hildebrandt, J. Appl. Physiol. 28: 365-372, 1970). This behavior is inconsistent with linear viscoelasticity and has been interpreted in terms of plastoelasticity. We have reinvestigated this phenomenon in isolated lungs from 12 Wistar rats by measuring 1) the changes in Ptp after 0.5-ml step volume changes (initial Ptp of 5 cmH2O) and 2) their response to sinusoidal pressure forcing from 0.01 to 0.67 Hz (2 cmH2O peak to peak, mean Ptp of 6 cmH2O). Stress adaptation curves were found to fit approximately Hildebrandt's logarithmic model [delta Ptp/delta V = A - B.log(t)] from 0.2 to 100 s, where delta V is the step volume change, A and B are coefficients, and t is time. A and B averaged 1.06 +/- 0.11 and 0.173 +/- 0.019 cmH2O/ml, respectively, with minor differences between stress relaxation and stress recovery curves. The response to sinusoidal forcing was characterized by the effective resistance (Re) and elastance (EL). Re decreased from 2.48 +/- 0.41 cmH2O.ml-1.s at 0.01 Hz to 0.18 +/- 0.03 cmH2O.ml-1.s at 0.5 Hz, and EL increased from 0.99 +/- 0.10 to 1.26 +/- 0.20 cmH2O/ml on the same frequency range. These data were analyzed with the frequency-domain version of the same model, complemented by a Newtonian resistance (R) to account for airway resistance: Re = R + B/ (9.2f) and EL = A + 0.25B + B . log 2 pi f, where f is the frequency.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2246156

  18. Identification of rat lung – prominent genes by a parallel DNA microarray hybridization

    PubMed Central

    Chen, Zhongming; Chen, Jiwang; Weng, Tingting; Jin, Nili; Liu, Lin

    2006-01-01

    Background The comparison of organ transcriptomes is an important strategy for understanding gene functions. In the present study, we attempted to identify lung-prominent genes by comparing the normal transcriptomes of rat lung, heart, kidney, liver, spleen, and brain. To increase the efficiency and reproducibility, we first developed a novel parallel hybridization system, in which 6 samples could be hybridized onto a single slide at the same time. Results We identified the genes prominently expressed in the lung (147) or co-expressed in lung-heart (23), lung-liver (37), lung-spleen (203), and lung-kidney (98). The known functions of the lung-prominent genes mainly fell into 5 categories: ligand binding, signal transducer, cell communication, development, and metabolism. Real-time PCR confirmed 13 lung-prominent genes, including 5 genes that have not been investigated in the lung, vitamin D-dependent calcium binding protein (Calb3), mitogen activated protein kinase 13 (Mapk13), solute carrier family 29 transporters, member 1 (Slc29a1), corticotropin releasing hormone receptor (Crhr1), and lipocalin 2 (Lcn2). Conclusion The lung-prominent genes identified in this study may provide an important clue for further investigation of pulmonary functions. PMID:16533406

  19. 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. PMID:22628374

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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. PMID:21551015

  7. 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

  8. 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

  9. 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.

  10. Effect of Bile Acid on Fetal Lung in Rat Model of Intrahepatic Cholestasis of Pregnancy

    PubMed Central

    Yu, Ling; Ding, Yiling; Huang, Ting; Huang, Xiaoxia

    2014-01-01

    Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats. PMID:24778648

  11. Effects of inactivated Bordetella pertussis on phosphodiesterase in the lung of ovalbumin sensitized and challenged rats.

    PubMed

    Wang, Ya-Juan; Song, Shun-De; Chen, Jun-Chun; Wang, Xue-Feng; Jiang, Ya-Li; Xie, Qiang-Min; Chen, Ji-Qiang; Li, Zi-Gang; Tang, Hui-Fang

    2014-01-01

    This paper indicated that inactivated Bordetella pertussis (iBp) can enhance the lung airway hyperreactivity of the rats sensitized and challenged with OVA. The mechanisms were involved in the upregulation of cAMP-PDE activity and PDE4A, PDE4D, and PDE3 gene expression in the lungs. But only PDE4 activity was different between the OVA and OVA+iBp groups, and PDE4D expression was significantly increased in iBp rats alone. So, our data suggested that cosensitization with OVA and iBp affects lung airway reactivity by modulating the lung cAMP-PDE activity and PDE4D gene expression. PMID:25120928

  12. 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.

  13. 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. PMID:3209007

  14. Isolation and Culture of Alveolar Epithelial Type I and Type II Cells from Rat Lungs

    PubMed Central

    Gonzalez, Robert F.; Dobbs, Leland G.

    2014-01-01

    The pulmonary alveolar epithelium, comprised of alveolar Type I (TI) and Type II (TII) cells, covers more than 99% of the internal surface area of the lungs. The study of isolated and cultured alveolar epithelial TI and TII cells has provided a large amount of information about the functions of both cell types. This chapter provides information about methods for isolating and culturing both of these cell types from rat lungs. PMID:23097106

  15. Lung and systemic oxidant and antioxidant activity after graded smoke exposure in the rat.

    PubMed

    Lalonde, C; Picard, L; Campbell, C; Demling, R

    1994-01-01

    We wanted to determine the effect of a graded smoke inhalation on lung and systemic oxidant stress, and its relationship to physiological and histological change. Male Wistar rats were given 12 breaths of 10 ml/kg (n = 8) (group 1) or 20 ml/kg (n = 8) (group 2) tidal volume, using cotton toweling smoke through the trachea using positive pressure. Rats were monitored, then killed at 24 hr. Data were compared to controls (n = 8). Peak group 1 and group 2 carboxyhemoglobins were 22 +/- 6 and 46 +/- 6%, with a mortality prior to 24 hr of 14% and 50%, respectively. Group 1 rats showed only moderate lung dysfunction but with severe airway inflammation and edema, alveolar inflammation and atelectasis, with a decrease in PaO2 from the control of 96 +/- 4 to 72 +/- 5 torr. No increase in lung, liver, or kidney oxidant-induced lipid peroxidation, measured as malondialdehyde lung, liver, or kidney oxidant-induced lipid peroxidation, measured as malondialdehyde (MDA), or decrease in the antioxidant defenses catalase was noted. Group 2 rats demonstrated severe airways edema, alveolar atelectasis, and alveolar edema, and a PaO2 decreasing below 60 torr, corresponding with a 3-fold increase in lung tissue MDA and 35% decrease in catalase. In addition, liver and kidney tissue MDA doubled, and catalase activity decreased by 40%. Increased oxygen consumption was also demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8149511

  16. Effect of Stem Cell Therapy on Amiodarone Induced Fibrosing Interstitial Lung Disease in Albino Rat

    PubMed Central

    Zaglool, Somaya Saad; Zickri, Maha Baligh; Abd El Aziz, Dalia Hussein; Mabrouk, Doaa; Metwally, Hala Gabr

    2011-01-01

    Background and Objectives: The fibrosing forms of interstitial lung disease (ILD) are associated with significant morbidity and mortality. ILD may be idiopathic, secondary to occupational, infection, complicate rheumatic diseases or drug induced. Efficacy of antifibrotic agents is as far as, limited and uncertain. No effective treatment was confirmed for pulmonary fibrosis except lung transplantation. The present study aimed at investigating the possible effect of human cord blood mesenchymal stem cell (MSC) therapy on fibrosing ILD. This was accomplished by using amiodarone as a model of induced lung damage in albino rat. Methods and Results: Seventeen adult male albino rats were divided into 3 groups. Rats of amiodarone group were given 30 mg/kg of amiodarone orally 6 days/ week for 6 weeks. Rats of stem cell therapy group were injected with stem cells in the tail vein following confirmation of lung damage and left for 4 weeks before sacrifice. Obstructed bronchioles, thickened interalveolar septa and thickened wall of pulmonary vessels were found and proved morphometrically. Reduced type I pneumocytes and increased area% of collagen fibers were recorded. All findings regressed on stem cell therapy. Conclusions: Cord blood MSC therapy proved definite amelioration of fibrosing interstitial lung disease provided therapy starts early in the development of the pathogenesis. PMID:24298346

  17. 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

  18. Effects of chronic exposure to ozone on collagen in rat lung

    SciTech Connect

    Wright, E.S.; Kehrer, J.P.; White, D.M.; Smiler, K.L.

    1988-03-15

    Pulmonary fibrosis is a consequence of severe injury from some toxic agents including high doses of ozone. It is not known, however, whether chronic exposure to low doses of ozone, such as those encountered in polluted ambient atmospheres, could also result in abnormal accumulations of lung collagen. Rats were exposed to ozone for 20 hr per day, 7 days per week for 3, 6, 12, and 18 months at concentrations of 0.12, 0.25, or 0.50 ppm. Controls were exposed under identical conditions to purified air. Upon removal from the chambers, rats were euthanized and lung tissue slices incubated with (14C)proline. The incorporation of 14C into hydroxyproline and the total hydroxyproline content of lung tissue were measured as estimates of lung collagen synthesis and content, respectively. The formation of labeled hydroxyproline tended to decrease significantly with time in controls and at the three ozone doses. There were, however, no significant dose-related changes at any of the time points tested. Total lung hydroxyproline increased with age in all groups, but no dose-related changes were detected at any time point. It was concluded that chronic exposure of rats to ozone at concentrations which approximate ambient urban concentrations did not affect normal age-related changes in either synthesis or accumulation of lung collagen.

  19. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

    PubMed Central

    Chang, S W; Feddersen, C O; Henson, P M; Voelkel, N F

    1987-01-01

    Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3 +/- 1.3 to 13.7 +/- 2.0 ng/ml (P less than 0.01) and lung PAF from 32.3 +/- 4.9 to 312.3 +/- 19.6 ng (P less than 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63-441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia. PMID:3553241

  20. Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses.

    PubMed

    Demenesku, Jelena; Popov Aleksandrov, Aleksandra; Mirkov, Ivana; Ninkov, Marina; Zolotarevski, Lidija; Kataranovski, Dragan; Brceski, Ilija; Kataranovski, Milena

    2016-08-10

    The impact of genetic background on effects of acute i.p. cadmium administration (0.5mg/kg and 1mg/kg) on basic immune activity of spleen and lungs was examined in two rat strains, Albino Oxford (AO) and Dark Agouti (DA), known to react differently to chemicals. More pronounced inhibition of Concanavalin A (ConA)-induced and Interleukin (IL)-2 stimulated spleen cell proliferation as well as higher levels of nitric oxide (known to decrease cell's proliferative ability) in DA rats at 1mg/kg, along with greater inhibition of ConA-induced Interferon (IFN-γ)-production by total and mononuclear (MNC) spleen cells and IL-17 production by spleen MNC in DA vs. AO rats at this dose show greater susceptibility of this strain to Cd effects on spleen cells response. More pronounced infiltration of neutrophils/CD11b(+) cells to lungs of DA rats treated with 1mg/kg of Cd and decreased IL-17 lung cell responses noted solely in DA rats speaks in favor of their higher susceptibility to this metal. However, lack of strain disparity in lung cells IFN-γ responses show that there are regional differences as well. Novel data from this study depict complexity of the influence of genetic background on the effects of cadmium on host immune reactivity. PMID:27234498

  1. Influence of age on the biochemical response of rat lung to ozone exposure

    SciTech Connect

    Mustafa, M.G.; Elsayed, N.M.; Ospital, J.J.; Hacker, A.D.

    1985-11-01

    We have previously examined the influence of animal age on the pulmonary response to ozone (O3) in rats between 7 and 90 days of age. In the present study, we expanded the age groups of rats, and examined in greater detail the relationship between animal age and pulmonary response to inhaled O3. We exposed 7 groups of specific pathogen free, male Sprague-Dawley rats, aged 24, 30, 45, 60, 90, 180, and 365 days, to 0.8 ppm (1568 micrograms/m3) O3 continuously for 3 days. After O3 exposure, we sacrificed the exposed rats and a matched number of controls from each age group, and analyzed their lungs for a series of physical and biochemical parameters, including glutathione metabolizing and NADPH producing enzyme activities. We observed that in control rats all the parameters increased as a function of age. However, the rate of increase was generally slower after age 60 days. After O3 exposure there was an increase in all the parameters for all age groups relative to their corresponding controls, but the extent of increase was significantly larger in rats 60 days and older than in younger rats. A regression of the difference in mean values between control and exposed animals for each parameter against age showed a linear correlation, indicating that the response was age-dependent. Since the magnitude of such increases is thought to reflect the degree of lung injury, the results suggest that O3 exposure causes greater lung injury in older rats than in younger rats. We tested this assumption by exposing rats from four different age groups (24, 45, 60 and 90 days) to a lethal dose of O3 (4 ppm or 7840 micrograms/m3 for 8 hours). The mortality rates were 50% and 83% for 24 and 45 day old rats, respectively, and 100% for 60 and 90 day old rats. The results of these studies further demonstrate that older rats are more susceptible to lung injury from O3 than younger rats.

  2. Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram

    PubMed Central

    Buttini, M; Mir, A; Appel, K; Wiederhold, K H; Limonta, S; Gebicke-Haerter, P J; Boddeke, H W G M

    1997-01-01

    We have investigated the effects of the phosphodiesterase (PDE) type IV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-α) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS).After intravenous administration of LPS, a similar time-dependent induction of both TNF-α mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after administration of LPS.In situ hybridization experiments with a specific antisense TNF-α riboprobe suggested that the cells responsible for TNF-α production in the brain were microglia.Intraperitoneal administration of methylprednisolone inhibited the induction of TNF-α protein in a dose-dependent manner. A maximal inhibition of TNF-α protein production by 42.9±10.2% was observed at a dose regimen consisting of two injections of each 30 mg kg−1 methylprednisolone.Intraperitoneal administration of rolipram also inhibited the induction of TNF-α protein in a dose-dependent manner. The maximal inhibition of TNF-α protein production was 96.1±12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg−1 rolipram.In situ hybridization experiments showed that the level of TNF-α mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2×15 mg kg−1) and of rolipram (3×3 mg kg−1).We suggest that peripheral administration of LPS induces a time-dependent expression of TNF-α in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS-induced expression of TNF-α in these cells via a decrease of TNF-α mRNA stability and/or TNF-α gene transcription. PMID:9421299

  3. 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.

  4. Biodistribution and tumour localisation of 131I SWA11 recognising the cluster w4 antigen in patients with small cell lung cancer.

    PubMed

    Ledermann, J A; Marston, N J; Stahel, R A; Waibel, R; Buscombe, J R; Ell, P J

    1993-07-01

    The biodistribution of radiolabelled SWA11, a mouse monoclonal antibody recognising the cluster w4 group antigen associated with small cell lung cancer (SCLC) was studied in patients with SCLC. Five patients were injected intravenously with approximately 5 mCi of 131I conjugated to 1 mg of SWA11. The half-life of the radiolabel in blood was short but there was a prolonged second phase of clearance with a half-life of about 40 h. Tumour was detected by gamma camera imaging two patients. However, most of the whole body radioactivity was located in the bone marrow. At least 35% of the radioactivity in blood 18 h after injection was bound to circulating granulocytes and this probably accounted for the unusual biodistribution of the radiolabel in man. This study shows that the biodistribution of radiolabelled SWA11 in man differs from human tumour xenograft models and that the antibody in unsuitable for targeting therapy to SCLC in man. PMID:8391302

  5. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer

    PubMed Central

    Lecharpentier, A; Vielh, P; Perez-Moreno, P; Planchard, D; Soria, J C; Farace, F

    2011-01-01

    Background: Circulating tumour cells (CTC) have a crucial role in metastasis formation and can consistently provide information on patient prognosis. Epithelial-mesenchymal transition (EMT) is considered as an essential process in the metastatic cascade, but there is currently very few data demonstrating directly the existence of the EMT process in CTCs. Methods: CTCs were enriched by blood filtration using ISET (isolation by size of epithelial tumour cells), triply labelled with fluorescent anti-vimentin, anti-pan-keratin antibodies and SYTOX orange nuclear dye, and examined by confocal microscopy in six patients with metastatic non-small cell lung cancer (NSCLC). In parallel, CTCs were morphocytologically identified by an experienced cytopathologist. Results: Isolated or clusters of dual CTCs strongly co-expressing vimentin and keratin were evidenced in all patients (range 5–88/5 ml). CTCs expressing only vimentin were detected in three patients, but were less frequent (range 3–15/5 ml). No CTC expressing only keratin was detected. Conclusion: We showed for the first time the existence of hybrid CTCs with an epithelial/mesenchymal phenotype in patients with NSCLC. Their characterisation should provide further insight on the significance of EMT in CTCs and on the mechanism of metastasis in patients with NSCLC. PMID:21970878

  6. Distribution of lymphoid nodules, aberrant crypt foci and tumours in the colon of carcinogen-treated rats.

    PubMed Central

    Cameron, I. L.; Garza, J.; Hardman, W. E.

    1996-01-01

    Sprague-Dawley rats were given eight weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH) or of vehicle then were sacrificed at 1, 5 or 24 weeks after the last injection of DMH. The locations of pre-existing aggregates of lymphoid nodules (ALNs), the location and multiplicity (size) of aberrant crypt foci (ACF), and the locations of tumours in the colon were determined. A trimodal distribution of pre-existing ALNs along the length of the colon was significantly correlated with the timodal distribution of DMH-induced adenocarcinomas (ACs). A unimodal peak in ACF of all sizes occurred between the sites of two distal ALNs. Thus, the distribution of ACF at 1 or 5 weeks did not correlate with distribution of AC found at 24 weeks. Of the 2640 ACF observed at 1 or at 5 weeks, none were found in the proximal 25% of the colon where ACs eventually occurred. It was concluded that: (1) ALNs play a promotional role in AC formation; (2) the ACs which form in the proximal quarter of the colon seldom if ever form via an ACF precursor; and (3) the location, the number and the size of ACF observed early after DMH exposure did not correlate with the location or predict the incidence of ACs which eventually formed in the colon. Images Figure 1 PMID:8611402

  7. Effects of lysine clonixinate on cyclooxygenase I and II in rat lung and stomach preparations.

    PubMed

    Franchi, A M; Di Girolamo, G; de los Santos, A R; Martí, M L; Gimeno, M A

    1998-06-01

    Lysine clonixinate (LC) is a drug of antiinflammatory antipyretic and analgesic activity that produces minor digestive side-effects. This fact induced us to think that LC is possibly a weak COX-1 inhibitor. In order to investigate our hypothesis we inhibited cyclooxygenase activity with LC or indomethacin (INDO) in rat lung and stomach obtained from rats treated with lipopolysacharide (LPS) and control rats. Rat lung preparations incubated with 14C-arachidonic acid synthesise mainly PGE2. LC at 2.5 and 4.1 x 10(-5) M does not modify the basal production of PGE2 (probably COX-1) but at 6.8 x 10(-5) M significantly inhibited PGE2 production (approximately 48.5% inhibition, P<0.001). On the other hand, INDO at 10(-6) inhibited the basal production of PGE2 by around 73%. In LPS-treated rats, the production of PGE2 was significantly higher than in the lungs of control rats, probably due to the induction of COX-2. The addition of LC at 2.7 and 4.1 x 10(-5) M recovered the control values of PGE2 inhibiting, probably only from COX-2 activity. LC at higher concentrations (6.8 x 10(-5) M) and INDO 10(-6) M inhibited PGE2 formed by COX-2 and also partly by COX-1 activity. PMID:10189073

  8. Modification of the erythrocyte surface in rats bearing Yoshida ascites sarcoma is brought about by a tumour variant of alpha2-macroglobulin.

    PubMed Central

    Sanjay, A; Kalraiya, R D; Mehta, N G

    1997-01-01

    Erythrocytes from the circulation of rats bearing Yoshida ascites sarcoma exhibit higher concanavalin A (ConA)-mediated agglutinability than those from normal animals. A tetrameric glycoprotein of subunit molecular mass 170 kDa, purified from the cell-free ascites fluid, was found to confer higher ConA-mediated agglutinability on erythrocytes in vitro. An antiserum to this tumour-derived protein failed to detect any cross-reactive component in normal rat plasma or in any of the normal tissues examined. An immunoreactive protein was, however, detected in blood plasma when the acute-phase reaction was stimulated by injection of turpentine. The cross-reactive acute-phase protein was purified by ConA-affinity, gel-filtration and ion-exchange chromatography, and identified as alpha2-macroglobulin. The acute-phase protein and the protein obtained from the ascites fluid have identical or very similar native and subunit molecular masses, subunit arrangement and pI. They both are able to inhibit trypsin and, as a consequence, acquire greater mobility in native PAGE. In addition, the two proteins bind to rat erythrocytes non-specifically, and in similar amounts. However, despite these similarities, the acute-phase protein is unable to enhance the agglutinability of erythrocytes. The two proteins differ in their carbohydrate content, but this differential glycosylation is not the cause of the difference in their surface modification activity. The chemically deglycosylated proteins show a small but consistent difference in the size of their polypeptides. Their tryptic peptide maps, although largely similar, show some differences, as do their amino acid compositions. It is probable that the proteins are independent members of the same (alpha-macroglobulin) family. The rat embryo is also found to express a soluble protein consisting of a 170 kDa polypeptide that cross-reacts with the antibody to the tumour-derived protein. The purified embryo protein is able to alter the Con

  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. 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. PMID:26944086

  11. 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.

  12. Biochemical detection of type I cell damage after nitrogen dioxide-induced lung injury in rats.

    PubMed

    McElroy, M C; Pittet, J F; Allen, L; Wiener-Kronish, J P; Dobbs, L G

    1997-12-01

    We have previously shown that injury to lung epithelial type I cells can be detected biochemically by measuring the airway fluid content of a type I cell-specific protein, rTI40, in a model of severe acute lung injury [M. C. McElroy, J.-F. Pittet, S. Hashimoto, L. Allen, J. P. Wiener-Kronish, and L. G. Dobbs. Am. J. Physiol. 268 (Lung Cell. Mol. Physiol. 12): L181-L186, 1995]. The first objective of the present study was to evaluate the utility of rTI40 in the assessment of alveolar injury in a model of milder acute lung injury. Rats were exposed to 18 parts/ million NO2 for 12 h; control rats received filtered air for 12 h. In NO2-exposed rats, the total amount of rTI40 in bronchoalveolar fluid was elevated 2-fold compared with control values (P < 0.001); protein concentration was 8.5-fold of control values (P < 0.001). The increase in rTI40 was associated with morphological evidence of injury to type I cells limited to the proximal alveolar regions of the lung. The second objective was to correlate the severity of alveolar type I cell injury with functional measurements of lung epithelial barrier integrity. NO2 inhalation stimulated distal air space fluid clearance despite a significant increase in lung endothelial and epithelial permeability to protein. These data demonstrate that rTI40 is a useful biochemical marker for mild focal injury and that exposure to NO2 alters lung barrier function. Taken together with our earlier studies, these results suggest that the quantity of recoverable rTI40 can be used as an index of the severity of damage to the alveolar epithelium. PMID:9435578

  13. 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.

  14. 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. PMID:25711042

  15. Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome

    PubMed Central

    Hagawane, T.N.; Gaikwad, R.V.; Kshirsagar, N.A.

    2016-01-01

    Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. PMID

  16. Brevetoxin Forms Covalent DNA Adducts in Rat Lung Following Intratracheal Exposure

    PubMed Central

    Radwan, Faisal F.Y.; Ramsdell, John S.

    2008-01-01

    Background Human exposure to brevetoxins produced by the red tide organism, Karenia brevis, is an increasing public health concern. Using in vitro exposure of rat liver cells to brevetoxin B (PbTx-2), the primary toxin product of K. brevis, we previously showed that it formed C27,28-epoxy brevetoxin metabolites capable of covalently binding to nucleic acids, a common initiation step for carcinogenesis. Objective This study was undertaken to evaluate nucleic acid adduction in lung following in vitro and in vivo brevetoxin exposures. Methods To clarify reactions of brevetoxin epoxide with DNA, we analyzed reaction products of PbTx-6 (a C27,28 epoxide metabolite of brevetoxin B) with nucleosides. We also analyzed adducts from nucleic acid hydrolysates of isolated rat lung cells treated with PbTx-2 or PbTx-6 in vitro and lung tissue from rats after intratracheal exposure to PbTx-2 or PbTx-6 at 45 μg toxin/kg body weight. Results Our results indicate that PbTx-2 forms DNA adducts with cytidine after treatment of isolated lung cells, and forms DNA adducts with adenosine and guanosine after intratracheal exposure. Conclusions These results are consistent with metabolic activation of highly reactive brevetoxin intermediates that bind to nucleic acid. These findings provide a basis for monitoring exposure and assessing the hazard associated with depurination of brevetoxin–nucleotide adducts in lung tissue. PMID:18629316

  17. 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.

  18. Effects of Anoectochilus formosanus Hayata extract and glucocorticoid on lung maturation in preterm rats.

    PubMed

    Chen, C M; Wang, L F; Cheng, K T; Hsu, H H; Gau, B; Su, B

    2004-09-01

    We investigated the effects of maternal administration of Anoectochilus formosanus extract and dexamethasone on lung maturation in preterm rats. A. formosanus group mothers were tube-fed A. formosanus extract (300 mg/kg body wt./day) for 7 days from days 12-18 of gestation. Dexamethasone group mothers were injected intraperitoneally with dexamethasone (0.2 mg/kg body wt.) in saline on day 18 of gestation. Control group mothers were similarly injected with saline alone. On day 19 of gestation, fetuses were delivered by cesarean section. A. formosanus treatment significantly increased the fetal lung/body weight ratio, as compared to dexamethasone treatment. Saturated phosphatidylcholine levels in fetal lung tissue and growth hormone levels in maternal serum were significantly increased in the A. formosanus- and dexamethasone-treated groups as compared to controls. The histological appearance of preterm rat lungs revealed extensive branching of intermediate airways, denser mesenchyme, and more epithelial tubules in the dexamethasone and A. formosanus groups as compared with the control group. These results suggest that antenatal A. formosanus treatment may play a role in accelerating fetal rat lung maturation. PMID:15500262

  19. PRENATAL DEXAMETHASONE ADMINISTRATION DISRUPTS THE PATTERN OF CELLULAR DEVELOPMENT IN RAT LUNG

    EPA Science Inventory

    To examine whether prenatal exposure to glucocorticoids could adversely affect subsequent cellular development of the lung, we administered 0.2 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19. ungs of the offspring were then examined for patterns of cel...

  20. FORMATION OF CIGARETTE SMOKE-INDUCED DNA ADDUCTS IN THE RAT LUNG AND NASAL MUCOSA

    EPA Science Inventory

    The formation of DNA adducts in the nasal, lung, and liver tissues of rats exposed daily to fresh smoke from a University of Kentucky refernece cigarette (2R1) for up to 40 weeks was examined. he amount of smoke total particulate matter (TPM) inhaled and the blood carboxyhemoglob...

  1. CHANGES IN COMPLEX CARBOHYDRATE CONTENT AND STRUCTURE IN RAT LUNGS CAUSED BY PROLONGED OZONE INHALATION

    EPA Science Inventory

    EPA GRANT NUMBER: R828112C065III
    Title: Changes in Complex Carbohydrate Content and Structure in Rat Lungs Caused by Prolonged Ozone Inhalation
    Investigator: Bhandaru Radhakrishnamurthy
    Institution: Tulane University of Louisiana
    EPA...

  2. 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...

  3. Surfactant therapy restores gas exchange in lung injury due to paraquat intoxication in rats.

    PubMed

    So, K L; de Buijzer, E; Gommers, D; Kaisers, U; van Genderen, P J; Lachmann, B

    1998-08-01

    Paraquat is a weed killer which causes often fatal lung damage in humans and other animals. There is evidence that the pulmonary surfactant system is involved in the pathophysiology of respiratory failure after paraquat intoxication and, therefore, the possible therapeutic effect of intratracheal surfactant administration on gas exchange in rats with progressive lung injury induced by paraquat poisoning was studied. In one group of rats, the time course of the development of lung injury due to paraquat intoxication was characterized. In a second group of rats, 72 h after paraquat intoxication, the animals underwent mechanical ventilation and only those animals in which the arterial oxygen tension/inspiratory oxygen fraction (Pa,O2/FI,O2) decreased to below 20 kPa (150 mmHg) received exogenous surfactant (200 mg x kg(-1) body weight). Within 3 days the rats in group 1 developed progressive respiratory failure, demonstrated not only by impaired gas exchange and lung mechanics but also by increased minimal surface tension and increased protein concentration in bronchoalveolar lavage fluid. In group 2, intratracheal surfactant administration increased Pa,O2/FI,O2 significantly within 5 min (14.4+/-2.4 kPa (108+/-18 mmHg)) to (55.2+/-53 kPa (414+/-40 mmHg)) and sustained this level for at least 2 h. It is concluded that intratracheal surfactant administration is a promising approach in the treatment of severe respiratory failure caused by paraquat poisoning. PMID:9727775

  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. 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

  6. 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

  7. The lectin-like domain of tumor necrosis factor improves lung function after rat lung transplantation—Potential role for a reduction in reactive oxygen species generation*

    PubMed Central

    Hamacher, Jürg; Stammberger, Uz; Roux, Jeremie; Kumar, Sanjiv; Yang, Guang; Xiong, Chenling; Schmid, Ralph A.; Fakin, Richard M.; Chakraborty, Trinad; Hossain, Hamid M. D.; Pittet, Jean-François; Wendel, Albrecht; Black, Stephen M.; Lucas, Rudolf

    2016-01-01

    Objective To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required. Design Prospective, randomized laboratory investigation. Setting University-affiliated laboratory. Subjects Adult female rats. Interventions Tuberoinfundibular peptide, mimicking the lectin-like domain of tumor necrosis factor, mutant TIP peptide, N,N′-diacetylchitobiose/TIP peptide, and amiloride/TIP peptide were instilled intratracheally in the left lung immediately before the isotransplantation was performed. An additional group received an intravenous TIP peptide treatment, 1.5 mins before transplantation. Studies using isolated rat type II alveolar epithelial cell monolayers and ovine pulmonary endothelial cells were also performed. Measurements and Main Results Intratracheal pretreatment of the transplantable left lung with the TIP peptide, but not with an inactive mutant TIP peptide, resulted in significantly improved oxygenation 24 hrs after transplantation. This treatment led to a significantly reduced neutrophil content in the lavage fluid. Both the effects on oxygenation and neutrophil infiltration were inhibited by the epithelial sodium channel blocker amiloride. The TIP peptide blunted reactive oxygen species production in pulmonary artery endothelial cells under hypoxia and reoxygenation and reduced reactive oxygen species content in the transplanted rat lungs in vivo. Ussing chamber experiments using monolayers of primary type II rat pneumocytes indicated that the primary site of action of the peptide was on the apical side of these cells. Conclusions These data demonstrate that the TIP

  8. Natural inhalation exposure to coal smoke and wood smoke induces lung cancer in mice and rats

    SciTech Connect

    Liang, C.K.; Quan, N.Y.; Cao, S.R.; He, X.Z.; Ma, F. )

    1988-06-01

    In a rural area with a high mortality rate of lung cancer in humans, mice and rats were placed in an environment in which they inhaled coal smoke and wood smoke in indoor air for 15 to 19 months. The incidences of lung cancer in mice in the control group, wood group, and coal group were 17.0% (29/171), 45.8% (81/177), and 89.5% (188/210), respectively: in rats the incidences were 0.9% (1/110), 0 (0/110), and 67.2% (84/125), respectively. In addition, the pollutants in the air were analyzed. The results indicate that coal smoke is a highly significant risk factor for lung cancer in humans in Xuan Wei County of Yun Nan Province in China.

  9. Time-dependent changes of autophagy and apoptosis in lipopolysaccharide-induced rat acute lung injury

    PubMed Central

    Lin, Li; Zhang, Lijun; Yu, Liangzhu; Han, Lu; Ji, Wanli; Shen, Hui; Hu, Zhenwu

    2016-01-01

    Objective(s): Abnormal lung cell death including autophagy and apoptosis is the central feature in acute lung injury (ALI). To identify the cellular mechanisms and the chronology by which different types of lung cell death are activated during lipopolysaccharide (LPS)-induced ALI, we decided to evaluate autophagy (by LC3-II and autophagosome) and apoptosis (by caspase-3) at different time points after LPS treatment in a rat model of LPS-induced ALI. Materials and Methods: Sprague-Dawley rats were randomly divided into two groups: control group and LPS group. ALI was induced by LPS intraperitoneal injection (3 mg/kg). The lung tissues were collected to measure lung injury score by histopathological evaluation, the protein expression of LC3-II and caspase-3 by Western blot, and microstructural changes by electron microscopy analysis. Results: During ALI, lung cell death exhibited modifications in the death process at different stages of ALI. At early stages (1 hr and 2 hr) of ALI, the mode of lung cell death started with autophagy in LPS group and reached a peak at 2 hr. As ALI process progressed, apoptosis was gradually increased in the lung tissues and reached its maximal level at later stages (6 hr), while autophagy was time-dependently decreased. Conclusion: These findings suggest that activated autophagy and apoptosis might play distinct roles at different stages of LPS-induced ALI. This information may enhance the understanding of lung pathophysiology at the cellular level during ALI and pulmonary infection, and thus help optimize the timing of innovating therapeutic approaches in future experiments with this model. PMID:27482344

  10. Lowering of innate resistance of the lungs to the growth of blood-borne cancer cells in states of topical and systemic stress.

    PubMed Central

    Van Den Brenk, H. A.; Stone, M. G.; Kelly, H.; Sharpington, C.

    1976-01-01

    The survival and clonogenic growth (measured in terms of colony forming efficiency (CFE) of intravenously injected (i.v.) Walker (W256) tumour cells in the lungs of rats was greatly enhanced by states of topical and systemic stress induced by the intraperitoneal (i.p.) injection of rats with a single dose of 10(-5)-10(-3) mmol g-1 body weight of adrenaline and other beta-adrenergic agonists, inflammatory agents (including local x-irradiation), convulsive seizures, "tumbling" or physical restraint. Lowering of innate resistance of the host to growth of seeded tumour cells induced by states of topical and systemic stress, and by the addition of an excess of lethally irradiated (LI) tumour cells to i.v. injected intact tumour cells, were all potentiated by treatment of rats with aminophylline, an inhibitor of cyclic AMP phosphodiesterase. Enhancement of tumour growth by systemic stress was inhibited by bilateral total or medullary adrenalectomy and is attributed to the release and actions of endogenous adreno-medullary hormones. Alpha-adrenergic and most non-adrenergic agents administered in maximum tolerated doses did not significantly affect host resistance to tumour growth in the lungs. These findings, correlated with measurements of cyclic AMP in the lungs of normal and stressed rats, suggest that changes in the resistance of the host to tumour growth involve changes in cyclic nucleotide metabolism in the target tissues (tumour bed); possible mechanisms of action of cyclic nucleotides in this respect are discussed. PMID:175820