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Sample records for nonfibrotic lung tissue

  1. Lung Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis Exhibit Genome-Wide Differences in DNA Methylation Compared to Fibroblasts from Nonfibrotic Lung

    PubMed Central

    Huang, Steven K.; Scruggs, Anne M.; McEachin, Richard C.; White, Eric S.; Peters-Golden, Marc

    2014-01-01

    Excessive fibroproliferation is a central hallmark of idiopathic pulmonary fibrosis (IPF), a chronic, progressive disorder that results in impaired gas exchange and respiratory failure. Fibroblasts are the key effector cells in IPF, and aberrant expression of multiple genes contributes to their excessive fibroproliferative phenotype. DNA methylation changes are critical to the development of many diseases, but the DNA methylome of IPF fibroblasts has never been characterized. Here, we utilized the HumanMethylation 27 array, which assays the DNA methylation level of 27,568 CpG sites across the genome, to compare the DNA methylation patterns of IPF fibroblasts (n = 6) with those of nonfibrotic patient controls (n = 3) and commercially available normal lung fibroblast cell lines (n = 3). We found that multiple CpG sites across the genome are differentially methylated (as defined by P value less than 0.05 and fold change greater than 2) in IPF fibroblasts compared to fibroblasts from nonfibrotic controls. These methylation differences occurred both in genes recognized to be important in fibroproliferation and extracellular matrix generation, as well as in genes not previously recognized to participate in those processes (including organ morphogenesis and potassium ion channels). We used bisulfite sequencing to independently verify DNA methylation differences in 3 genes (CDKN2B, CARD10, and MGMT); these methylation changes corresponded with differences in gene expression at the mRNA and protein level. These differences in DNA methylation were stable throughout multiple cell passages. DNA methylation differences may thus help to explain a proportion of the differences in gene expression previously observed in studies of IPF fibroblasts. Moreover, significant variability in DNA methylation was observed among individual IPF cell lines, suggesting that differences in DNA methylation may contribute to fibroblast heterogeneity among patients with IPF. These

  2. Lung tissue engineering.

    PubMed

    Hoganson, David M; Bassett, Erik K; Vacanti, Joseph P

    2014-01-01

    Lung tissue engineering is an emerging field focused on the development of lung replacement devices and tissue to treat patients with end stage lung disease. Microfluidic based lung assist devices have been developed that have biomimetically designed vascular networks that achieve physiologic blood flow. Gas exchange in these devices occurs across a thin respiratory membrane. Designed for intrathoracic implantation as a bridge to transplant or destination therapy, these lung assist devices will allow ambulation and hospital discharge for patients with end stage lung disease. Decellularized lungs subsequently recellularized with epithelial and endothelial cells have been implanted in small animal models with demonstration of initial gas exchange. Further development of these tissues and scaling to large animal models will validate this approach and may be an organ source for lung transplantation. Initial clinical success has been achieved with decellularized tracheal implants using autologous stem cells. Development of microfluidic lung models using similar architecture to the lung assist device technology allows study of lung biology and diseases with manipulation of lung cells and respiratory membrane strain. PMID:24896347

  3. High reactive oxygen species in fibrotic and nonfibrotic skin of patients with diffuse cutaneous systemic sclerosis.

    PubMed

    Bourji, Khalil; Meyer, Alain; Chatelus, Emmanuel; Pincemail, Joël; Pigatto, Erika; Defraigne, Jean-Olivier; Singh, François; Charlier, Corinne; Geny, Bernard; Gottenberg, Jacques-Eric; Punzi, Leonardo; Cozzi, Franco; Sibilia, Jean

    2015-10-01

    Systemic sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of reactive oxygen species (ROS) in affected patients have been shown, and ROS are suggested to play a role in fibrosis pathogenesis. In this study we evaluate ROS levels in nonfibrotic and fibrotic skin of patients with SSc and we compare them with those obtained from healthy controls. We enrolled nine SSc patients fulfilling the EULAR/ACR classification criteria and seven healthy controls. Patients included four men and five women with mean age of 46 ± 10 years. Controls were matched by sex and age. All patients were affected by the diffuse cutaneous form of SSc and the ANA pattern anti-Scl70. Mean disease duration was 7.5 ± 5 years. Skin involvement was evaluated by modified Rodnan skin score. Skin samples (4-mm punch biopsy) were taken from fibrotic skin and nonfibrotic skin of patients and from healthy controls as well. To detect ROS, specimens were analyzed immediately after sampling by electron paramagnetic resonance spectroscopy. Blood samples were drawn from all patients and controls to assess oxidative stress biomarkers. ROS levels (expressed as median and range, in nmol/L/min/mg of dry weight) were 24.7 (10.9-47.0) in fibrotic skin, 18.7 (7.3-34.0) in nonfibrotic skin, and 7.7 (3.5-13.6) in healthy control skin. ROS levels in fibrotic and nonfibrotic skin of SSc patients were significantly higher than in healthy controls (p = 0.002 and p = 0.009, respectively). ROS levels in fibrotic skin were raised in comparison to nonfibrotic skin, when samples related to each patient were compared (p = 0.01). ROS levels in fibrotic skin were correlated with forced vital capacity (r = -0.75, p = 0.02) and erythrocyte sedimentation rate (r = 0.70, p = 0.04). All other clinical and lab parameters showed no

  4. Integrative Quantitative Proteomics Unveils Proteostasis Imbalance in Human Hepatocellular Carcinoma Developed on Nonfibrotic Livers*

    PubMed Central

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-01-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen®, and AMMP®) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253. PMID:25225353

  5. Lung tissue classification using wavelet frames.

    PubMed

    Depeursinge, Adrien; Sage, Daniel; Hidki, Asmâa; Platon, Alexandra; Poletti, Pierre-Alexandre; Unser, Michael; Müller, Henning

    2007-01-01

    We describe a texture classification system that identifies lung tissue patterns from high-resolution computed tomography (HRCT) images of patients affected with interstitial lung diseases (ILD). This pattern recognition task is part of an image-based diagnostic aid system for ILDs. Five lung tissue patterns (healthy, emphysema, ground glass, fibrosis and microdules) selected from a multimedia database are classified using the overcomplete discrete wavelet frame decompostion combined with grey-level histogram features. The overall multiclass accuracy reaches 92.5% of correct matches while combining the two types of features, which are found to be complementary. PMID:18003452

  6. Strategies for Whole Lung Tissue Engineering

    PubMed Central

    Calle, Elizabeth A.; Ghaedi, Mahboobe; Sundaram, Sumati; Sivarapatna, Amogh; Tseng, Michelle K.

    2014-01-01

    Recent work has demonstrated the feasibility of using decellularized lung extracellular matrix scaffolds to support the engineering of functional lung tissue in vitro. Rendered acellular through the use of detergents and other reagents, the scaffolds are mounted in organ-specific bioreactors where cells in the scaffold are provided with nutrients and appropriate mechanical stimuli such as ventilation and perfusion. Though initial studies are encouraging, a great deal remains to be done to advance the field and transition from rodent lungs to whole human tissue engineered lungs. To do so, a variety of hurdles must be overcome. In particular, a reliable source of human-sized scaffolds, as well as a method of terminal sterilization of scaffolds, must be identified. Continued research in lung cell and developmental biology will hopefully help identify the number and types of cells that will be required to regenerate functional lung tissue. Finally, bioreactor designs must be improved in order to provide more precise ventilation stimuli and vascular perfusion in order to avoid injury to or death of the cells cultivated within the scaffold. Ultimately, the success of efforts to engineer a functional lung in vitro will critically depend on the ability to create a fully endothelialized vascular network that provides sufficient barrier function and alveolar-capillary surface area to exchange gas at rates compatible with healthy lung function. PMID:24691527

  7. Strategies for whole lung tissue engineering.

    PubMed

    Calle, Elizabeth A; Ghaedi, Mahboobe; Sundaram, Sumati; Sivarapatna, Amogh; Tseng, Michelle K; Niklason, Laura E

    2014-05-01

    Recent work has demonstrated the feasibility of using decellularized lung extracellular matrix scaffolds to support the engineering of functional lung tissue in vitro. Rendered acellular through the use of detergents and other reagents, the scaffolds are mounted in organ-specific bioreactors where cells in the scaffold are provided with nutrients and appropriate mechanical stimuli such as ventilation and perfusion. Though initial studies are encouraging, a great deal remains to be done to advance the field and transition from rodent lungs to whole human tissue engineered lungs. To do so, a variety of hurdles must be overcome. In particular, a reliable source of human-sized scaffolds, as well as a method of terminal sterilization of scaffolds, must be identified. Continued research in lung cell and developmental biology will hopefully help identify the number and types of cells that will be required to regenerate functional lung tissue. Finally, bioreactor designs must be improved in order to provide more precise ventilation stimuli and vascular perfusion in order to avoid injury to or death of the cells cultivated within the scaffold. Ultimately, the success of efforts to engineer a functional lung in vitro will critically depend on the ability to create a fully endothelialized vascular network that provides sufficient barrier function and alveolar-capillary surface area to exchange gas at rates compatible with healthy lung function. PMID:24691527

  8. Bioreactor Development for Lung Tissue Engineering

    PubMed Central

    Panoskaltsis-Mortari, Angela

    2015-01-01

    Rationale Much recent interest in lung bioengineering by pulmonary investigators, industry and the organ transplant field has seen a rapid growth of bioreactor development ranging from the microfluidic scale to the human-sized whole lung systems. A comprehension of the findings from these models is needed to provide the basis for further bioreactor development. Objective The goal was to comprehensively review the current state of bioreactor development for the lung. Methods A search using PubMed was done for published, peer-reviewed papers using the keywords “lung” AND “bioreactor” or “bioengineering” or “tissue engineering” or “ex vivo perfusion”. Main Results Many new bioreactors ranging from the microfluidic scale to the human-sized whole lung systems have been developed by both academic and commercial entities. Microfluidic, lung-mimic and lung slice cultures have the advantages of cost-efficiency and high throughput analyses ideal for pharmaceutical and toxicity studies. Perfused/ventilated rodent whole lung systems can be adapted for mid-throughput studies of lung stem/progenitor cell development, cell behavior, understanding and treating lung injury and for preliminary work that can be translated to human lung bioengineering. Human-sized ex vivo whole lung bioreactors incorporating perfusion and ventilation are amenable to automation and have been used for whole lung decellularization and recellularization. Clinical scale ex vivo lung perfusion systems have been developed for lung preservation and reconditioning and are currently being evaluated in clinical trials. Conclusions Significant advances in bioreactors for lung engineering have been made at both the microfluidic and the macro scale. The most advanced are closed systems that incorporate pressure-controlled perfusion and ventilation and are amenable to automation. Ex vivo lung perfusion systems have advanced to clinical trials for lung preservation and reconditioning. The biggest

  9. Bronchoalveolar Lavage and Lung Tissue Digestion

    PubMed Central

    Han, Hongwei; Ziegler, Steven F.

    2016-01-01

    Bronchoalveolar lavage (BAL) is a simple but valuable and typically performed technique commonly used for studying the pathogenesis of lung diseases such as asthma and COPD. Cell counts can be combined with new methods for examining inflammatory responses, such as ELISA, Flow cytometric analysis, immunohistochemistry, quantitative polymerase chain reaction, and HPLC to assess cellular expression for inflammatory cytokines and growth factor. Here we describe a basic procedure to collect BAL fluid and digest lung tissue for assessing a number of pulmonary components.

  10. Marrow cells as progenitors of lung tissue.

    PubMed

    Fine, Alan

    2004-01-01

    There is accumulating evidence showing that marrow-derived cells can engraft as differentiated epithelial cells of various tissues, including the lung. These findings challenge long-held views regarding the basic biology of stem cells. Elucidating the fundamental mechanisms controlling these processes is the major challenge of this field. Regardless, these experiments suggest new strategies for the treatment of chronic diseases. PMID:14757420

  11. Protein Signature of Lung Cancer Tissues

    PubMed Central

    Mehan, Michael R.; Ayers, Deborah; Thirstrup, Derek; Xiong, Wei; Ostroff, Rachel M.; Brody, Edward N.; Walker, Jeffrey J.; Gold, Larry; Jarvis, Thale C.; Janjic, Nebojsa; Baird, Geoffrey S.; Wilcox, Sheri K.

    2012-01-01

    Lung cancer remains the most common cause of cancer-related mortality. We applied a highly multiplexed proteomic technology (SOMAscan) to compare protein expression signatures of non small-cell lung cancer (NSCLC) tissues with healthy adjacent and distant tissues from surgical resections. In this first report of SOMAscan applied to tissues, we highlight 36 proteins that exhibit the largest expression differences between matched tumor and non-tumor tissues. The concentrations of twenty proteins increased and sixteen decreased in tumor tissue, thirteen of which are novel for NSCLC. NSCLC tissue biomarkers identified here overlap with a core set identified in a large serum-based NSCLC study with SOMAscan. We show that large-scale comparative analysis of protein expression can be used to develop novel histochemical probes. As expected, relative differences in protein expression are greater in tissues than in serum. The combined results from tissue and serum present the most extensive view to date of the complex changes in NSCLC protein expression and provide important implications for diagnosis and treatment. PMID:22509397

  12. Myocardial Sleeve Tissues in Surgical Lung Specimens.

    PubMed

    Yoshida, Akihiko; Kamata, Tsugumasa; Iwasa, Takeshi; Watanabe, Shun-ichi; Tsuta, Koji

    2015-10-01

    Left atrial myocardial extensions over the pulmonary veins (PVs), known as myocardial sleeves, are present in the physiological anatomy of most individuals. Although this structure has recently received clinical attention as a major origin of paroxysmal atrial fibrillation (AF), it has not been documented in surgical specimens. Here, we examine incidentally identified myocardial sleeve tissue in routinely processed lung resection specimens to determine its incidence and diagnostic implications. Among 694 lung resection specimens with evaluable PV margins, myocardial sleeve tissue was identified in 26 cases (3.7%). The tissue was located within the adventitia of the PVs, mostly in margin preparations, and existed outside the pericardium in the majority of cases. Carcinoma infiltration of the sleeves was evident in 6 cases. No heart injuries were observed, and no tumors invaded the heart. Preoperative electrocardiography showed sinus rhythm in all cases, whereas postoperative monitoring revealed sinus rhythm in all patients except one who showed AF and flutter. Myocardial sleeve tissue is an underrecognized incidental finding in lung resection specimens, and it is not indicative of heart injury. Cancer infiltration into this tissue indicates neither heart invasion nor, by itself, invasion into the pericardium. Although surgical transection of the myocardial sleeve did not evoke immediate arrhythmia in most cases, the overall influence of this procedure on the postsurgical risk of AF remains to be determined in further studies involving extensive rhythm assessment. PMID:26099012

  13. Analysis of Lung Tissue Using Ion Beams

    NASA Astrophysics Data System (ADS)

    Alvarez, J. L.; Barrera, R.; Miranda, J.

    2002-08-01

    In this work a comparative study is presented of the contents of metals in lung tissue from healthy patients and with lung cancer, by means of two analytical techniques: Particle Induced X-ray Emission (PIXE) and Rutherford Backscattering Spectrometry (RBS). The samples of cancerous tissue were taken from 26 autopsies made to individuals died in the National Institute of Respiratory Disease (INER), 22 of cancer and 4 of other non-cancer biopsies. When analyzing the entirety of the samples, in the cancerous tissues, there were increments in the concentrations of S (4%), K (635%), Co (85%) and Cu (13%). Likewise, there were deficiencies in the concentrations of Cl (59%), Ca (6%), Fe (26%) and Zn (7%). Only in the cancerous tissues there were appearances of P, Ca, Ti, V, Cr, Mn, Ni, Br and Sr. The tissue samples were classified according to cancer types (adenocarcinomas, epidermoides and of small cell carcinoma), personal habits (smokers and alcoholic), genetic predisposition and residence place. There was a remarkable decrease in the concentration of Ca and a marked increment in the Cu in the epidermoide tissue samples with regard to those of adenocarcinoma or of small cells cancer. Also, decrements were detected in K and increments of Fe, Co and Cu in the sample belonging to people that resided in Mexico City with regard to those that resided in the State of Mexico.

  14. Computational model of OCT in lung tissue

    NASA Astrophysics Data System (ADS)

    Reed, David C.; DiMarzio, Charles A.

    2010-02-01

    Lung research may have significant impact on human health. As two examples, recovery from collapse of the alveoli and the severe post surgery declines in forced vital capacity in patients under the effects of anesthesia are both poorly understood. Optical imaging is important to lung research for its inherently high resolution. Microscopy and color imaging are fundamentals of medicine, but interior lung tissue is usually viewed either endoscopically or ex vivo, stained slices. Techniques such as confocal microscopy and optical coherence tomography (OCT) have become increasingly popular in medical imaging because of their sectioning and depth penetration. Since OCT has the ability to achieve higher depth penetration than confocal it is more widely used in lung imaging, despite the difficulty of interpreting the images due to the poor numerical aperture (NA). To understand light propagation through the highly reflective and refractive surfaces of the lung, we developed a Finite-Difference Time Domain (FDTD) simulation. FDTD solves a discrete approximation to Maxwell's equations. Initial simulations have shown that structure up to 30 - 40μm below the surface is clearly visible. Deeper structures are hard to interpret, because of light scattering, compounded by speckle associated with coherent detection. Further simulations and experimental imaging may lead to improved collection and processing of images at deeper levels.

  15. A classification framework for lung tissue categorization

    NASA Astrophysics Data System (ADS)

    Depeursinge, Adrien; Iavindrasana, Jimison; Hidki, Asmâa; Cohen, Gilles; Geissbuhler, Antoine; Platon, Alexandra; Poletti, Pierre-Alexandre; Müller, Henning

    2008-03-01

    We compare five common classifier families in their ability to categorize six lung tissue patterns in high-resolution computed tomography (HRCT) images of patients affected with interstitial lung diseases (ILD) but also normal tissue. The evaluated classifiers are Naive Bayes, k-Nearest Neighbor (k-NN), J48 decision trees, Multi-Layer Perceptron (MLP) and Support Vector Machines (SVM). The dataset used contains 843 regions of interest (ROI) of healthy and five pathologic lung tissue patterns identified by two radiologists at the University Hospitals of Geneva. Correlation of the feature space composed of 39 texture attributes is studied. A grid search for optimal parameters is carried out for each classifier family. Two complementary metrics are used to characterize the performances of classification. Those are based on McNemar's statistical tests and global accuracy. SVM reached best values for each metric and allowed a mean correct prediction rate of 87.9% with high class-specific precision on testing sets of 423 ROIs.

  16. Solubility of inert gases in homogenates of canine lung tissue.

    PubMed

    Young, I H; Wagner, P D

    1979-06-01

    The solubility of sulfur hexafluoride (SF6), ethane, cyclopropane, halothane, diethyl ether, and acetone in homogenates of dog lung tissue were measured and compared with values obtained in dog blood. The measurements were made to provide data for a method for determining distribution of ventilation, blood flow, and tissue volume (Physiologist 20: 95, 1977) and for reasons discussed, the blood was not washed from the tissue prior to homogenization. All gases except SF6 were significantly more soluble in blood than lung tissue, whereas SF6 was 3.7 times more soluble in tissue than blood. It was further found that SF6 is 5 times more soluble, and ethane is twice as soluble in tissue obtained from lungs containing blood than in tissue obtained from rinsed lungs, suggesting that measurements of parenchymal solubility made on tissue from sinsed lungs may be considerably in error for some lipid-soluble gases. PMID:224018

  17. Estimation of lung tissue incompressibility variation throughout respiration for tumor targeting in lung radiotherapy

    NASA Astrophysics Data System (ADS)

    Shirzadi, Zahra; Samani, Abbas

    2013-03-01

    A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Lung tissue incompressibility variation stems from significant air content variation in the tissue throughout respiration. Estimating lung tissue incompressibility and its variation is critical for computer assisted tumor motion tracking. Continuous tumor motion during respiration is a major challenge in lung cancer treatment by external beam radiotherapy. If not accounted for, this motion leads to areas of radiation over dosage for the lung normal tissues. Since no effective imaging modality is available for real-time lung tumor tracking, computer based modeling which has the capability for accurate tissue deformation estimation can be a good alternative. Lung tissue deformation estimation can be made using the lung Finite Element (FE) model where its accuracy depends on input tissue biomechanical properties including incompressibility parameter. In this research, an optimization algorithm is proposed to estimate the incompressibility parameter function in terms of respiration cycle time. In this algorithm, the incompressibility parameter and lung pressure values are varied systematically until optimal values, which result in maximum similarity between acquired and simulated 4D CT images of the lung, are achieved for each respiration time point. The simulated images are constructed using a reference image in conjunction with the deformation field obtained from the lung's FE model in each respiration time increment. We demonstrated that utilizing the calculated function along with respiratory system FE modeling leads to accurate tumor targeting, hence potentially improving lung radiotherapy outcome.

  18. Computational fluid dynamics modeling of airflow inside lungs using heterogenous anisotropic lung tissue elastic properties.

    PubMed

    Ilegbusi, Olusegun; Li, Ziang; Min, Yugang; Meeks, Sanford; Kupelian, Patrick; Santhanam, Anand P

    2012-01-01

    The aim of this paper is to model the airflow inside lungs during breathing and its fluid-structure interaction with the lung tissues and the lung tumor using subject-specific elastic properties. The fluid-structure interaction technique simultaneously simulates flow within the airway and anisotropic deformation of the lung lobes. The three-dimensional (3D) lung geometry is reconstructed from the end-expiration 3D CT scan datasets of humans with lung cancer. The lung is modeled as a poro-elastic medium with anisotropic elastic property (non-linear Young's modulus) obtained from inverse lung elastography of 4D CT scans for the same patients. The predicted results include the 3D anisotropic lung deformation along with the airflow pattern inside the lungs. The effect is also presented of anisotropic elasticity on both the spatio-temporal volumetric lung displacement and the regional lung hysteresis. PMID:22356987

  19. Histopathology of lung disease in the connective tissue diseases.

    PubMed

    Vivero, Marina; Padera, Robert F

    2015-05-01

    The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD. PMID:25836637

  20. A study of photon interaction parameters in lung tissue substitutes.

    PubMed

    Manjunatha, H C

    2014-04-01

    The study of photon interaction with different composite materials has become a topic of prime importance for radiation physicists. Some parameters of dosimetric interest are the mass attenuation coefficient, effective atomic number, and electron density; these help in the basic understanding of photon interactions with composite materials. The photon interaction parameters such as mass attenuation coefficient (μ/ρ), effective atomic number (Zeff), and effective electron density (N el) must be identical for the phantom material and their tissue. In the present study, we have evaluated the photon interaction parameters such as (μ/ρ), Z eff and N el of 13 lung tissue substitutes. The variations of these parameters of lung tissue substitutes with photon energy are graphically represented. The photon interaction parameters of lung tissue substitutes are compared with that of lung tissue. The variation of photon interaction parameters of the studied lung tissue substitutes is similar that of the lung. Logically, it can be shown that Alderson lung is good substitute for lung than the other substitutes. PMID:24872609

  1. Overexpression of type VI collagen in neoplastic lung tissues

    PubMed Central

    VOILES, LARRY; LEWIS, DAVID E.; HAN, LING; LUPOV, IVAN P.; LIN, TSANG-LONG; ROBERTSON, MICHAEL J.; PETRACHE, IRINA; CHANG, HUA-CHEN

    2014-01-01

    Type VI collagen (COL6), an extracellular matrix protein, is important in maintaining the integrity of lung tissue. An increase in COL6 mRNA and protein deposition was found in the lungs of patients with pulmonary fibrosis, a chronic inflammatory condition with a strong association with lung cancer. In the present study, we demonstrated overexpression of COL6 in the lungs of non-small cell lung cancers. We hypothesized that excessive COL6 in the lung interstitium may exert stimulatory effects on the adjacent cells. In vitro stimulation of monocytes with COL6 resulted in the production of IL-23, which may promote tumor development in an environment of IL-23-mediated lung inflammation, where tissue modeling occurs concurrently with excessive COL6 production. In addition, COL6 was capable of stimulating signaling pathways that activate focal adhesion kinase and extracellular signal-regulated kinase 1/2 in lung epithelial cells, which may also facilitate the development of lung neoplasms. Taken together, our data suggest the potential role of COL6 in promoting lung neoplasia in diseased lungs where COL6 is overexpressed. PMID:25176343

  2. Differentiation of normal and cancerous lung tissues by multiphoton imaging

    NASA Astrophysics Data System (ADS)

    Wang, Chun-Chin; Li, Feng-Chieh; Wu, Ruei-Jr; Hovhannisyan, Vladimir A.; Lin, Wei-Chou; Lin, Sung-Jan; So, Peter T. C.; Dong, Chen-Yuan

    2010-02-01

    In this work, we utilized multiphoton microscopy for the label-free diagnosis of non-cancerous, lung adenocarcinoma (LAC), and lung squamous cell carcinoma (SCC) tissues from human. Our results show that the combination of second harmonic generation (SHG) and multiphoton excited autofluorescence (MAF) signals may be used to acquire morphological and quantitative information in discriminating cancerous from non-cancerous lung tissues. Specifically, non-cancerous lung tissues are largely fibrotic in structure while cancerous specimens are composed primarily of tumor masses. Quantitative ratiometric analysis using MAF to SHG index (MAFSI or SAAID) shows that the average MAFSI for noncancerous and LAC lung tissue pairs are 0.55 +/-0.23 and 0.87+/-0.15 respectively. In comparison, the MAFSIs for the noncancerous and SCC tissue pairs are 0.50+/-0.12 and 0.72+/-0.13 respectively. Intrinsic fluorescence ratio (FAD/NADH) of SCC and non-cancerous tissues are 0.40+/-0.05 and 0.53+/-0.05 respectively, the redox ratio of SCC diminishes significantly, indicating that increased cellular metabolic activity. Our study shows that nonlinear optical microscopy can assist in differentiating and diagnosing pulmonary cancer from non-cancerous tissues. With additional development, multiphoton microscopy may be used for the clinical diagnosis of lung cancers.

  3. TISSUE SLICES IN THE STUDY OF LUNG METABOLISM AND TOXICOLOGY

    EPA Science Inventory

    Lung tissue slices are model systems for the study of pulmonary metabolism. Because of the speed and simplicity of slice preparation, lung slices have been used in studies of oxygen, amino acid, carbohydrate and lipid utilization and adenine nucleotide metabolism. Dose-response c...

  4. Solubility of Freon 22 in human blood and lung tissue

    SciTech Connect

    Varene, N.; Choukroun, M.L.; Marthan, R.; Varene, P.

    1989-05-01

    The solubility of Freon 22 in human blood and lung tissue was determined using the chromatographic method of Wagner et al. In normal human blood, the mean Bunsen coefficient of solubility (alpha B) was 0.804 cm3 STPD.cm-3.ATA-1 at 37 degrees C. It increased with hematocrit (Hct) according to the equation alpha B = 0.274 Hct + 0.691. Tissue homogenates were prepared from macroscopically normal lung pieces obtained at thoracotomy from eight patients undergoing resection for lung carcinoma. The Bunsen solubility coefficients were 0.537 +/- 0.068 and 0.635 +/- 0.091 in washed and unwashed lung, respectively. These values can be used in the determination of both cardiac output and pulmonary tissue volume in humans by use of the rebreathing technique.

  5. Advances in pulmonary therapy and drug development: Lung tissue engineering to lung-on-a-chip.

    PubMed

    Doryab, Ali; Amoabediny, Ghassem; Salehi-Najafabadi, Amir

    2016-01-01

    Lung disease is one of the major causes of death, and the rate of pulmonary diseases has been increasing for decades. Although lung transplantation is the only treatment for majority of patients, this method has been limited due to lack of donors. Therefore, recently, attentions have increased to some new strategies with the aid of tissue engineering and microfluidics techniques not only for the functional analysis, but also for drug screening. In fact, in tissue engineering, the engineered tissue is able to grow by using the patient's own cells without intervention in the immune system. On the other hand, microfluidics devices are applied in order to evaluate drug screenings, function analysis and toxicity. This article reviews new advances in lung tissue engineering and lung-on-a-chip. Furthermore, future directions, difficulties and drawbacks of pulmonary therapy in these areas are discussed. PMID:26875777

  6. LUNG, ARSENIC EXPOSURE, AND TISSUE REMODELING

    EPA Science Inventory

    In Specific Aim 1, we will develop a lung model of in utero arsenic exposure. We will assess the best graft conditions, including size, site and initial stage to ensure optimal graft survival and maturation. In addition, we will study the pharmacokinetic relationship between a...

  7. Lung cancer tissue diagnosis in poor lung function: addressing the ongoing percutaneous lung biopsy FEV1 paradox using Heimlich valve.

    PubMed

    Abdullah, R; Tavare, A N; Creamer, A; Creer, D; Vancheeswaran, R; Hare, S S

    2016-08-01

    Many centres continue to decline percutaneous lung biopsy (PLB) in patients with poor lung function (particularly FEV1 <1 L) due to the theoretically increased risk of pneumothorax. This practice limits access to novel lung cancer therapies and minimally invasive surgical techniques. Our retrospective single-centre analysis of 212 patients undergoing PLB, all performed prospectively and blinded to lung function, demonstrates that using ambulatory Heimlich valve chest drain (HVCD) to treat significant postbiopsy pneumothorax facilitates safe, diagnostic, early discharge lung biopsy irrespective of lung function with neither FEV1 <1 L nor transfer coefficient for carbon monoxide (TLCO) <40% predicted shown to be independent predictors of HVCD insertion or pneumothorax outcomes. Incorporating ambulatory HVCD into standard PLB practice thereby elegantly bridges the gap that currently exists between tissue diagnosis in patients with poor lung function and the advanced therapeutic options available for this cohort. PMID:26980011

  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. Polarimetric phenomenology of photons with lung cancer tissue

    NASA Astrophysics Data System (ADS)

    Giakos, G. C.; Marotta, S.; Narayan, C.; Petermann, J.; Shrestha, S.; Baluch, J.; Pingili, D.; Sheffer, D. B.; Zhang, L.; Zervakis, M.; Livanos, G.; Kounelakis, M.

    2011-11-01

    The objective of this study is to explore the polarimetric phenomenology of light interaction with healthy and early-stage lung cancer tissue samples by applying efficient polarimetric backscattering detection techniques combined with polarimetric exploratory data analysis. Preliminary results indicate that enhanced discrimination signatures can be obtained for certain types of early-stage lung cancers based on their depolarization, backscattered intensity and retardance characteristics.

  10. [Morphological, immunohistochemical and radiological manifestation of lung tissue remodeling at lung sarcoidosis].

    PubMed

    Kogan, E A; Kichigina, O N; Demura, S A; Osipenko, V I

    2012-01-01

    Sarcoidosis is a group of diseases with chronic immune inflammation and granulomas formation in the lung, lymph nodes, and others organs. Under progress of disease remodeling of the lung tissue occurs and at 20-25% of patient with sarcoidosis lung fibrosis is developed. We studied biopsies from 50 patients with sarcoidosis and 10 biopsies of pathological intact lung tissue as a control group. Roentgenologic, morphologic and immunohistochemical methods with using of mono- and polyclonal antibody to MMP 1, 2, 9 and TIMP-1, PCNA, aSMA, apo-CAS were realized. The expression levels of growth factors, apoptosis, MMPs, TIMPs were different in various clinic-morphological courses of sarcoidosis. As a rule under sarcoidosis deep remodeling of lung tissue didn't occur in spite of granulomatous inflammation. Granulomatous process, alveolitis (bronchiolitis) and sclerotic changes resulted in alteration of the lung. Cells of sarcoidosis granulomas, produced low level of MMPs and TIMP can't induce evident fibrosis and so hypertension is absent or becomes apparent in the slight form. It apparently can be link with localization of pathologic process in lung tissue without any alterations in the bronchoalveolar zone. Alveolitis under sarcoidosis conditions is notable for low activity of inflammation and doesn't result in interstitial fibrosis developing. PMID:22937579

  11. Integrated quantitative proteomic and transcriptomic analysis of lung tumor and control tissue: a lung cancer showcase

    PubMed Central

    Huwer, Hanno; Hildebrandt, Andreas; Lenhof, Hans-Peter; Wesse, Tanja; Franke, Andre; Keller, Andreas

    2016-01-01

    Proteomics analysis of paired cancer and control tissue can be applied to investigate pathological processes in tumors. Advancements in data-independent acquisition mass spectrometry allow for highly reproducible quantitative analysis of complex proteomic patterns. Optimized sample preparation workflows enable integrative multi-omics studies from the same tissue specimens. We performed ion mobility enhanced, data-independent acquisition MS to characterize the proteome of 21 lung tumor tissues including adenocarcinoma and squamous cell carcinoma (SCC) as compared to control lung tissues of the same patient each. Transcriptomic data were generated for the same specimens. The quantitative proteomic patterns and mRNA abundances were subsequently analyzed using systems biology approaches. We report a significantly (p = 0.0001) larger repertoire of proteins in cancer tissues. 12 proteins were higher in all tumor tissues as compared to matching control tissues. Three proteins, CAV1, CAV2, and RAGE, were vice versa higher in all controls. We also identified characteristic SCC and adenocarcinoma protein patterns. Principal Component Analysis provided evidence that not only cancer from control tissue but also tissue from adenocarcinoma and SCC can be differentiated. Transcriptomic levels of key proteins measured from the same matched tissue samples correlated with the observed protein patterns. The applied study set-up with paired lung tissue specimens of which different omics are measured, is generally suited for an integrated multi-omics analysis. PMID:26930711

  12. Management of interstitial lung disease associated with connective tissue disease.

    PubMed

    Mathai, Stephen C; Danoff, Sonye K

    2016-01-01

    The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation ("lung dominant" CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD, whereas both non-invasive and invasive assessments of pulmonary hemodynamics are needed to diagnose pulmonary hypertension. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. Furthermore, treatment strategies vary according to the clinical situation-for example, the treatment of a patient newly diagnosed as having CTD-ILD differs from that of someone with an acute exacerbation of the disease. Immunosuppression is indicated only in select cases of pulmonary arterial hypertension related to CTD; more commonly, selective pulmonary vasodilators are used. For both diseases, comorbidities such as sleep disordered breathing, symptoms of dyspnea, and cough should be evaluated and treated. Lung transplantation should be considered in patients with advanced disease but is not always feasible because

  13. Association Between RT-Induced Changes in Lung Tissue Density and Global Lung Function

    SciTech Connect

    Ma Jinli; Zhang Junan; Zhou Sumin; Hubbs, Jessica L.; Foltz, Rodney J.; Hollis, Donna R.; Light, Kim L.; Wong, Terence Z.; Kelsey, Christopher R.; Marks, Lawrence B.

    2009-07-01

    Purpose: To assess the association between radiotherapy (RT)-induced changes in computed tomography (CT)-defined lung tissue density and pulmonary function tests (PFTs). Methods and Materials: Patients undergoing incidental partial lung RT were prospectively assessed for global (PFTs) and regional (CT and single photon emission CT [SPECT]) lung function before and, serially, after RT. The percent reductions in the PFT and the average changes in lung density were compared (Pearson correlations) in the overall group and subgroups stratified according to various clinical factors. Comparisons were also made between the CT- and SPECT-based computations using the Mann-Whitney U test. Results: Between 1991 and 2004, 343 patients were enrolled in this study. Of these, 111 patients had a total of 203 concurrent post-RT evaluations of changes in lung density and PFTs available for the analyses, and 81 patients had a total of 141 concurrent post-RT SPECT images. The average increases in lung density were related to the percent reductions in the PFTs, albeit with modest correlation coefficients (range, 0.20-0.43). The analyses also indicated that the association between lung density and PFT changes is essentially equivalent to the corresponding association with SPECT-defined lung perfusion. Conclusion: We found a weak quantitative association between the degree of increase in lung density as defined by CT and the percent reduction in the PFTs.

  14. Relationship Between Diseased Lung Tissues on Computed Tomography and Motion of Fiducial Marker Near Lung Cancer

    SciTech Connect

    Onodera, Yuya; Nishioka, Noriko; Yasuda, Koichi; Fujima, Noriyuki; Torres, Mylin; Kamishima, Tamotsu; Ooyama, Noriko; Onimaru, Rikiya; Terae, Satoshi; Ooizumi, Satoshi; Nishimura, Masaharu; Shirato, Hiroki

    2011-04-01

    Purpose: For lung cancer patients with poor pulmonary function because of emphysema or fibrosis, it is important to predict the amplitude of internal tumor motion to minimize the irradiation of the functioning lung tissue before undergoing stereotactic body radiotherapy. Methods and Materials: Two board-certified diagnostic radiologists independently assessed the degree of pulmonary emphysema and fibrosis on computed tomography scans in 71 patients with peripheral lung tumors before real-time tumor-tracking radiotherapy. The relationships between the computed tomography findings of the lung parenchyma and the motion of the fiducial marker near the lung tumor were investigated. Of the 71 patients, 30 had normal pulmonary function, and 29 had obstructive pulmonary dysfunction (forced expiratory volume in 1 s/forced vital capacity ratio of <70%), 6 patients had constrictive dysfunction (percentage of vital capacity <80%), and 16 had mixed dysfunction. Results: The upper region was associated with smaller tumor motion, as expected (p = .0004), and the presence of fibrosis (p = .088) and pleural tumor contact (p = .086) were weakly associated with tumor motion. The presence of fibrotic changes in the lung tissue was associated with smaller tumor motion in the upper region (p <.05) but not in the lower region. The findings of emphysema and pulmonary function tests were not associated with tumor motion. Conclusion: Tumors in the upper lung region with fibrotic changes have smaller motion than those in the upper region of the lungs without fibrotic changes. The tumor motion in the lower lung region was not significantly different between patients with and without lung fibrosis. Emphysema was not associated with the amplitude of tumor motion.

  15. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue

    PubMed Central

    Joly-Battaglini, Albane; Hammarström, Clara; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan; Brustugun, Odd Terje; Helland, Åslaug; Øynebråten, Inger; Corthay, Alexandre

    2016-01-01

    Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab. PMID:27081474

  16. Impact of Statins on Gene Expression in Human Lung Tissues

    PubMed Central

    Lane, Jérôme; van Eeden, Stephan F.; Obeidat, Ma’en; Sin, Don D.; Tebbutt, Scott J.; Timens, Wim; Postma, Dirkje S.; Laviolette, Michel; Paré, Peter D.; Bossé, Yohan

    2015-01-01

    Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin

  17. On the preparation of lung strip for tissue mechanics measurement.

    PubMed

    Leite-Júnior, José Henrique; Rocco, Patricia R M; Faffe, Débora S; Romero, Pablo V; Zin, Walter A

    2003-03-28

    It is widely believed that it is fundamental to degas and/or rinse the lung prior to the measurement of the tissue mechanics, so that the undesirable effects of surfactant and localized gas trapping are eliminated. However, one could hypothesize that these mechanisms are bound to disappear in the in vitro preparation since the small tissue sample remains suspended oscillating in an organ bath. To investigate the real necessity to follow these procedures, dynamic mechanical properties were studied in strips of lungs previously rinsed with saline, degassed by ventilation with 100% O(2), or without any of these prior procedures. Resistance, elastance, hysteresivity, and the amounts of airway, blood vessel, and alveolar wall were computed. There was no difference in either tissue mechanics or morphology among the groups. In conclusion, the time-consuming degassing and rinsing steps are not necessary to adequately prepare lung tissue for in vitro mechanical analysis, and eliminating these steps potentially helps preserving the intact microstructure of the tissue. PMID:12660105

  18. The Lung Tissue Microbiome in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Sze, Marc A.; Dimitriu, Pedro A.; Hayashi, Shizu; Elliott, W. Mark; McDonough, John E.; Gosselink, John V.; Cooper, Joel; Sin, Don D.; Mohn, William W.

    2012-01-01

    Rationale: Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others. Objectives: To extend these findings to human lung tissue samples. Methods: DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing. Measurement and Main Results: Total bacterial populations within lung tissue were small (20–1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007). Conclusions: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD. PMID:22427533

  19. Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model.

    PubMed

    Klatt, Niklas; Scherschel, Katharina; Schad, Claudia; Lau, Denise; Reitmeier, Aline; Kuklik, Pawel; Muellerleile, Kai; Yamamura, Jin; Zeller, Tanja; Steven, Daniel; Baldus, Stephan; Schäffer, Benjamin; Jungen, Christiane; Eickholt, Christian; Wassilew, Katharina; Schwedhelm, Edzard; Willems, Stephan; Meyer, Christian

    2016-09-01

    Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n = 7) or ANG II (n = 9) for 8 weeks. Mean arterial blood pressure in the ANG II-treated group increased from 87.4 ± 5.3 to 111.8 ± 6.9 mmHg (P = 0.00013). Cardiovascular magnetic resonance imaging showed an increase in left ventricular mass from 112 ± 12.6 g to 131 ± 18.7 g after 7 weeks (P = 0.0017). This was confirmed by postmortem measurement of left ventricular wall thickness which was higher in ANG II-treated animals compared to the control group (18 ± 4 mm vs. 13 ± 2 mm, respectively, P = 0.002). However, ANG II-treated sheep did not reveal any signs of fibrosis or inflammatory infiltrates as defined by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show any differences in epicardial conduction velocity and heterogeneity. These data demonstrate that chronic ANG II treatment using osmotic minipumps presents a reliable, minimally invasive approach to establish hypertension and nonfibrotic LVH in sheep. PMID:27613823

  20. [Study of remanent magnetization of the human body: lung and liver tissues].

    PubMed

    Sakai, H; Wang, H; Murai, Y; Soukejima, S; Kagamimori, S

    2001-07-01

    In this study, we used lung and liver tissue specimens distracted from tissue to investigate remanant magnetization, and found that specimens with a volume of 6 mm3 had an intensity of 10(-10) Am2, which was significantly stronger than the noise level of the superconducting magnetometer. This finding indicates that both lung and liver tissues contain magnetic materials. We speculated that biological magnetite is the magnetic material in these tissues. In addition, we found that lung tissue specimens with strong magnetization had correspondingly strong magnetized findings in the liver tissue specimens. In a comparison of magnetization in lung cancer tissue specimens and normal lung tissue, no significant relationship was noted, but two of the lung cancer tissue specimens showed strong magnetization. The number of lung cancer specimens studies was insufficient to investigate the relation between the magnetization (accumulation of magnetic materials) and lung cancer, and further studies are necessary. The magnetic properties of two lung cancer tissue specimens showing strong magnetization were further investigated, and an alternating field demagnetization experiment showed that their magnetization was composed of a unit stable vector, which indicates that the lung tissue may have been magnetized after the accumulation of magnetic materials. The Wohlfarth ratio (Moskowitz et al., 1989) of them was less than 0.5, which suggests that magnetic materials are distributed in clusters in lung tissue. PMID:11519186

  1. Interpretation of autoantibody positivity in interstitial lung disease and lung-dominant connective tissue disease*

    PubMed Central

    Pereira, Daniel Antunes Silva; Kawassaki, Alexandre de Melo; Baldi, Bruno Guedes

    2013-01-01

    The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease. PMID:24473767

  2. Connective Tissue Disease-Associated Interstitial Lung Diseases: Unresolved Issues.

    PubMed

    Aparicio, Irene Jarana; Lee, Joyce S

    2016-06-01

    Interstitial lung disease (ILD) complicating connective tissue disorders, such as scleroderma and rheumatoid arthritis, is associated with significant morbidity and mortality. Progress has been made in our understanding of these collective diseases; however, there are still many unanswered questions. In this review, we describe the current views on epidemiology, clinical presentation, treatment, and prognosis in patients with connective tissue disease (CTD)-associated ILD. We also highlight several areas that remain unresolved and in need of further investigation, including interstitial pneumonia with autoimmune features, histopathologic phenotype, and pharmacologic management. A multidisciplinary and multidimensional approach to diagnosis, management, and investigation of CTD-associated ILD patients is essential to advance our understanding of the epidemiology and pathobiology of this challenging group of diseases. PMID:27231868

  3. Processing of CT images for analysis of diffuse lung disease in the lung tissue research consortium

    NASA Astrophysics Data System (ADS)

    Karwoski, Ronald A.; Bartholmai, Brian; Zavaletta, Vanessa A.; Holmes, David; Robb, Richard A.

    2008-03-01

    The goal of Lung Tissue Resource Consortium (LTRC) is to improve the management of diffuse lung diseases through a better understanding of the biology of Chronic Obstructive Pulmonary Disease (COPD) and fibrotic interstitial lung disease (ILD) including Idiopathic Pulmonary Fibrosis (IPF). Participants are subjected to a battery of tests including tissue biopsies, physiologic testing, clinical history reporting, and CT scanning of the chest. The LTRC is a repository from which investigators can request tissue specimens and test results as well as semi-quantitative radiology reports, pathology reports, and automated quantitative image analysis results from the CT scan data performed by the LTRC core laboratories. The LTRC Radiology Core Laboratory (RCL), in conjunction with the Biomedical Imaging Resource (BIR), has developed novel processing methods for comprehensive characterization of pulmonary processes on volumetric high-resolution CT scans to quantify how these diseases manifest in radiographic images. Specifically, the RCL has implemented a semi-automated method for segmenting the anatomical regions of the lungs and airways. In these anatomic regions, automated quantification of pathologic features of disease including emphysema volumes and tissue classification are performed using both threshold techniques and advanced texture measures to determine the extent and location of emphysema, ground glass opacities, "honeycombing" (HC) and "irregular linear" or "reticular" pulmonary infiltrates and normal lung. Wall thickness measurements of the trachea, and its branches to the 3 rd and limited 4 th order are also computed. The methods for processing, segmentation and quantification are described. The results are reviewed and verified by an expert radiologist following processing and stored in the public LTRC database for use by pulmonary researchers. To date, over 1200 CT scans have been processed by the RCL and the LTRC project is on target for recruitment of the

  4. Tissue Heterogeneity in IMRT Dose Calculation for Lung Cancer

    SciTech Connect

    Pasciuti, Katia; Iaccarino, Giuseppe; Strigari, Lidia; Malatesta, Tiziana; Benassi, Marcello; Di Nallo, Anna Maria; Mirri, Alessandra; Pinzi, Valentina; Landoni, Valeria

    2011-07-01

    The aim of this study was to evaluate the differences in accuracy of dose calculation between 3 commonly used algorithms, the Pencil Beam algorithm (PB), the Anisotropic Analytical Algorithm (AAA), and the Collapsed Cone Convolution Superposition (CCCS) for intensity-modulated radiation therapy (IMRT). The 2D dose distributions obtained with the 3 algorithms were compared on each CT slice pixel by pixel, using the MATLAB code (The MathWorks, Natick, MA) and the agreement was assessed with the {gamma} function. The effect of the differences on dose-volume histograms (DVHs), tumor control, and normal tissue complication probability (TCP and NTCP) were also evaluated, and its significance was quantified by using a nonparametric test. In general PB generates regions of over-dosage both in the lung and in the tumor area. These differences are not always in DVH of the lung, although the Wilcoxon test indicated significant differences in 2 of 4 patients. Disagreement in the lung region was also found when the {Gamma} analysis was performed. The effect on TCP is less important than for NTCP because of the slope of the curve at the level of the dose of interest. The effect of dose calculation inaccuracy is patient-dependent and strongly related to beam geometry and to the localization of the tumor. When multiple intensity-modulated beams are used, the effect of the presence of the heterogeneity on dose distribution may not always be easily predictable.

  5. [Comparative proteomic analysis of cancerous and adjacent normal lung tissues].

    PubMed

    Lee, Ki Beom; Pi, Kyung Bae

    2010-01-01

    Lung cancer is the leading cause of cancer-related mortality in industrialized countries. Unfortunately, most lung cancers are found too late for a cure, therefore early detection and treatment is very important. We have applied proteomic analysis by using two-dimensional gel electrophoresis and peptide mass fingerprinting techniques for examination of cancerous and adjacent non-cancerous lung tissues from the same patient. The aim of the study was to find proteins, which could be used as biomarkers for diagnosis and monitoring of this disease. Indeed, we found differences in expression of several proteins, related to various cellular activities, such as, chaperoning (e.g., GRP96, GRP78, HSP27), metabolism and oxidation stress (e.g., L-fucose, GST), cytoskeleton (e.g., tubulin beta 2/3, beta actin), cell adhesion (e.g., annexin A5/3), binding proteins (e.g., 14-3-3 theta) and signal transduction. These changes may be important for progression of carcinogenesis; they may be used as the molecular-support for future diagnostic markers. PMID:21395069

  6. Tissue heterogeneity in IMRT dose calculation for lung cancer.

    PubMed

    Pasciuti, Katia; Iaccarino, Giuseppe; Strigari, Lidia; Malatesta, Tiziana; Benassi, Marcello; Di Nallo, Anna Maria; Mirri, Alessandra; Pinzi, Valentina; Landoni, Valeria

    2011-01-01

    The aim of this study was to evaluate the differences in accuracy of dose calculation between 3 commonly used algorithms, the Pencil Beam algorithm (PB), the Anisotropic Analytical Algorithm (AAA), and the Collapsed Cone Convolution Superposition (CCCS) for intensity-modulated radiation therapy (IMRT). The 2D dose distributions obtained with the 3 algorithms were compared on each CT slice pixel by pixel, using the MATLAB code (The MathWorks, Natick, MA) and the agreement was assessed with the γ function. The effect of the differences on dose-volume histograms (DVHs), tumor control, and normal tissue complication probability (TCP and NTCP) were also evaluated, and its significance was quantified by using a nonparametric test. In general PB generates regions of over-dosage both in the lung and in the tumor area. These differences are not always in DVH of the lung, although the Wilcoxon test indicated significant differences in 2 of 4 patients. Disagreement in the lung region was also found when the Γ analysis was performed. The effect on TCP is less important than for NTCP because of the slope of the curve at the level of the dose of interest. The effect of dose calculation inaccuracy is patient-dependent and strongly related to beam geometry and to the localization of the tumor. When multiple intensity-modulated beams are used, the effect of the presence of the heterogeneity on dose distribution may not always be easily predictable. PMID:20970989

  7. Biomarkers in connective tissue disease-associated interstitial lung disease.

    PubMed

    Bonella, Francesco; Costabel, Ulrich

    2014-04-01

    This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies. PMID:24668534

  8. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

    PubMed

    Shaver, Ciara M; Grove, Brandon S; Clune, Jennifer K; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  9. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

    PubMed Central

    Shaver, Ciara M.; Grove, Brandon S.; Clune, Jennifer K.; Mackman, Nigel; Ware, Lorraine B.; Bastarache, Julie A.

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  10. Quantification of Regional Interstitial Lung Disease from CT-derived Fractional Tissue Volume: A Lung Tissue Research Consortium Study

    PubMed Central

    Yilmaz, Cuneyt; Watharkar, Snehal S.; de Leon, Alberto Diaz; Garcia, Christine K.; Patel, Nova C.; Jordan, Kirk G.; Hsia, Connie C.W.

    2011-01-01

    Rationale and Objectives Evaluation of chest CT is usually qualitative or semi-quantitative, resulting in subjective descriptions often by different observers over time and imprecise determinations of disease severity within distorted lobes. There is a need for standardized imaging biomarkers to quantify regional disease, maximize diagnostic yield, and facilitate multi-center comparisons. We applied lobe-based voxelwise image analysis to derive regional air (Vair) and tissue (Vtissue) volumes and fractional tissue volume (FTV=tissue/[tissue+air] volume) as internally standardized parameter for assessing interstitial lung disease (ILD). Materials and Methods High-resolution CT was obtained at supine and prone end-inspiration and supine end-expiration in 29 patients with ILD and 20 normal subjects. Lobar Vair, Vtissue, and FTV were expressed along standard coordinate axes. Results In normal subjects from end-inspiration to end-expiration, total Vair declined 43%, FTV increased ~80% while Vtissue remained unchanged. With increasing ILD, Vair declined and Vtissue rose in all lobes; FTV increased with a peripheral-to-central progression inversely correlated to spirometry and lung diffusing capacity (R2=0.57–0.75, prone end-inspiration). Inter- and intra-lobar coefficients of variation (CVs) of FTV increased 84–148% in mild-to-moderate ILD, indicating greater spatial heterogeneity, then normalized in severe ILD. Analysis of discontinuous images incurs <3% error compared to consecutive images. Conclusions These regional attenuation-based biomarkers could quantify heterogeneous parenchymal disease in distorted lobes, detect mild ILD involvement in all lobes and describe the pattern of disease progression. The next step would be to study a larger series, examine reproducibility and follow longitudinal changes in correlation with clinical and functional indices. PMID:21596593

  11. Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs.

    PubMed

    Korfei, Martina; Schmitt, Sigrid; Ruppert, Clemens; Henneke, Ingrid; Markart, Philipp; Loeh, Benjamin; Mahavadi, Poornima; Wygrecka, Malgorzata; Klepetko, Walter; Fink, Ludger; Bonniaud, Philippe; Preissner, Klaus T; Lochnit, Günter; Schaefer, Liliana; Seeger, Werner; Guenther, Andreas

    2011-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up-regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up-regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re-epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation. PMID:21319792

  12. Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

    PubMed

    Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D; Clune, Jennifer K; Lawson, William E; Carnahan, Robert H; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2015-11-01

    Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI. PMID:25884207

  13. Formaldehyde induces lung inflammation by an oxidant and antioxidant enzymes mediated mechanism in the lung tissue.

    PubMed

    Lino-dos-Santos-Franco, Adriana; Correa-Costa, Matheus; Durão, Ana Carolina Cardoso dos Santos; de Oliveira, Ana Paula Ligeiro; Breithaupt-Faloppa, Ana Cristina; Bertoni, Jônatas de Almeida; Oliveira-Filho, Ricardo Martins; Câmara, Niels Olsen Saraiva; Marcourakis, Tânia; Tavares-de-Lima, Wothan

    2011-12-15

    Formaldehyde (FA) is an indoor and outdoor pollutant widely used by many industries, and its exposure is associated with inflammation and oxidative stress in the airways. Our previous studies have demonstrated the role of reactive oxygen species (ROS) in lung inflammation induced by FA inhalation but did not identify source of the ROS. In the present study, we investigate the effects of FA on the activities and gene expression of glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD) 1 and 2, catalase (CAT), nitric oxide synthase (iNOS and cNOS) and cyclooxygenase (COX) 1 and 2. The hypothesized link between NADPH-oxidase, nitric oxide synthase and cyclooxygenase, the lung inflammation after FA inhalation was also investigated. For experiments, male Wistar rats were submitted to FA inhalation (1%, 90 min daily) for 3 consecutive days. The treatments with apocynin and indomethacin before the FA exposure reduced the number of neutrophils recruited into the lung. Moreover, the treatments with apocynin and indomethacin blunted the effect of FA on the generation of IL-1β, while the treatments with L-NAME and apocynin reduced the generation of IL-6 by lung explants when compared to the untreated group. FA inhalation increased the levels of NO and hydrogen peroxide by BAL cells cultured and the treatments with apocynin and l-NAME reduced these generations. FA inhalation did not modify the activities of GPX, GR, GST and CAT but reduced the activity of SOD when compared to the naïve group. Significant increases in SOD-1 and -2, CAT, iNOS, cNOS and COX-1 expression were observed in the FA group compared to the naïve group. The treatments with apocynin, indomethacin and L-NAME reduced the gene expression of antioxidant and oxidant enzymes. In conclusion, our results indicate that FA causes a disruption of the physiological balance between oxidant and antioxidant enzymes in lung tissue, most likely favoring the

  14. Fluorescence spectroscopy and cryoimaging of rat lung tissue mitochondrial redox state

    NASA Astrophysics Data System (ADS)

    Sepehr, R.; Audi, S.; Staniszewski, K.; Maleki, S.; Ranji, M.

    2011-07-01

    The objective of this study was to demonstrate the utility of optical cryoimaging and fluorometry to evaluate tissue redox state of the mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavin Adenine Dinucleotide) in intact rat lungs. The ratio (NADH/FAD), referred to as mitochondrial redox ratio (RR), is a measure of the lung tissue mitochondrial redox state. Isolated rat lungs were connected to a ventilation-perfused system. Surface NADH and FAD fluorescence signals were acquired before and after lung perfusion in the absence (control perfusate) or presence of potassium cyanide (KCN, complex IV inhibitor) to reduce the mitochondrial respiratory chain (state 5 respiration). Another group of lungs were perfused with control perfusate or KCN-containing perfusate as above, after which the lungs were deflated and frozen rapidly for subsequent 3D cryoimaging. Results demonstrate that lung treatment with KCN increased lung surface NADH signal by 22%, decreased FAD signal by 8%, and as result increased RR by 31% as compared to control perfusate (baseline) values. Cryoimaging results also show that KCN increased mean lung tissue NADH signal by 37%, decreased mean FAD signal by 4%, and increased mean RR by 47%. These results demonstrate the utility of these optical techniques to evaluate the effect of pulmonary oxidative stress on tissue mitochondrial redox state in intact lungs.

  15. Bag-of-features approach for improvement of lung tissue classification in diffuse lung disease

    NASA Astrophysics Data System (ADS)

    Kato, Noriji; Fukui, Motofumi; Isozaki, Takashi

    2009-02-01

    Many automated techniques have been proposed to classify diffuse lung disease patterns. Most of the techniques utilize texture analysis approaches with second and higher order statistics, and show successful classification result among various lung tissue patterns. However, the approaches do not work well for the patterns with inhomogeneous texture distribution within a region of interest (ROI), such as reticular and honeycombing patterns, because the statistics can only capture averaged feature over the ROI. In this work, we have introduced the bag-of-features approach to overcome this difficulty. In the approach, texture images are represented as histograms or distributions of a few basic primitives, which are obtained by clustering local image features. The intensity descriptor and the Scale Invariant Feature Transformation (SIFT) descriptor are utilized to extract the local features, which have significant discriminatory power due to their specificity to a particular image class. In contrast, the drawback of the local features is lack of invariance under translation and rotation. We improved the invariance by sampling many local regions so that the distribution of the local features is unchanged. We evaluated the performance of our system in the classification task with 5 image classes (ground glass, reticular, honeycombing, emphysema, and normal) using 1109 ROIs from 211 patients. Our system achieved high classification accuracy of 92.8%, which is superior to that of the conventional system with the gray level co-occurrence matrix (GLCM) feature especially for inhomogeneous texture patterns.

  16. Activation of the Canonical Bone Morphogenetic Protein (BMP) Pathway during Lung Morphogenesis and Adult Lung Tissue Repair

    PubMed Central

    Sountoulidis, Alexandros; Stavropoulos, Athanasios; Giaglis, Stavros; Apostolou, Eirini; Monteiro, Rui; Chuva de Sousa Lopes, Susana M.; Chen, Huaiyong; Stripp, Barry R.; Mummery, Christine; Andreakos, Evangelos; Sideras, Paschalis

    2012-01-01

    Signaling by Bone Morphogenetic Proteins (BMP) has been implicated in early lung development, adult lung homeostasis and tissue-injury repair. However, the precise mechanism of action and the spatio-temporal pattern of BMP-signaling during these processes remains inadequately described. To address this, we have utilized a transgenic line harboring a BMP-responsive eGFP-reporter allele (BRE-eGFP) to construct the first detailed spatiotemporal map of canonical BMP-pathway activation during lung development, homeostasis and adult-lung injury repair. We demonstrate that during the pseudoglandular stage, when branching morphogenesis progresses in the developing lung, canonical BMP-pathway is active mainly in the vascular network and the sub-epithelial smooth muscle layer of the proximal airways. Activation of the BMP-pathway becomes evident in epithelial compartments only after embryonic day (E) 14.5 primarily in cells negative for epithelial-lineage markers, located in the proximal portion of the airway-tree, clusters adjacent to neuro-epithelial-bodies (NEBs) and in a substantial portion of alveolar epithelial cells. The pathway becomes activated in isolated E12.5 mesenchyme-free distal epithelial buds cultured in Matrigel suggesting that absence of reporter activity in these regions stems from a dynamic cross-talk between endoderm and mesenchyme. Epithelial cells with activated BMP-pathway are enriched in progenitors capable of forming colonies in three-dimensional Matrigel cultures. As lung morphogenesis approaches completion, eGFP-expression declines and in adult lung its expression is barely detectable. However, upon tissue-injury, either with naphthalene or bleomycin, the canonical BMP-pathways is re-activated, in bronchial or alveolar epithelial cells respectively, in a manner reminiscent to early lung development and in tissue areas where reparatory progenitor cells reside. Our studies illustrate the dynamic activation of canonical BMP-pathway during lung

  17. Combinational feature optimization for classification of lung tissue images

    NASA Astrophysics Data System (ADS)

    Samala, Ravi K.; Zhukov, Tatyana; Zhang, Jianying; Tockman, Melvyn; Qian, Wei

    2010-03-01

    A novel approach to feature optimization for classification of lung carcinoma using tissue images is presented. The methodology uses a combination of three characteristics of computational features: F-measure, which is a representation of each feature towards classification, inter-correlation between features and pathology based information. The metadata provided from pathological parameters is used for mapping between computational features and biological information. Multiple regression analysis maps each category of features based on how pathology information is correlated with the size and location of cancer. Relatively the computational features represented the tumor size better than the location of the cancer. Based on the three criteria associated with the features, three sets of feature subsets with individual validation are evaluated to select the optimum feature subset. Based on the results from the three stages, the knowledgebase produces the best subset of features. An improvement of 5.5% was observed for normal Vs all abnormal cases with Az value of 0.731 and 74/114 correctly classified. The best Az value of 0.804 with 66/84 correct classification and improvement of 21.6% was observed for normal Vs adenocarcinoma.

  18. Expression and clinicopathological implication of DcR3 in lung cancer tissues: a tissue microarray study with 365 cases

    PubMed Central

    Zhang, Yu; Luo, Jie; He, Rongquan; Huang, Wenting; Li, Zuyun; Li, Ping; Dang, Yiwu; Chen, Gang; Li, Shikang

    2016-01-01

    Background Decoy receptor 3 (DcR3) has been reported to be involved in different cancers. However, few related researches have been accomplished on the role of DcR3 in lung cancer. Objective To explore the expression level and clinicopathological implication of DcR3 protein in lung cancer tissues. Materials and methods Immunohistochemistry was used to examine DcR3 protein expression in lung cancer (n=365) and normal lung tissues (n=26). The relationships between DcR3 expression and clinical parameters were further investigated. Furthermore, the diagnostic and clinicopathological value of DcR3 mRNA was analyzed based on The Cancer Genome Atlas database in lung cancer patients. Results Compared to normal lung tissues, DcR3 expression was significantly higher in lung cancer (P=0.007) tissues, including small-cell lung cancer (P=0.001) and non-small-cell lung cancer (P=0.008). In addition, DcR3 expression was related to tumor-node-metastasis (TNM) stage (P<0.001), tumor diameter (P=0.007), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) in lung cancers. When concerning non-small-cell lung cancer, consistent correlations between DcR3 expression and TNM stage (P<0.001), tumor diameter (P=0.019), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) were found. Simultaneously, in small-cell lung cancer, TNM stage (P=0.004) and lymph node metastasis (P=0.005) were also associated with DcR3 expression. Additionally, receiver operator characteristic curve revealed that the area under curve (AUC) of DcR3 was 0.637 (95% confidence interval [CI] 0.531–0.742) for lung cancer. Furthermore, DcR3 was overexpressed in both adenocarcinoma and squamous cell carcinoma tissues than in noncancerous lung tissues (all P<0.0001) based on the data from The Cancer Genome Atlas. AUC of DcR3 was 0.726 (95% CI 0.644–0.788) for lung adenocarcinoma patients and 0.647 (95% CI 0.566–0.728) for squamous cell carcinoma patients. DcR3 expression was also related to

  19. Expression of a phosphorylated form of ATF4 in lung and non-small cell lung cancer tissues.

    PubMed

    Fan, Chui-Feng; Miao, Yuan; Lin, Xu-Yong; Zhang, Di; Wang, En-Hua

    2014-01-01

    ATF4 is a member of the cAMP-responsive element-binding protein family of basic zipper-containing proteins, a family of transcription factors phosphorylated at serines residues by protein kinase A. The family has been proved to be able to stimulate the transcription of the genes containing CRE elements. Elevated ATF4 expression was detected in some tumors including breast carcinoma compared to their corresponding nontumor tissues. p-ATF4 (ser 245), a phosphorylated form of ATF4 protein at serine 245 site, was believed to be an active type of this protein. However, its expression and clinical significance in malignant tumors including non-small cell lung cancer were not reported up to date. In the current study, we investigate the expression of p-ATF4 (ser 245) in non-small cell lung cancer using tissue microarray and immunohistochemistry. p-ATF4 (ser 245) immunostaining was detected in nucleus and cytoplasm in cancer cells and normal lung epithelial cells. Compared to bronchial epithelium and submucosal glands (total positive rate, 14.6% (12/82)), there was increased expression of p-ATF4 (ser 245) in non-small cell lung cancer cells (total positive rate, 42.7% (35/82)) (p < 0.05). In addition, increased expression of p-ATF4 (ser 245) was associated with lymph node metastasis and advanced TNM stages (III and IV) in non-small cell lung cancer (p < 0.05). Immunofluorescent staining confirmed nuclear and cytoplasmic expression of p-ATF4 (ser 245) in lung and cancer tissues, and also in non-small cell lung cancer cell lines including NCI-H157 and LTE cells. These results indicate that increased expression of p-ATF4 (ser 245) may contribute to cancer development of non-small cell lung cancer and may be a potential cancer marker. PMID:23975372

  20. Soft tissue metastases and lung cancer recurrence detected by Tc-99m depreotide scintigraphy.

    PubMed

    Miliziano, John S; Bradley, Yong C

    2002-06-01

    A 63-year-old woman with previously treated stage I lung cancer was reexamined 5 years later for recurrence. A conventional work-up using computed tomographic scanning and transbronchial biopsy showed nothing abnormal. A Tc-99m depreotide scan, however, led to a noninvasive diagnosis of lung cancer recurrence with metastases, and it directed a noninvasive tissue diagnosis. PMID:12045431

  1. 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

  2. Lipogenesis in liver, lung and adipose tissue of rats fed with oleoylanilide.

    PubMed Central

    Casals, C; Garcia-Barreno, P; Municio, A M

    1983-01-01

    Oleoylanilide was administered orally to groups of rats according to different patterns. Subcellular fractionation of liver, lung and adipose tissue was then carried out in order to study the main enzyme activities involved in the lipogenesis. The observed findings indicate that adipose tissue and lung are the main target organs for the anilide, adipose tissue being involved in a general decrease of the enzyme activities, whereas transacylation reaction exhibits the most marked depletion of all the enzyme activities in the lung. The enzyme activities in liver were not markedly affected by this oral administration, although some data support the existence of a latent liver toxicity. These data suggest that oleoylanilide has the capacity to alter lipid metabolism of lung and adipose tissue to a considerable extent, whereas no major effect was produced in the liver. This different organ response could be related to the lymphatic gland via absorption of the substance. PMID:6882376

  3. Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption.

    PubMed

    Lysov, Zakhar; Swystun, Laura L; Kuruvilla, Sara; Arnold, Andrew; Liaw, Patricia C

    2015-01-01

    Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear. The aim of this study was to determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor activity on endothelial cells, A549 cells, and monocytes. Tissue factor activity, tissue factor antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells. Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface tissue factor activity. However, elevated tissue factor antigen levels were observed only on cisplatin-treated and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition, attenuated tissue factor activity. Furthermore, increased tissue factor activity was reversed by reducing cysteines with dithiothreitol. These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells and A549 cells by tissue factor decryption through a disulfide bond formation in a PDI-dependent mechanism. PMID:24911456

  4. Toxic effects of the Fe2O3 nanoparticles on the liver and lung tissue.

    PubMed

    Sadeghi, L; Yousefi Babadi, V; Espanani, H R

    2015-01-01

    Iron oxide nanoparticles are magnetic nanoparticles which have widespread application in MRI and heat therapy of cancer as contrast elements. They are also used effectively for drug and gene delivery because of effective penetrating to the cells and tissues. However, these features cause Fe2O3 nanoparticles have toxic effects that are not completely understood yet. In this study, effects of iron oxide nanoparticles on lung tissue in adult male Wistar rats were studied. We used pulmonary inhalation method for nanoparticle administration and used ether as a helper. Our results showed administered nanoparticles penetrated to the circulation and rapidly reached to liver and created serious inflammation in lung and liver tissues. This study used two different nanoparticle doses (20 and 40 mg/kg) and two exposing numbers (7 and 14 times). Results showed significant enhancement of free radicals and reduction of the GSH in lung tissue. Histological studies showed nanoparticle treatment of rats caused pulmonary emphysema, interstitial hyperemia and inflammation in lungs. By increasing the administrated dose lung tissue showed all of the mentioned symptoms with increased intensity. Nanoparticle exposition causes presence of neutrophils, lymphocytes and eosinophils in the lung tissue that confirmed there is a serious pathologic condition. Hepatic cells injuries cause penetration of the hepatic enzymes in to the blood serum (Tab. 2, Fig. 4, Ref. 32). Text in PDF www.elis.sk. PMID:26084739

  5. Coming to terms with tissue engineering and regenerative medicine in the lung.

    PubMed

    Prakash, Y S; Tschumperlin, Daniel J; Stenmark, Kurt R

    2015-10-01

    Lung diseases such as emphysema, interstitial fibrosis, and pulmonary vascular diseases cause significant morbidity and mortality, but despite substantial mechanistic understanding, clinical management options for them are limited, with lung transplantation being implemented at end stages. However, limited donor lung availability, graft rejection, and long-term problems after transplantation are major hurdles to lung transplantation being a panacea. Bioengineering the lung is an exciting and emerging solution that has the ultimate aim of generating lung tissues and organs for transplantation. In this article we capture and review the current state of the art in lung bioengineering, from the multimodal approaches, to creating anatomically appropriate lung scaffolds that can be recellularized to eventually yield functioning, transplant-ready lungs. Strategies for decellularizing mammalian lungs to create scaffolds with native extracellular matrix components vs. de novo generation of scaffolds using biocompatible materials are discussed. Strengths vs. limitations of recellularization using different cell types of various pluripotency such as embryonic, mesenchymal, and induced pluripotent stem cells are highlighted. Current hurdles to guide future research toward achieving the clinical goal of transplantation of a bioengineered lung are discussed. PMID:26254424

  6. NEW TECHNIQUES FOR IMAGING AND ANALYZING LUNG TISSUE

    EPA Science Inventory

    The recent technological revolution in the field of imaging techniques has provided pathologists and toxicologists with an expanding repertoire of analytical techniques for studying the interaction between the lung and the various exogenous materials to which it is exposed. Analy...

  7. Thermal effect of endoscopic thermal vapour ablation on the lung surface in human ex vivo tissue

    PubMed Central

    Henne, Erik; Anderson, Joseph C.; Barry, Robert; Kesten, Steven

    2012-01-01

    Purpose: An investigation of the thermal effect and the potential for injury at the lung surface following thermal vapour ablation (InterVapor), an energy-based method of achieving endoscopic lung volume reduction. Methods: Heated water vapour was delivered to fifteen ex vivo human lungs using standard clinical procedure, and the thermal effect at the visceral pleura was monitored with an infrared camera. The time–temperature response was analysed mathematically to determine a cumulative injury quotient, which was compared to published thresholds. Results: The cumulative injury quotients for all 71 treatments of ex vivo tissue were found to be below the threshold for first degree burn and no other markers of tissue injury at the lung surface were observed. Conclusion: The safety profile for thermal vapour ablation is further supported by the demonstration that the thermal effect in a worst-case model is not expected to cause injury at the lung surface. PMID:22690896

  8. Microstructural Analysis of Peripheral Lung Tissue through CPMG Inter-Echo Time R2 Dispersion

    PubMed Central

    Kurz, Felix T.; Kampf, Thomas; Buschle, Lukas R.; Schlemmer, Heinz-Peter; Heiland, Sabine; Bendszus, Martin; Ziener, Christian H.

    2015-01-01

    Since changes in lung microstructure are important indicators for (early stage) lung pathology, there is a need for quantifiable information of diagnostically challenging cases in a clinical setting, e.g. to evaluate early emphysematous changes in peripheral lung tissue. Considering alveoli as spherical air-spaces surrounded by a thin film of lung tissue allows deriving an expression for Carr-Purcell-Meiboom-Gill transverse relaxation rates R2 with a dependence on inter-echo time, local air-tissue volume fraction, diffusion coefficient and alveolar diameter, within a weak field approximation. The model relaxation rate exhibits the same hyperbolic tangent dependency as seen in the Luz-Meiboom model and limiting cases agree with Brooks et al. and Jensen et al. In addition, the model is tested against experimental data for passively deflated rat lungs: the resulting mean alveolar radius of RA = 31.46 ± 13.15 μm is very close to the literature value (∼34 μm). Also, modeled radii obtained from relaxometer measurements of ageing hydrogel foam (that mimics peripheral lung tissue) are in good agreement with those obtained from μCT images of the same foam (mean relative error: 0.06 ± 0.01). The model’s ability to determine the alveolar radius and/or air volume fraction will be useful in quantifying peripheral lung microstructure. PMID:26544068

  9. Microstructural Analysis of Peripheral Lung Tissue through CPMG Inter-Echo Time R2 Dispersion.

    PubMed

    Kurz, Felix T; Kampf, Thomas; Buschle, Lukas R; Schlemmer, Heinz-Peter; Heiland, Sabine; Bendszus, Martin; Ziener, Christian H

    2015-01-01

    Since changes in lung microstructure are important indicators for (early stage) lung pathology, there is a need for quantifiable information of diagnostically challenging cases in a clinical setting, e.g. to evaluate early emphysematous changes in peripheral lung tissue. Considering alveoli as spherical air-spaces surrounded by a thin film of lung tissue allows deriving an expression for Carr-Purcell-Meiboom-Gill transverse relaxation rates R2 with a dependence on inter-echo time, local air-tissue volume fraction, diffusion coefficient and alveolar diameter, within a weak field approximation. The model relaxation rate exhibits the same hyperbolic tangent dependency as seen in the Luz-Meiboom model and limiting cases agree with Brooks et al. and Jensen et al. In addition, the model is tested against experimental data for passively deflated rat lungs: the resulting mean alveolar radius of RA = 31.46 ± 13.15 μm is very close to the literature value (∼34 μm). Also, modeled radii obtained from relaxometer measurements of ageing hydrogel foam (that mimics peripheral lung tissue) are in good agreement with those obtained from μCT images of the same foam (mean relative error: 0.06 ± 0.01). The model's ability to determine the alveolar radius and/or air volume fraction will be useful in quantifying peripheral lung microstructure. PMID:26544068

  10. The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues.

    PubMed

    Foronjy, Robert F; Majka, Susan M

    2012-12-01

    Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases. PMID:23626909

  11. Expression and clinical significance of A‐kinase anchor protein 4 in lung adenocarcinoma tissue

    PubMed Central

    Guo, Kang; Yu, Xiao‐Yun; Yu, Zhuang; Xu, Ping

    2015-01-01

    Abstract Background The A‐kinase anchor proteins (AKAP) are a growing family of scaffolding proteins involved in the occurrence, proliferation, and metastasis of tumors by controlling intracellular signals. In this study, the expression and significance of AKAP4 were analyzed in patients with lung adenocarcinoma and adjacent non‐cancerous tissues. Methods Using reverse transcriptase‐polymerase chain reaction and Western blot, AKAP4 messenger ribonucleic acid (mRNA) and protein expression levels were measured in 108 cases of lung adenocarcinoma and adjacent non‐cancerous tissues. Results AKAP4 mRNA and protein were expressed in lung adenocarcinoma tissues, but not in adjacent non‐cancerous tissues. The expression of AKAP4 mRNA and protein was closely associated with lymphatic metastasis (P < 0.05), but had no relationship with stage, differentiation degree, gender, age or smoking (P > 0.05). AKAP4 expression had an adverse effect on the overall survival rate (P < 0.05). Conclusion The expression of AKAP4 was high in lung adenocarcinoma tissue, which may be closely related to the lymphatic metastasis of lung adenocarcinoma. AKAP4 may be a novel lung adenocarcinoma molecule marker and a predictor of poor prognosis. PMID:27148411

  12. 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

  13. 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.

  14. Lung tissue engineering and preservation of alveolar microstructure using a novel casting method.

    PubMed

    Kajbafzadeh, A-M; Sabetkish, N; Sabetkish, S; Tavangar, S M; Hossein Beigi, R S; Talebi, M A; Akbarzadeh, A; Nikfarjam, L

    2015-02-01

    We used a rat model to decellularize and seed alveolar cells on a three-dimensional lung scaffold to preserve alveolar microarchitecture. We verified the preservation of terminal respiratory structure by casting and by scanning electron microscopy (SEM) of the casts after decellularization. Whole lungs were obtained from 12 healthy Sprague-Dawley rats, cannulated through the trachea under sterile conditions, and decellularized using a detergent-based method. Casting of both natural and decellularized lungs was performed to verify preservation of the inner microstructure of scaffolds for further cell seeding. Alveolar cell seeding was performed using green fluorescent protein (GFP) lung cells and non-GFP lung cells, and a peristaltic pump. We assessed cell seeding using histological and immunohistochemical staining, and enzymatic evaluation. All cellular components were removed completely from the scaffolds, and histological staining and SEM of casts were used to verify the preservation of tissue structure. Tensile tests verified conservation of biomechanical properties. The hydroxyproline content of decellularized lungs was similar to native lung. Histological and immunohistochemical evaluations showed effective cell seeding on decellularized matrices. Enzymatic measurement of trypsin and alpha 1 antitrypsin suggested the potential functional properties of the regenerated lungs. Casts produced by our method have satisfactory geometrical properties for further cell seeding of lung scaffolds. Preservation of micro-architecture and terminal alveoli that was confirmed by SEM of lung casts increases the probability of an effective cell seeding process. PMID:25268847

  15. Toward in vivo lung's tissue incompressibility characterization for tumor motion modeling in radiation therapy

    SciTech Connect

    Shirzadi, Zahra; Sadeghi-Naini, Ali; Samani, Abbas

    2013-05-15

    Purpose: A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Estimating lung tissue incompressibility parameter variations resulting from air content variation throughout respiration is critical for computer assisted tumor motion tracking. Continuous tumor motion is a major challenge in lung cancer radiotherapy, especially with external beam radiotherapy. If not accounted for, this motion may lead to areas of radiation overdosage for normal tissue. Given the unavailability of imaging modality that can be used effectively for real-time lung tumor tracking, computer assisted approach based on tissue deformation estimation can be a good alternative. This approach involves lung biomechanical model where its fidelity depends on input tissue properties. This investigation shows that considering variable tissue incompressibility parameter is very important for predicting tumor motion accurately, hence improving the lung radiotherapy outcome. Methods: First, an in silico lung phantom study was conducted to demonstrate the importance of employing variable Poisson's ratio for tumor motion predication. After it was established that modeling this variability is critical for accurate tumor motion prediction, an optimization based technique was developed to estimate lung tissue Poisson's ratio as a function of respiration cycle time. In this technique, the Poisson's ratio and lung pressure value were varied systematically until optimal values were obtained, leading to maximum similarity between acquired and simulated 4D CT lung images. This technique was applied in an ex vivo porcine lung study where simulated images were constructed using the end exhale CT image and deformation fields obtained from the lung's FE modeling of each respiration time increment. To model the tissue, linear elastic and Marlow hyperelastic material models in conjunction with variable Poisson's ratio were used. Results: The phantom study showed that

  16. Multimodal imaging of lung tissue using optical coherence tomography and two photon microscopy

    NASA Astrophysics Data System (ADS)

    Gaertner, Maria; Cimalla, Peter; Geissler, Stefan; Meissner, Sven; Schnabel, Christian; Kuebler, Wolfgang M.; Koch, Edmund

    2012-02-01

    In the context of protective artificial ventilation strategies for patients with severe lung diseases, the contribution of ventilator settings to tissue changes on the alveolar level of the lung is still a question under debate. To understand the impact of respiratory settings as well as the dynamic process of respiration, high-resolution monitoring and visualization of the dynamics of lung alveoli are essential. An instrument allowing 3D imaging of lung tissue as well as imaging of functional constituents, such as elastin fibers, in in situ experimental conditions is presented in this study using a combination of Fourier domain optical coherence tomography (FD-OCT) and fiber-guided two photon microscopy. In a comparative study, fixed lung tissue, stained with sulforhodamine B for elastin fibers, was used to illustrate the ability of fiber-guided two photon excitation and single photon excitation for the visualization of elastin fibers within the tissue. Together with the fast 3D imaging capability of OCT, a new tool is given for the monitoring of alveolar lung dynamics in future in vivo experiments.

  17. Differentially Expressed miRNAs in Tumor, Adjacent, and Normal Tissues of Lung Adenocarcinoma

    PubMed Central

    Tian, Fei; Li, Rui; Chen, Zhenzhu; Shen, Yanting; Lu, Jiafeng; Xie, Xueying; Ge, Qinyu

    2016-01-01

    Lung cancer is the leading cause of cancer deaths. Non-small-cell lung cancer (NSCLC) is the major type of lung cancer. The aim of this study was to characterize the expression profiles of miRNAs in adenocarcinoma (AC), one major subtype of NSCLC. In this study, the miRNAs were detected in normal, adjacent, and tumor tissues by next-generation sequencing. Then the expression levels of differential miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the results, 259, 401, and 389 miRNAs were detected in tumor, adjacent, and normal tissues of pooled AC samples, respectively. In addition, for the first time we have found that miR-21-5p and miR-196a-5p were gradually upregulated from normal to adjacent to tumor tissues; miR-218-5p was gradually downregulated with 2-fold or greater change in AC tissues. These 3 miRNAs were validated by qRT-PCR. Lastly, we predicted target genes of these 3 miRNAs and enriched the potential functions and regulatory pathways. The aberrant miR-21-5p, miR-196a-5p, and miR-218-5p may become biomarkers for diagnosis and prognosis of lung adenocarcinoma. This research may be useful for lung adenocarcinoma diagnosis and the study of pathology in lung cancer. PMID:27247934

  18. Lung tissue flap repairs esophagus defection with an inner chitosan tube stent

    PubMed Central

    Chen, Gang; Shi, Wen-Jun

    2009-01-01

    AIM: To repair the partial esophagus defect with a chitosan stent, a new esophageal prosthesis made of pulmonary tissue with vascular pedicle. METHODS: Fifteen Japanese big ear white rabbits were divided into experimental group (n = 10) and control group (n = 5). Esophagus defect in rabbits of experimental group was repaired using lung tissue flap with a chitosan tube stent, gross and histological appearance was observed at week 2, 4 and 8 after operation, and barium sulphate X-ray screen was performed at week 10 after operation. Esophagus defect of rabbits in control group was repaired using lung tissue flap with no chitosan tube stent, gross and histological appearance was observed at week 2, 4 and 8 after operation, and barium sulphate X-ray screen was performed at week 10 after operation. RESULTS: In the experimental group, 6 rabbits survived for over two weeks, the lung tissue flap healed esophageal defection, and squamous metaplasia occurred on the surface of lung tissue flap. At week 10 after operation, barium sulphate examination found that barium was fluent through the esophagus with no stricture or back stream, the creeping was good. In the control group, 4 rabbits survived for two weeks, the lung tissue flap healed esophageal defection with fibrous tissue hyperplasia, barium sulphate examination found that barium was fluent through the esophagus with a slight stricture or back stream, and the creeping was not good at week 10 after operation. CONCLUSION: Esophagus defect can be repaired using lung tissue flap with an inner chitosan tube stent. PMID:19322927

  19. Comprehensive Analysis of Transcriptome Sequencing Data in the Lung Tissues of COPD Subjects

    PubMed Central

    Lim, Jae Hyun; Lee, Jae Seung; Lee, Sang-Do; Oh, Yeon-Mok

    2015-01-01

    Background and Objectives. Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airflow limitation. Although airway inflammation and oxidative stress are known to be important in the pathogenesis of COPD, the mechanism underlying airflow obstruction is not fully understood. Gene expression profiling of lung tissue was performed to define the molecular pathways that are dysregulated in COPD. Methods. RNA was isolated from lung tissues obtained from 98 subjects with COPD and 91 control subjects with normal spirometry. The RNA samples were processed with RNA-seq using the HiSeq 2000 system. Genes expressed differentially between the two groups were identified using Student's t-test. Results. After filtering for genes with zero counts and noncoding genes, 16,676 genes were evaluated. A total of 2312 genes were differentially expressed between the lung tissues of COPD and control subjects (false discovery rate corrected q < 0.01). The expression of genes related to oxidative phosphorylation and protein catabolism was reduced and genes related to chromatin modification were dysregulated in lung tissues of COPD subjects. Conclusions. Oxidative phosphorylation, protein degradation, and chromatin modification were the most dysregulated pathways in the lung tissues of COPD subjects. These findings may have clinical and mechanistic implications in COPD. PMID:25834810

  20. Regional Normal Lung Tissue Density Changes in Patients Treated With Stereotactic Body Radiation Therapy for Lung Tumors

    SciTech Connect

    Diot, Quentin; Kavanagh, Brian; Schefter, Tracey; Gaspar, Laurie; Stuhr, Kelly; Miften, Moyed

    2012-11-15

    Purpose: To describe regional lung tissue density changes in normal lung tissue of patients with primary and metastatic lung tumors who received stereotactic body radiation therapy (SBRT). Methods and Materials: A total of 179 post-SBRT follow-up computed tomography (CT) scans of 62 patients who received SBRT between 2003 and 2009 were studied. Median prescription dose was 54 Gy (range, 30-60 Gy) in 3 to 5 fractions. SBRT-induced lung density changes on post-SBRT follow-up CT were evaluated at approximately 3, 6, 12, 18, 24, and 30 months after treatment. Dose-response curves (DRC) were generated for SBRT-induced lung damage by averaging CT number (HU) changes for regions of the lungs receiving the same dose at 5-Gy intervals. Results: For all follow-up interval periods, CT numbers linearly increased with dose until 35 Gy and were constant thereafter. For 3, 18, 24, and 30 months, the rate of relative electron density increase with dose was approximately 0.24% per Gy. At 6 months, the rate was also similar below 20 Gy but then rose to 0.6% per Gy above this threshold. After 6 months, DRCs were mostly time-independent. When split between patients treated with 3 fractions of 12 to 20 Gy (median, 20 Gy; average tumor volume, 12 {+-} 16 cm{sup 3}) and with >3 fractions of 6 to 12.5 Gy (median, 9 Gy; average tumor volume, 30 {+-} 40 cm{sup 3}), DRCs differed significantly. In both cases, CT changes at 3, 18, 24, and 30 months were identical to those of the population DRC; however, patients who received >3 fractions showed 6-month CT changes that were more than twice those for the group that received 3 fractions. Conclusions: This analysis of SBRT-induced normal lung density changes indicates that lung normal tissue has more pronounced self-limited acute effects than late effects. Differences in acute CT changes following treatments in 3 fractions were considerably less than for treatments in >3 fractions.

  1. Three-Dimensionally Engineered Normal Human Lung Tissue-Like Assemblies: Target Tissues for Human Respiratory Viral Infections

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J.; McCarthy, M.; Lin, Y-H.; Deatly, A. M.

    2008-01-01

    In vitro three-dimensional (3D) human lung epithelio-mesenchymal tissue-like assemblies (3D hLEM TLAs) from this point forward referred to as TLAs were engineered in Rotating Wall Vessel (RWV) technology to mimic the characteristics of in vivo tissues thus providing a tool to study human respiratory viruses and host cell interactions. The TLAs were bioengineered onto collagen-coated cyclodextran microcarriers using primary human mesenchymal bronchial-tracheal cells (HBTC) as the foundation matrix and an adult human bronchial epithelial immortalized cell line (BEAS-2B) as the overlying component. The resulting TLAs share significant characteristics with in vivo human respiratory epithelium including polarization, tight junctions, desmosomes, and microvilli. The presence of tissue-like differentiation markers including villin, keratins, and specific lung epithelium markers, as well as the production of tissue mucin, further confirm these TLAs differentiated into tissues functionally similar to in vivo tissues. Increasing virus titers for human respiratory syncytial virus (wtRSVA2) and the detection of membrane bound glycoproteins over time confirm productive infection with the virus. Therefore, we assert TLAs mimic aspects of the human respiratory epithelium and provide a unique capability to study the interactions of respiratory viruses and their primary target tissue independent of the host s immune system.

  2. Analysis of speckle patterns in phase-contrast images of lung tissue

    NASA Astrophysics Data System (ADS)

    Kitchen, M. J.; Paganin, D.; Lewis, R. A.; Yagi, N.; Uesugi, K.

    2005-08-01

    Propagation-based phase-contrast images of mice lungs have been obtained at the SPring-8 synchrotron research facility. Such images exhibit a speckled intensity pattern that bears a superficial resemblance to alveolar structures. This speckle results from focussing effects as projected air-filled alveoli form aberrated compound refractive lenses. An appropriate phase-retrieval algorithm has been utilized to reconstruct the approximate projected lung tissue thickness from single-phase-contrast mice chest radiographs. The results show projected density variations across the lung, highlighting regions of low density corresponding to air-filled regions. Potentially, this offers a better method than conventional radiography for detecting lung diseases such as fibrosis, emphysema and cancer, though this has yet to be demonstrated. As such, the approach can assist in continuing studies of lung function utilizing propagation-based phase-contrast imaging.

  3. Fibrocytes and the tissue niche in lung repair.

    PubMed

    Andersson-Sjöland, Annika; Nihlberg, Kristian; Eriksson, Leif; Bjermer, Leif; Westergren-Thorsson, Gunilla

    2011-01-01

    Human fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of markers related to leukocytes, hematopoietic stem cells and a diverse set of fibroblast phenotypes. Fibrocytes can be recruited from the circulation to the tissue where they further can differentiate and proliferate into various mesenchymal cell types depending on the tissue niche. This local tissue niche is important because it modulates the fibrocytes and coordinates their role in tissue behaviour and repair. However, plasticity of a niche may be co-opted in chronic airway diseases such as asthma, idiopathic pulmonary fibrosis and obliterative bronchiolitis. This review will therefore focus on a possible role of fibrocytes in pathological tissue repair processes in those diseases. PMID:21658209

  4. Three Dimensional Imaging of Paraffin Embedded Human Lung Tissue Samples by Micro-Computed Tomography

    PubMed Central

    Scott, Anna E.; Vasilescu, Dragos M.; Seal, Katherine A. D.; Keyes, Samuel D.; Mavrogordato, Mark N.; Hogg, James C.; Sinclair, Ian; Warner, Jane A.; Hackett, Tillie-Louise; Lackie, Peter M.

    2015-01-01

    Background Understanding the three-dimensional (3-D) micro-architecture of lung tissue can provide insights into the pathology of lung disease. Micro computed tomography (µCT) has previously been used to elucidate lung 3D histology and morphometry in fixed samples that have been stained with contrast agents or air inflated and dried. However, non-destructive microstructural 3D imaging of formalin-fixed paraffin embedded (FFPE) tissues would facilitate retrospective analysis of extensive tissue archives of lung FFPE lung samples with linked clinical data. Methods FFPE human lung tissue samples (n = 4) were scanned using a Nikon metrology µCT scanner. Semi-automatic techniques were used to segment the 3D structure of airways and blood vessels. Airspace size (mean linear intercept, Lm) was measured on µCT images and on matched histological sections from the same FFPE samples imaged by light microscopy to validate µCT imaging. Results The µCT imaging protocol provided contrast between tissue and paraffin in FFPE samples (15mm x 7mm). Resolution (voxel size 6.7 µm) in the reconstructed images was sufficient for semi-automatic image segmentation of airways and blood vessels as well as quantitative airspace analysis. The scans were also used to scout for regions of interest, enabling time-efficient preparation of conventional histological sections. The Lm measurements from µCT images were not significantly different to those from matched histological sections. Conclusion We demonstrated how non-destructive imaging of routinely prepared FFPE samples by laboratory µCT can be used to visualize and assess the 3D morphology of the lung including by morphometric analysis. PMID:26030902

  5. [Biochemical and histological research on lung tissue in experimental carbon disulfide exposure].

    PubMed

    Mikhaĭlova, A; Petrova, S; Donchev, N

    1987-01-01

    During an experiment on two species of test animals (guinea pigs and white male rats) is studied the effect of carbon sulfide on the biochemical and structural characteristic of the lung. Duration of the experiments 30 days with guinea pigs and 90 days-white male rats. A complex of biochemical and histological methods is applied. Disturbances in the metabolic processes of the lung are established: a) raised activity of the hydrolytic enzymes; b) increased activity of the glycolytic enzymes and c) stronger protein synthesis. The observed metabolic disturbances are based, most probably, on the circulation infringements, occurring in the lung tissue under the effect of carbon sulfide. PMID:3441458

  6. Regulation of Na+ channels in frog lung epithelium: a target tissue for aldosterone action.

    PubMed

    Fischer, H; Clauss, W

    1990-04-01

    Sodium transport across isolated lung tissue of the frog Xenopus laevis was measured in Ussing chambers under voltage-clamp conditions. Perfusing the lungs with NaCl-Ringer's solutions on both sides, a basal distinct amiloride-blockable Na+ current was present. Incubating the lungs with 1 mumol/l aldosterone from the pleural side raised the short circuit current after a 1-h latent period. Maximal values were reached after 4-5 h of aldosterone treatment, at which time the transepithelial Na+ current was more than doubled compared to the control. The stimulatory effect was totally inhibited when the aldosterone treatment was preceded by incubation of the lung tissues with spironolactone in 2000-fold excess. In the presence of amiloride (0.5-8 mumol/l) in the alveolar compartment, a Lorentzian noise component appeared in the power spectrum of the fluctuations in the short circuit current. This enabled the calculation of single Na+ channel current and Na+ channel density under both experimental conditions. Aldosterone stimulation did not change single Na+ channel current. On the other hand, the number of conducting Na+ channels increased in parallel with the transepithelial Na+ transport. This suggests that the alveolar epithelium may be a physiological target tissue for aldosterone. Since fluid absorption in the lung is secondary to active Na+ transport, aldosterone may be a potent regulator for maintaining the relatively fluid-free state of the lumen of the lung in some cases of fluid accumulation. PMID:2162035

  7. Ectopic Intrathoracic Hepatic Tissue and Accessory Lung Lobe Aplasia in a Dog.

    PubMed

    Lande, Rachel; Dvorak, Laura; Gardiner, David W; Bahr, Anne

    2015-01-01

    A 6 yr old male Yorkshire terrier was presented for an ~6 yr history of progressive cough and dyspnea. Thoracic radiographs revealed a 6 cm diameter mass within the right caudal thorax. Thoracic ultrasound identified an intrathoracic mass ultrasonographically consistent with liver tissue and a chronic diaphragmatic hernia was suspected. Exploratory laparotomy was performed, but no evidence of a diaphragmatic hernia was identified. Thoracic exploration identified abnormal lung parenchyma. The accessory lung lobe was removed using a stapling devise near its base. The consolidated mass had the gross appearance of liver and was histologically identified as ectopic hepatic tissue. Ectopic hepatic tissue, unlike ectopic splenic and pancreatic tissue, is rare and generally has a subdiaphragmatic distribution. This solitary case report demonstrates that ectopic intrathoracic hepatic tissue should be considered a differential diagnosis for a caudal mediastinal mass. PMID:26355587

  8. 2009 pandemic H1N1 influenza virus replicates in human lung tissues

    PubMed Central

    Zhang, Jinxia; Zhang, Zengfeng; Fan, Xiaohui; Liu, Yuansheng; Wang, Jia; Zheng, Zuoyi; Chen, Rirong; Wang, Pui; Song, Wenjun; Chen, Honglin; Guan, Yi

    2009-01-01

    Replication activity of 2009 pandemic H1N1 influenza virus in human lung cells was evaluated in this study. Twenty-two surgically removed human lung tissue samples were infected ex vivo with pandemic H1N1, A/California/04/2009, seasonal human H1N1 virus, A/ST/92/2009, or a highly pathogenic H5N1 virus, A/Vietnam/1194/04. Examination of nucleoprotein (NP) protein expression and vRNA replication in infected human lung tissues showed that while CA/04 replication varied between tissue samples, overall, it replicated more efficiently than seasonal H1N1 but less efficiently than H5N1 virus. Double immunostaining for viral antigens and cellular markers indicated that CA/04 replicates in type II alveolar epithelial cells. PMID:20370480

  9. Histopathology effects of nickel nanoparticles on lungs, liver, and spleen tissues in male mice

    NASA Astrophysics Data System (ADS)

    Ajdari, Marziyeh; Ziaee Ghahnavieh, Marziyeh

    2014-09-01

    Because of the classification of the nickel compounds as carcinogenic substances, there is a need for in vivo tests to nickel nanoparticles (NiNPs) for observing their effects on health experimentally. Spherical NiNPs with 10 nm in diameter and 75 ppm concentration were applied for investigating their toxicities within male albino mice as an in vivo model. We randomly made sham group, control group, and 75 ppm group (with five animals in each group). Then, the nanoparticles were injected into mice intraperitonealy for 7 days and after that their lungs, liver, and spleen were removed for histopathological observations. At the end of the test, section microscopic observations of liver, spleen, and lung in sham and control groups showed normal tissues but these tissues underwent significant abnormal effects in 75 ppm group. NiNPs can cause undesirable effects in lungs, liver, and spleen tissues with same condition of this study.

  10. Beyond volutrauma in ARDS: the critical role of lung tissue deformation

    PubMed Central

    2011-01-01

    Ventilator-induced lung injury (VILI) consists of tissue damage and a biological response resulting from the application of inappropriate mechanical forces to the lung parenchyma. The current paradigm attributes VILI to overstretching due to very high-volume ventilation (volutrauma) and cyclic changes in aeration due to very low-volume ventilation (atelectrauma); however, this model cannot explain some research findings. In the present review, we discuss the relevance of cyclic deformation of lung tissue as the main determinant of VILI. Parenchymal stability resulting from the interplay of respiratory parameters such as tidal volume, positive end-expiratory pressure or respiratory rate can explain the results of different clinical trials and experimental studies that do not fit with the classic volutrauma/atelectrauma model. Focusing on tissue deformation could lead to new bedside monitoring and ventilatory strategies. PMID:21489320

  11. Intra-vital microscopy of lung tissue: A simulation based analysis of the image formation

    NASA Astrophysics Data System (ADS)

    Gaertner, Maria; Schirrmann, Kerstin; Schnabel, Christian; Meissner, Sven; Kertzscher, Ulrich; Kirsten, Lars; Koch, Edmund

    2013-06-01

    In the course of pulmonary research, understanding alveolar tissue dynamics plays a critical role in the treatment of patients suffering from acute lung diseases. As a gold standard technique for monitoring micro scale changes of lung tissue, real-time intra-vital microscopy (IVM) has been established to evaluate the behavior of the alveolar tissue. To allow profound qualitative and quantitative conclusions, characteristic features of the obtained images have to be thoroughly understood. These factors are strongly influenced by the imaging setup and physiological condition of the lung. To circumvent misinterpretations, a ray-tracing approach has been applied in this study using an idealized geometry of the mouse lung parenchyma deduced from optical coherence tomography (OCT) as a complementary imaging technique. Basic features of IVM images are double ring structures and disappearing of alveoli related to liquid infiltration. Ray propagation analysis reveals the formation of these features by two major reflection processes: partial reflection and total internal reflection. The results give rise to quantification errors of the alveolar area related to reflexes misinterpreted as alveolar borders and should further be used to yield a correction factor for future IVM lung tissue studies.

  12. 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

  13. Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

    PubMed Central

    Walker, Natalie; Badri, Linda; Wettlaufer, Scott; Flint, Andrew; Sajjan, Uma; Krebsbach, Paul H.; Keshamouni, Venkateshwar G.; Peters-Golden, Marc; Lama, Vibha N.

    2011-01-01

    Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft–derived MSCs uniquely express embryonic lung mesenchyme–associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stable in vivo fibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 by in situ hybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs. PMID:21641374

  14. Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures.

    PubMed

    Uhl, Franziska E; Vierkotten, Sarah; Wagner, Darcy E; Burgstaller, Gerald; Costa, Rita; Koch, Ina; Lindner, Michael; Meiners, Silke; Eickelberg, Oliver; Königshoff, Melanie

    2015-10-01

    Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage (per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs. PMID:25929950

  15. Oxidative damage induced by cigarette smoke exposure in mice: impact on lung tissue and diaphragm muscle*,**

    PubMed Central

    de Carlos, Samanta Portão; Dias, Alexandre Simões; Forgiarini, Luiz Alberto; Patricio, Patrícia Damiani; Graciano, Thaise; Nesi, Renata Tiscoski; Valença, Samuel; Chiappa, Adriana Meira Guntzel; Cipriano, Gerson; de Souza, Claudio Teodoro; Chiappa, Gaspar Rogério da Silva

    2014-01-01

    OBJECTIVE: To evaluate oxidative damage (lipid oxidation, protein oxidation, thiobarbituric acid-reactive substances [TBARS], and carbonylation) and inflammation (expression of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin [p-AMPK and p-mTOR, respectively]) in the lung parenchyma and diaphragm muscles of male C57BL-6 mice exposed to cigarette smoke (CS) for 7, 15, 30, 45, or 60 days. METHODS: Thirty-six male C57BL-6 mice were divided into six groups (n = 6/group): a control group; and five groups exposed to CS for 7, 15, 30, 45, and 60 days, respectively. RESULTS: Compared with control mice, CS-exposed mice presented lower body weights at 30 days. In CS-exposed mice (compared with control mice), the greatest differences (increases) in TBARS levels were observed on day 7 in diaphragm-muscle, compared with day 45 in lung tissue; the greatest differences (increases) in carbonyl levels were observed on day 7 in both tissue types; and sulfhydryl levels were lower, in both tissue types, at all time points. In lung tissue and diaphragm muscle, p-AMPK expression exhibited behavior similar to that of TBARS. Expression of p-mTOR was higher than the control value on days 7 and 15 in lung tissue, as it was on day 45 in diaphragm muscle. CONCLUSION: Our data demonstrate that CS exposure produces oxidative damage, not only in lung tissue but also (primarily) in muscle tissue, having an additional effect on respiratory muscle, as is frequently observed in smokers with COPD. PMID:25210964

  16. Monte Carlo estimation of dose difference in lung from 192Ir brachytherapy due to tissue inhomogeneity.

    PubMed

    Gialousis, G; Dimitriadis, A; Yakoumakis, E

    2011-09-01

    Lung brachytherapy using high-dose rate (192)Ir technique is a well-established technique of radiation therapy. However, many commercial treatment planning systems do not have the ability to consider the inhomogeneity of lung in relation to normal tissue. Under such circumstances dose calculations for tissues and organs at risk close to the target are inaccurate. The purpose of the current study was to estimate the dose difference due to tissue inhomogeneity using the Monte Carlo simulation code MCNP-5. Results showed that there was a relative sub dosage by treatment planning systems calculations in neighbouring tissues around the radioactive source due to inhomogeneity ignorance. The presence of lung instead of normal tissue resulted in an increase in relative dose, which approached 8 % at 4-cm distance from the source. Additionally, the relative increase was small for the lung (2.1 %) and larger for organs at risk such as the heart (6.8 %) and bone marrow (7.6 %). PMID:21831865

  17. Changes in lung composition and regional perfusion and tissue distribution in patients with ARDS

    PubMed Central

    Dakin, Jonathan; Jones, Andrew T; Hansell, David M; Hoffman, Eric A; Evans, Timothy W

    2011-01-01

    Background & objective ARDS is characterised by bilateral pulmonary infiltrates and refractory hypoxemia attributed to V/Q mismatch. We used dynamic CT to characterise changes in lung composition, regional perfusion and tissue distribution in patients with ARDS in comparison to healthy subjects. Methods The Fick principle was applied to serial attenuation measurements constructed from sequential CT images acquired during the passage of a bolus of iodinated contrast medium in healthy subjects (n=3) and patients with ARDS (n=11). Perfusion was calculated by the Mullani-Gould method and mapped throughout both lungs. Gradients of perfusion and tissue density against vertical height were constructed. Results In comparison to normal individuals, the tissue component of lungs from patients with ARDS was significantly increased (p<0.05). Blood fraction was unchanged. There was a discernable gradient in tissue density from non dependent to dependent regions in the patients with ARDS that was significantly different from controls. The proportion of perfusion applied to consolidated areas (ie shunt) correlated significantly (p<0.05) with the severity of hypoxaemia. Conclusions In patients with ARDS there are changes in both lung composition and the distribution of tissue and perfusion that may account in part for the physiological changes that define the syndrome. PMID:21883676

  18. Drug-related death: adulterants from cocaine preparations in lung tissue and blood.

    PubMed

    Pawlik, Evelyn; Mahler, Hellmut; Hartung, Benno; Plässer, Gerd; Daldrup, Thomas

    2015-04-01

    The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue. PMID:25747329

  19. Improved OCT imaging of lung tissue using a prototype for total liquid ventilation

    NASA Astrophysics Data System (ADS)

    Schnabel, Christian; Meissner, Sven; Koch, Edmund

    2011-06-01

    Optical coherence tomography (OCT) is used for imaging subpleural alveoli in animal models to gain information about dynamic and morphological changes of lung tissue during mechanical ventilation. The quality of OCT images can be increased if the refraction index inside the alveoli is matched to the one of tissue via liquid-filling. Thereby, scattering loss can be decreased and higher penetration depth and tissue contrast can be achieved. Until now, images of liquid-filled lungs were acquired in isolated and fixated lungs only, so that an in vivo measurement situation is not present. To use the advantages of liquid-filling for in vivo imaging of small rodent lungs, it was necessary to develop a liquid ventilator. Perfluorodecalin, a perfluorocarbon, was selected as breathing fluid because of its refraction index being similar to the one of water and the high transport capacity for carbon dioxide and oxygen. The setup is characterized by two independent syringe pumps to insert and withdraw the fluid into and from the lung and a custom-made control program for volume- or pressure-controlled ventilation modes. The presented results demonstrate the liquid-filling verified by optical coherence tomography and intravital microscopy (IVM) and the advantages of liquid-filling to OCT imaging of subpleural alveoli.

  20. Complex Sources of Variation in Tissue Expression Data: Analysis of the GTEx Lung Transcriptome.

    PubMed

    McCall, Matthew N; Illei, Peter B; Halushka, Marc K

    2016-09-01

    The sources of gene expression variability in human tissues are thought to be a complex interplay of technical, compositional, and disease-related factors. To better understand these contributions, we investigated expression variability in a relatively homogeneous tissue expression dataset from the Genotype-Tissue Expression (GTEx) resource. In addition to identifying technical sources, such as sequencing date and post-mortem interval, we also identified several biological sources of variation. An in-depth analysis of the 175 genes with the greatest variation among 133 lung tissue samples identified five distinct clusters of highly correlated genes. One large cluster included surfactant genes (SFTPA1, SFTPA2, and SFTPC), which are expressed exclusively in type II pneumocytes, cells that proliferate in ventilator associated lung injury. High surfactant expression was strongly associated with death on a ventilator and type II pneumocyte hyperplasia. A second large cluster included dynein (DNAH9 and DNAH12) and mucin (MUC5B and MUC16) genes, which are exclusive to the respiratory epithelium and goblet cells of bronchial structures. This indicates heterogeneous bronchiole sampling due to the harvesting location in the lung. A small cluster included acute-phase reactant genes (SAA1, SAA2, and SAA2-SAA4). The final two small clusters were technical and gender related. To summarize, in a collection of normal lung samples, we found that tissue heterogeneity caused by harvesting location (medial or lateral lung) and late therapeutic intervention (mechanical ventilation) were major contributors to expression variation. These unexpected sources of variation were the result of altered cell ratios in the tissue samples, an underappreciated source of expression variation. PMID:27588449

  1. Lung surgery

    MedlinePlus

    ... balloon-like tissues (blebs) that cause lung collapse ( pneumothorax ) Wedge resection, to remove part of a lobe ... Treat injuries that cause lung tissue to collapse ( pneumothorax or hemothorax ) Treat permanently collapsed lung tissue ( atelectasis ) ...

  2. High concentrations of chromium in lung tissue from lung cancer patients

    SciTech Connect

    Anttila, S.; Kokkonen, P.; Paeaekkoe PRai; Rainio, P.; Kalliomaeki, P.L.P.; Pallon, J.; Malmqvist, K.; Pakarinen, P.; Naentoe, V.Su.; Sutinen, S.

    1989-02-01

    The pulmonary chromium content was determined by plasma atomic emission spectrometer (DCP-AES) from 53 lung cancer and 43 control patients, and compared with smoking habits, severity of emphysema and occupational history. The chromium content from the lung cancer patients was higher than that from the smoking (P less than 0.025) or nonsmoking control patients (6.4 +/- 4.3, 4.0 +/- 4.0, and 2.2 +/- 0.6 microgram/g dry weight, respectively). A positive correlation between the pulmonary chromium and smoking time (P less than 0.025) and the severity of emphysema (P less than 0.001) was found in the control but not in the cancer patients. The difference in the pulmonary chromium content was greatest between those lung cancer and control patients who were light smokers or had mild emphysema. This group of lung cancer patients included subjects with occupational exposure to chromium. The possibility of occupational cancer should be considered especially with light smokers. The grade of emphysema and metals such as chromium accumulating from tobacco could serve as objective indicators of smoking.

  3. Synchrotron-based dynamic computed tomography of tissue motion for regional lung function measurement

    PubMed Central

    Dubsky, Stephen; Hooper, Stuart B.; Siu, Karen K. W.; Fouras, Andreas

    2012-01-01

    During breathing, lung inflation is a dynamic process involving a balance of mechanical factors, including trans-pulmonary pressure gradients, tissue compliance and airway resistance. Current techniques lack the capacity for dynamic measurement of ventilation in vivo at sufficient spatial and temporal resolution to allow the spatio-temporal patterns of ventilation to be precisely defined. As a result, little is known of the regional dynamics of lung inflation, in either health or disease. Using fast synchrotron-based imaging (up to 60 frames s−1), we have combined dynamic computed tomography (CT) with cross-correlation velocimetry to measure regional time constants and expansion within the mammalian lung in vivo. Additionally, our new technique provides estimation of the airflow distribution throughout the bronchial tree during the ventilation cycle. Measurements of lung expansion and airflow in mice and rabbit pups are shown to agree with independent measures. The ability to measure lung function at a regional level will provide invaluable information for studies into normal and pathological lung dynamics, and may provide new pathways for diagnosis of regional lung diseases. Although proof-of-concept data were acquired on a synchrotron, the methodology developed potentially lends itself to clinical CT scanning and therefore offers translational research opportunities. PMID:22491972

  4. Airway mechanics and lung tissue viscoelasticity: effects of altered blood hematocrit in the pulmonary circulation.

    PubMed

    Peták, Ferenc; Fodor, Gergely H; Babik, Barna; Habre, Walid

    2016-07-01

    The contribution of the hematocrit (Hct) of the blood in the pulmonary vasculature to the overall lung mechanics has not been characterized. We therefore set out to establish how changes of the Hct level in the pulmonary circulation affect the airway and lung tissue viscoelastic properties. The Hct level of the blood in an isolated perfused rat lung model was randomly altered. Intermediate (26.5%), followed by low (6.6%) or normal (43.7%), Hct was set in two consecutive sequences. The pulmonary capillary pressure was maintained constant throughout the experiment, and the pulmonary hemodynamic parameters were monitored continuously. The airway resistance (Raw), the viscous (G) and elastic (H) parameters, and the hysteresivity (η = G/H) of the lung tissues were obtained from measurements of forced oscillatory input impedance data. Raw was not affected by the alterations of the Hct levels. As concerns the lung tissues, the decrease of Hct to intermediate or low levels resulted in close to proportional decreases in the viscoelastic parameters G [16.5 ± 7.7% (SD), 12.1 ± 9.5%, P < 0.005] and H (13.2 ± 8.6%, 10.8 ± 4.7%, P < 0.001). No significant changes in η were detected in a wide range of Hct, which indicates that coupled processes cause alterations in the resistive and elastic properties of the lungs following Hct changes in the pulmonary circulation. The diminishment of the viscous and elastic parameters of the pulmonary parenchyma following a reduction of blood Hct demonstrates the significant contribution of the red blood cells to the overall lung viscoelasticity. PMID:27283919

  5. TISSUE REMODELING IN THE HUMAN LUNG IN RELATION TO PARTICLE CONCENTRATION AND METAL CONTENT

    EPA Science Inventory

    TISSUE REMODELING IN THE HUMAN LUNG IN RELATION TO PARTICLE CONCENTRATION AND METAL CONTENT. J Gallagher1, J Inmon1, S Schlaegle2, A Levine2, T Rogers3, J Scott1, F Green4, M Schenker5, K Pinkerton5 1NHEERL, US-EPA, RTP, NC, USA; 2RJ Lee Group Inc, Monroeville, Pa, USA; ...

  6. Detection and Localization of Pre-Cancerous Lesions and Early Lung Cancer Using Tissue Autofluorescence.

    NASA Astrophysics Data System (ADS)

    Hung, Jaclyn Yip-Chan

    In this work, two different yet related hypotheses were tested by experimental means as follows: (i) pre-cancerous and non-invasive (early) lung cancer can be detected and localized using the fluorescence properties of tumour localizing drugs at non-photosensitizing doses to skin tissue; (ii) significant differences exist in laser-induced autofluorescence between normal, pre-cancerous and cancerous tissues such that these differences alone can be exploited to detect and delineate early lung cancer without using exogenous drug(s). Exogenous fluorescent tumour markers such as hematoporphyrin derivatives (e.g. Photofrin) have been used to enhance to detection of occult lung lesions. Photofrin is preferentially retained in tumor tissues compared to the surrounding normal tissues; it fluoresces at 630 nm and 690 nm when excited at -405 nm. Based on this principle several imaging and non-imaging devices have been developed. However, wider clinical applications were limited due to the skin photosensitivity property of Photofrin. We have postulated that this could be solved by employing a much lower dose of Photofrin (0.25 mg/kg) which was believed to be less photosensitizing to human patients. This postulate was experimentally tested by ratio fluorometry and early lung cancers were detected with no false negative results and no apparent skin photosensitivity. An important finding in this study was that the mechanism for detection of early cancer was mainly due to the differences in the green autofluorescence between normal and malignant tissues, rather than fluorescence of tumour localizing drug. This discovery led to the second postulate of this thesis that tissue autofluorescence alone can be exploited for the detection of early lung cancer. The results indicated that algorithm(s) could be developed to clearly delineate early lesions from the normal tissues. Several algorithms were then tested using a non-imaging ratio fluorometer device and a prototype imaging

  7. Heme-related gene expression signatures of meat intakes in lung cancer tissues.

    PubMed

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M; Pesatori, Angela C; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E; Landi, Maria Teresa

    2014-07-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤ 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID:23681825

  8. Heme-related gene expression signatures of meat intakes in lung cancer tissues

    PubMed Central

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M.; Pesatori, Angela C.; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E.; Landi, Maria Teresa

    2014-01-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the Environment and Genetics in Lung cancer Etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a False Discovery Rate (FDR) ≤0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR=0.12). Sixty-three (~28%) of the 232 identified genes (12 expected by chance, p-value<0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, UCP3) and oxidative stress (e.g., TPO, SGK2, MTHFR) that may be indirectly related to heme-toxicity. The study’s results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID:23681825

  9. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.

    PubMed

    Soroosh, Pejman; Doherty, Taylor A; Duan, Wei; Mehta, Amit Kumar; Choi, Heonsik; Adams, Yan Fei; Mikulski, Zbigniew; Khorram, Naseem; Rosenthal, Peter; Broide, David H; Croft, Michael

    2013-04-01

    Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3(+) iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3(+) Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma. PMID:23547101

  10. Distribution of particulate matter and tissue remodeling in the human lung.

    PubMed Central

    Pinkerton, K E; Green, F H; Saiki, C; Vallyathan, V; Plopper, C G; Gopal, V; Hung, D; Bahne, E B; Lin, S S; Ménache, M G; Schenker, M B

    2000-01-01

    We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter. PMID:11102298

  11. Global Gene Expression Profiling in Lung Tissues of Rat Exposed to Lunar Dust Particles

    NASA Technical Reports Server (NTRS)

    Yeshitla, Samrawit A.; Lam, Chiu-Wing; Kidane, Yared H.; Feiveson, Alan H.; Ploutz-Snyder, Robert; Wu, Honglu; James, John T.; Meyers, Valerie E.; Zhang, Ye

    2014-01-01

    The Moon's surface is covered by a layer of fine, potential reactive dust. Lunar dust contain about 1-2% respirable very fine dust (less than 3 micrometers). The habitable area of any lunar landing vehicle and outpost would inevitably be contaminated with lunar dust that could pose a health risk. The purpose of the study is to analyze the dynamics of global gene expression changes in lung tissues of rats exposed to lunar dust particles. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.8, 21, and 61 mg/m3 of lunar dust. Animals were euthanized at 1 day and 13 weeks after the last inhalation exposure. After being lavaged, lung tissue from each animal was collected and total RNA was isolated. Four samples of each dose group were analyzed using Agilent Rat GE v3 microarray to profile global gene expression of 44K transcripts. After background subtraction, normalization, and log transformation, t tests were used to compare the mean expression levels of each exposed group to the control group. Correction for multiple testing was made using the method of Benjamini, Krieger, and Yekuteli (1) to control the false discovery rate. Genes with significant changes of at least 1.75 fold were identified as genes of interest. Both low and high doses of lunar dust caused dramatic, dose-dependent global gene expression changes in the lung tissues. However, the responses of lung tissue to low dose lunar dust are distinguished from those of high doses, especially those associated with 61mg/m3 dust exposure. The data were further integrated into the Ingenuity system to analyze the gene ontology (GO), pathway distribution and putative upstream regulators and gene targets. Multiple pathways, functions, and upstream regulators have been identified in response to lunar dust induced damage in the lung tissue.

  12. Rapid detection of Mannheimia haemolytica in lung tissues of sheep and from bacterial culture

    PubMed Central

    Kumar, Jyoti; Dixit, Shivendra Kumar; Kumar, Rajiv

    2015-01-01

    Aim: This study was aimed to detect Mannheimia haemolytica in lung tissues of sheep and from a bacterial culture. Introduction: M. haemolytica is one of the most important and well-established etiological agents of pneumonia in sheep and other ruminants throughout the world. Accurate diagnosis of M. haemolytica primarily relies on bacteriological examination, biochemical characteristics and, biotyping and serotyping of the isolates. In an effort to facilitate rapid M. haemolytica detection, polymerase chain reaction assay targeting Pasteurella haemolytica serotype-1 specific antigens (PHSSA), Rpt2 and 12S ribosomal RNA (rRNA) genes were used to detect M. haemolytica directly from lung tissues and from bacterial culture. Materials and Methods: A total of 12 archived lung tissues from sheep that died of pneumonia on an organized farm were used. A multiplex polymerase chain reaction (mPCR) based on two-amplicons targeted PHSSA and Rpt2 genes of M. haemolytica were used for identification of M. haemolytica isolates in culture from the lung samples. All the 12 lung tissue samples were tested for the presence M. haemolytica by PHSSA and Rpt2 genes based PCR and its confirmation by sequencing of the amplicons. Results: All the 12 lung tissue samples tested for the presence of PHSSA and Rpt2 genes of M. haemolytica by mPCR were found to be positive. Amplification of 12S rRNA gene fragment as internal amplification control was obtained with each mPCR reaction performed from DNA extracted directly from lung tissue samples. All the M. haemolytica were also positive for mPCR. No amplified DNA bands were observed for negative control reactions. All the three nucleotide sequences were deposited in NCBI GenBank (Accession No. KJ534629, KJ534630 and KJ534631). Sequencing of the amplified products revealed the identity of 99-100%, with published sequence of PHSSA and Rpt2 genes of M. haemolytica available in the NCBI database. Sheep specific mitochondrial 12S rRNA gene sequence

  13. Modeling the effect of refraction on OCT imaging of lung tissue: a ray-tracing approach

    NASA Astrophysics Data System (ADS)

    Golabchi, Fatemeh N.; Golabchi, Ali; Brooks, Dana H.; Gouldstone, Andrew; DiMarzio, Charles A.

    2012-03-01

    Determining the structure of lung tissue is difficult in ex-vivo samples. Optical coherence tomography (OCT) can image alveoli but ignores optical effects that distort the images. For example, light refracts and changes speed at the alveolar air-tissue surface. We employ ray-tracing to model OCT imaging with directional and speed changes included, using spherical shapes in 2D. Results show apparent thickening of inter-aveolar walls and distortion of shape and depth. Our approach suggests a correction algorithm by combining the model with image analysis. Distortion correction will allow inference of tissue mechanical properties and deeper imaging.

  14. Tracking lung tissue motion and expansion/compression with inverse consistent image registration and spirometry

    SciTech Connect

    Christensen, Gary E.; Song, Joo Hyun; Lu, Wei; Naqa, Issam El; Low, Daniel A.

    2007-06-15

    Breathing motion is one of the major limiting factors for reducing dose and irradiation of normal tissue for conventional conformal radiotherapy. This paper describes a relationship between tracking lung motion using spirometry data and image registration of consecutive CT image volumes collected from a multislice CT scanner over multiple breathing periods. Temporal CT sequences from 5 individuals were analyzed in this study. The couch was moved from 11 to 14 different positions to image the entire lung. At each couch position, 15 image volumes were collected over approximately 3 breathing periods. It is assumed that the expansion and contraction of lung tissue can be modeled as an elastic material. Furthermore, it is assumed that the deformation of the lung is small over one-fifth of a breathing period and therefore the motion of the lung can be adequately modeled using a small deformation linear elastic model. The small deformation inverse consistent linear elastic image registration algorithm is therefore well suited for this problem and was used to register consecutive image scans. The pointwise expansion and compression of lung tissue was measured by computing the Jacobian of the transformations used to register the images. The logarithm of the Jacobian was computed so that expansion and compression of the lung were scaled equally. The log-Jacobian was computed at each voxel in the volume to produce a map of the local expansion and compression of the lung during the breathing period. These log-Jacobian images demonstrate that the lung does not expand uniformly during the breathing period, but rather expands and contracts locally at different rates during inhalation and exhalation. The log-Jacobian numbers were averaged over a cross section of the lung to produce an estimate of the average expansion or compression from one time point to the next and compared to the air flow rate measured by spirometry. In four out of five individuals, the average log

  15. Surface fluorescence studies of tissue mitochondrial redox state in isolated perfused rat lungs.

    PubMed

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

    2013-04-01

    We designed a fiber-optic-based optoelectronic fluorometer to measure emitted fluorescence from the auto-fluorescent electron carriers NADH and FAD of the mitochondrial electron transport chain (ETC). The ratio of NADH to FAD is called the redox ratio (RR = NADH/FAD) and is an indicator of the oxidoreductive state of tissue. We evaluated the fluorometer by measuring the fluorescence intensities of NADH and FAD at the surface of isolated, perfused rat lungs. Alterations of lung mitochondrial metabolic state were achieved by the addition of rotenone (complex I inhibitor), potassium cyanide (KCN, complex IV inhibitor) and/or pentachlorophenol (PCP, uncoupler) into the perfusate recirculating through the lung. Rotenone- or KCN-containing perfusate increased RR by 21 and 30%, respectively. In contrast, PCP-containing perfusate decreased RR by 27%. These changes are consistent with the established effects of rotenone, KCN, and PCP on the redox status of the ETC. Addition of blood to perfusate quenched NADH and FAD signal, but had no effect on RR. This study demonstrates the capacity of fluorometry to detect a change in mitochondrial redox state in isolated perfused lungs, and suggests the potential of fluorometry for use in in vivo experiments to extract a sensitive measure of lung tissue health in real-time. PMID:23238793

  16. Optical studies of tissue mitochondrial redox in isolated perfused rat lungs

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

    Through the monitoring of the auto-fluorescent mitochondrial metabolic coenzymes, NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavoprotein Adenine Dinucleotide), the redox state of metabolism can be probed in real time in many intact organs, but its use has not been fully developed in lungs. The ratio of these fluorophores, (NADH/FAD), referred to as the mitochondrial redox ratio (RR), can be used as a quantitative metabolic marker of tissue. We have designed a fluorometer that can be used to monitor lung surface NADH and FAD fluorescence in isolated perfused lungs. Surface fluorescence NADH and FAD signals were acquired in the absence (control) and presence of pentachlorophenol (PCP), rotenone, and potassium cyanide (KCN). Rotenone, an inhibitor of complex I, increased RR by 18%, predominantly due to an increase in NADH signal. KCN, an inhibitor of complex IV reduced the chain and resulted in an increase of 33% in RR, as a result of 23% increase in NADH and 8% in FAD . PCP, an uncoupler which oxidizes the respiratory chain, decreased RR by 18% as a result of 14% decrease in NADH signal and 4% increase in FAD signal. These results demonstrate the ability of surface fluorometry to detect changes in lung tissue mitochondrial redox state in isolated perfused lungs.

  17. Structural and Biomechanical Properties of the Exchange Tissue of the Avian Lung.

    PubMed

    Maina, John N

    2015-10-01

    The blood capillaries (BC) and the air capillaries (ACs) are the terminal gas exchange units of the avian lung. The minuscule structures are astonishingly strong. It is only recently that the morphologies and the biomechanical properties of the BCs and the ACs were investigated. Regarding size and shape, the BCs and the ACs differ remarkably. While they were previously claimed to be tubular (cylindrical) in shape, the ACs are rather rotund structures which interconnect across short, narrow passageways. Atypical of those in other tissues, the BCs in the exchange tissue of the avian lung comprise of distinct segments which are about as long as they are wide and which are coupled in three-dimensions. The thin blood-gas barrier (BGB) which separates the ACs from the BCs is peculiarly strong. The causes of the strengths of the ACs and the BCs in general and the BGB in particular are varied and controversial. Here, the recent morphological and physiological findings on the structure, biomechanical properties, and the strengths of the respiratory units of the avian lung and the BGB have been critically examined. Also, in light of the new morphological findings of the ACs and the BCs, the functional model which is currently in use to assess the gas exchange efficiency of the avian lung should be revised and the inappropriateness of the terms 'blood capillary' and 'air capillary' for the gas exchange units of the avian lung is pointed out. PMID:25857723

  18. The correlation of tissue motion within the lung: implications on fiducial based treatments

    SciTech Connect

    Smith, Ryan L.; Yang Deshan; Lee, Andrew; Mayse, Martin L.; Low, Dan A.; Parikh, Parag J.

    2011-11-15

    In radiation therapy many motion management and alignment techniques rely on the accuracy of an internal fiducial acting as a surrogate for target motion within the lung. Although fiducials are routinely used as surrogates for tumor motion, the extent to which varying spatial locations in the lung move similarly to other locations has yet to be quantitatively analyzed. In an attempt to analyze the motion correlation throughout the lung, ten primary lung cancer patients underwent IRB-approved 4DCT scans in the supine position. Deformable registration produced motion vectors for each voxel between exhalation and inhalation. Modeling was performed for each vector and all surrounding vectors within the lung in order to determine the mean 3D Euclidean distance necessary for an implanted fiducial to correlate with surrounding tissue motion to within 3 mm (left lower: 1.7 cm, left upper: 2.1 cm, right lower 1.6 cm, and right upper 2.9 cm). No general implantation rule of where to position a fiducial with respect to the tumor was found as the motion is highly patient and lobe specific. Correlation maps are presented showcasing spatial anisotropy of the motion of tissue surrounding the tumor.

  19. Airway and tissue impedances of canine lungs after step volume changes.

    PubMed

    Bates, J H; Donoso, F A; Peslin, R

    1993-10-01

    We investigated the changes in pulmonary mechanics in five anesthetized paralyzed tracheostomized open-chest dogs after step changes in lung volume. We applied small-amplitude (10-ml) volume oscillations at 6 Hz at the tracheal opening for 50-s periods, during which we applied a step volume change of 250, 500, or 750 ml to the lungs. Alveolar capsule measurements of alveolar pressure allowed us to calculate cycle-by-cycle values for airway resistance (Raw) and reactance (Xaw) and lung tissue resistance (Rti) and reactance (Xti). Before the step changes in lung volume, when transpulmonary pressure (Ptp) had a mean value of 0.65 kPa, Raw was markedly greater than Rti. The situation was reversed after the step changes, however, when Raw decreased and Rti increased. Both Raw and Xaw showed negative dependences on Ptp and hence on airway caliber, as expected, and also decreased transiently after the step volume changes, almost certainly due to a vagally mediated bronchodilation reflex. Both Rti and Xti showed clear linear dependences on Ptp and were themselves tightly coupled. Furthermore, our estimate of bulk modulus for lung tissue at 6 Hz is comparable to its previously reported values at much lower oscillation frequencies. PMID:8282590

  20. Data on CUX1 isoforms in idiopathic pulmonary fibrosis lung and systemic sclerosis skin tissue sections.

    PubMed

    Ikeda, Tetsurou; Fragiadaki, Maria; Shi-Wen, Xu; Ponticos, Markella; Khan, Korsa; Denton, Christopher; Garcia, Patricia; Bou-Gharios, George; Yamakawa, Akio; Morimoto, Chikao; Abraham, David

    2016-09-01

    This data article contains complementary figures related to the research article entitled, "Transforming growth factor-β-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts" (Ikeda et al. (2016) [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022), which presents that TGF-β increased CUX1 binding in the proximal promoter and enhancer of the COL1A2 and regulated COL1. Further, in the scleroderma (SSc) lung and diffuse alveolar damage lung sections, CUX1 localized within the α- smooth muscle actin (α-SMA) positive cells (Fragiadaki et al., 2011) [1], "High doses of TGF-beta potently suppress type I collagen via the transcription factor CUX1" (Ikeda et al., 2016) [2]. Here we show that CUX1 isoforms are localized within α-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary fibrosis (IPF) lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, CUX1 and α-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, CUX1 localized within the α-smooth muscle actin (α-SMA) positive cells. PMID:27583344

  1. The correlation of tissue motion within the lung: implications on fiducial based treatments

    PubMed Central

    Smith, Ryan L.; Yang, Deshan; Lee, Andrew; Mayse, Martin L.; Low, Dan A.; Parikh, Parag J.

    2011-01-01

    In radiation therapy many motion management and alignment techniques rely on the accuracy of an internal fiducial acting as a surrogate for target motion within the lung. Although fiducials are routinely used as surrogates for tumor motion, the extent to which varying spatial locations in the lung move similarly to other locations has yet to be quantitatively analyzed. In an attempt to analyze the motion correlation throughout the lung, ten primary lung cancer patients underwent IRB-approved 4DCT scans in the supine position. Deformable registration produced motion vectors for each voxel between exhalation and inhalation. Modeling was performed for each vector and all surrounding vectors within the lung in order to determine the mean 3D Euclidean distance necessary for an implanted fiducial to correlate with surrounding tissue motion to within 3 mm (left lower: 1.7 cm, left upper: 2.1 cm, right lower 1.6 cm, and right upper 2.9 cm). No general implantation rule of where to position a fiducial with respect to the tumor was found as the motion is highly patient and lobe specific. Correlation maps are presented showcasing spatial anisotropy of the motion of tissue surrounding the tumor. PMID:22047363

  2. New techniques for imaging and analyzing lung tissue.

    PubMed Central

    Roggli, V L; Ingram, P; Linton, R W; Gutknecht, W F; Mastin, P; Shelburne, J D

    1984-01-01

    The recent technological revolution in the field of imaging techniques has provided pathologists and toxicologists with an expanding repertoire of analytical techniques for studying the interaction between the lung and the various exogenous materials to which it is exposed. Analytical problems requiring elemental sensitivity or specificity beyond the range of that offered by conventional scanning electron microscopy and energy dispersive X-ray analysis are particularly appropriate for the application of these newer techniques. Electron energy loss spectrometry, Auger electron spectroscopy, secondary ion mass spectrometry, and laser microprobe mass analysis each offer unique advantages in this regard, but also possess their own limitations and disadvantages. Diffraction techniques provide crystalline structural information available through no other means. Bulk chemical techniques provide useful cross-checks on the data obtained by microanalytical approaches. It is the purpose of this review to summarize the methodology of these techniques, acknowledge situations in which they have been used in addressing problems in pulmonary toxicology, and comment on the relative advantages and disadvantages of each approach. It is necessary for an investigator to weigh each of these factors when deciding which technique is best suited for any given analytical problem; often it is useful to employ a combination of two or more of the techniques discussed. It is anticipated that there will be increasing utilization of these technologies for problems in pulmonary toxicology in the decades to come. Images FIGURE 3. A FIGURE 3. B FIGURE 3. C FIGURE 3. D FIGURE 4. FIGURE 5. FIGURE 7. A FIGURE 7. B FIGURE 8. A FIGURE 8. B FIGURE 8. C FIGURE 9. A FIGURE 9. B FIGURE 10. PMID:6090115

  3. Mineral fibres, fibrosis, and asbestos bodies in lung tissue from deceased asbestos cement workers.

    PubMed Central

    Albin, M; Johansson, L; Pooley, F D; Jakobsson, K; Attewell, R; Mitha, R

    1990-01-01

    Lung tissue from 76 deceased asbestos cement workers (seven with mesothelioma) exposed to chrysotile asbestos and small amounts of amphiboles, has been studied by transmission electron microscopy, together with lung tissue from 96 controls. The exposed workers with mesothelioma had a significantly higher total content of asbestos fibre in the lungs than those without mesothelioma, who in turn, had higher concentrations than the controls (medians 189, 50, and 29 x 10(6) fibres/g (f/g]. Chrysotile was the major type of fibre. The differences were most pronounced for the amphibole fibres (62, 4.7, and 0.15 f/g), especially crocidolite (54, 1.8 and less than 0.001 f/g), but were evident also for tremolite (2.9, less than 0.001, and less than 0.001 f/g) and anthophyllite (1.7, less than 0.001, and less than 0.001 f/g). For amosite, there was no statistically significant difference between lungs from workers with and without mesothelioma; the lungs of workers had, however, higher concentrations than the controls. Strong correlations were found between duration of exposure and content of amphibole fibres in the lungs. Asbestos bodies, counted by light microscopy, were significantly correlated with the amphibole but not with the chrysotile contents. Fibrosis was correlated with the tremolite but not the chrysotile content in lungs from both exposed workers and controls. Overall, similar results were obtained using fibre counts and estimates of mass. PMID:2173948

  4. Tissue spray ionization mass spectrometry for rapid recognition of human lung squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Wei, Yiping; Chen, Liru; Zhou, Wei; Chingin, Konstantin; Ouyang, Yongzhong; Zhu, Tenggao; Wen, Hua; Ding, Jianhua; Xu, Jianjun; Chen, Huanwen

    2015-05-01

    Tissue spray ionization mass spectrometry (TSI-MS) directly on small tissue samples has been shown to provide highly specific molecular information. In this study, we apply this method to the analysis of 38 pairs of human lung squamous cell carcinoma tissue (cancer) and adjacent normal lung tissue (normal). The main components of pulmonary surfactants, dipalmitoyl phosphatidylcholine (DPPC, m/z 757.47), phosphatidylcholine (POPC, m/z 782.52), oleoyl phosphatidylcholine (DOPC, m/z 808.49), and arachidonic acid stearoyl phosphatidylcholine (SAPC, m/z 832.43), were identified using high-resolution tandem mass spectrometry. Monte Carlo sampling partial least squares linear discriminant analysis (PLS-LDA) was used to distinguish full-mass-range mass spectra of cancer samples from the mass spectra of normal tissues. With 5 principal components and 30 - 40 Monte Carlo samplings, the accuracy of cancer identification in matched tissue samples reached 94.42%. Classification of a tissue sample required less than 1 min, which is much faster than the analysis of frozen sections. The rapid, in situ diagnosis with minimal sample consumption provided by TSI-MS is advantageous for surgeons. TSI-MS allows them to make more informed decisions during surgery.

  5. Tissue spray ionization mass spectrometry for rapid recognition of human lung squamous cell carcinoma

    PubMed Central

    Wei, Yiping; Chen, Liru; Zhou, Wei; Chingin, Konstantin; Ouyang, Yongzhong; Zhu, Tenggao; Wen, Hua; Ding, Jianhua; Xu, Jianjun; Chen, Huanwen

    2015-01-01

    Tissue spray ionization mass spectrometry (TSI-MS) directly on small tissue samples has been shown to provide highly specific molecular information. In this study, we apply this method to the analysis of 38 pairs of human lung squamous cell carcinoma tissue (cancer) and adjacent normal lung tissue (normal). The main components of pulmonary surfactants, dipalmitoyl phosphatidylcholine (DPPC, m/z 757.47), phosphatidylcholine (POPC, m/z 782.52), oleoyl phosphatidylcholine (DOPC, m/z 808.49), and arachidonic acid stearoyl phosphatidylcholine (SAPC, m/z 832.43), were identified using high-resolution tandem mass spectrometry. Monte Carlo sampling partial least squares linear discriminant analysis (PLS-LDA) was used to distinguish full-mass-range mass spectra of cancer samples from the mass spectra of normal tissues. With 5 principal components and 30 – 40 Monte Carlo samplings, the accuracy of cancer identification in matched tissue samples reached 94.42%. Classification of a tissue sample required less than 1 min, which is much faster than the analysis of frozen sections. The rapid, in situ diagnosis with minimal sample consumption provided by TSI-MS is advantageous for surgeons. TSI-MS allows them to make more informed decisions during surgery. PMID:25961911

  6. Effects of superimposed tissue weight on regional compliance of injured lungs.

    PubMed

    Pellegrini, Mariangela; Derosa, Savino; Tannoia, Angela; Rylander, Christian; Fiore, Tommaso; Larsson, Anders; Hedenstierna, Göran; Perchiazzi, Gaetano

    2016-07-01

    Computed tomography (CT), together with image analysis technologies, enable the construction of regional volume (VREG) and local transpulmonary pressure (PTP,REG) maps of the lung. Purpose of this study is to assess the distribution of VREG vs PTP,REG along the gravitational axis in healthy (HL) and experimental acute lung injury conditions (eALI) at various positive end-expiratory pressures (PEEPs) and inflation volumes. Mechanically ventilated pigs underwent inspiratory hold maneuvers at increasing volumes simultaneously with lung CT scans. eALI was induced via the iv administration of oleic acid. We computed voxel-level VREG vs PTP,REG curves into eleven isogravitational planes by applying polynomial regressions. Via F-test, we determined that VREG vs PTP,REG curves derived from different anatomical planes (p-values<1.4E-3), exposed to different PEEPs (p-values<1.5E-5) or subtending different lung status (p-values<3E-3) were statistically different (except for two cases of adjacent planes). Lung parenchyma exhibits different elastic behaviors based on its position and the density of superimposed tissue which can increase during lung injury. PMID:26976688

  7. Biphasic positive airway pressure minimizes biological impact on lung tissue in mild acute lung injury independent of etiology

    PubMed Central

    2013-01-01

    Introduction Biphasic positive airway pressure (BIVENT) is a partial support mode that employs pressure-controlled, time-cycled ventilation set at two levels of continuous positive airway pressure with unrestricted spontaneous breathing. BIVENT can modulate inspiratory effort by modifying the frequency of controlled breaths. Nevertheless, the optimal amount of inspiratory effort to improve respiratory function while minimizing ventilator-associated lung injury during partial ventilatory assistance has not been determined. Furthermore, it is unclear whether the effects of partial ventilatory support depend on acute lung injury (ALI) etiology. This study aimed to investigate the impact of spontaneous and time-cycled control breaths during BIVENT on the lung and diaphragm in experimental pulmonary (p) and extrapulmonary (exp) ALI. Methods This was a prospective, randomized, controlled experimental study of 60 adult male Wistar rats. Mild ALI was induced by Escherichia coli lipopolysaccharide either intratracheally (ALIp) or intraperitoneally (ALIexp). After 24 hours, animals were anesthetized and further randomized as follows: (1) pressure-controlled ventilation (PCV) with tidal volume (Vt) = 6 ml/kg, respiratory rate = 100 breaths/min, PEEP = 5 cmH2O, and inspiratory-to-expiratory ratio (I:E) = 1:2; or (2) BIVENT with three spontaneous and time-cycled control breath modes (100, 75, and 50 breaths/min). BIVENT was set with two levels of CPAP (Phigh = 10 cmH2O and Plow = 5 cmH2O). Inspiratory time was kept constant (Thigh = 0.3 s). Results BIVENT was associated with reduced markers of inflammation, apoptosis, fibrogenesis, and epithelial and endothelial cell damage in lung tissue in both ALI models when compared to PCV. The inspiratory effort during spontaneous breaths increased during BIVENT-50 in both ALI models. In ALIp, alveolar collapse was higher in BIVENT-100 than PCV, but decreased during BIVENT-50, and diaphragmatic injury was lower during BIVENT-50 compared

  8. Routes of conjugation in normal and cancerous tissue from human lung

    NASA Astrophysics Data System (ADS)

    Cohen, Gerald M.; Gibby, Elizabeth M.; Mehta, Rekha

    1981-06-01

    The selective toxicity of drugs leading to major advances in antibacterial chemotherapy has often resulted from the identification and exploitation of major biochemical differences between bacterial and mammalian species1. Similar progress has not been made in cancer chemotherapy, partly due to a lack of suitable biochemical differences between normal and cancerous tissue other than in DNA synthesis, but also because of many other problems such as those of metastases and resistance, and the presence in tumours of cells at different states of the cell cycle. Here we report a major biochemical difference in the routes of conjugation between normal lung and tumour tissue from patients with lung cancer. Conjugation with glucuronic acid and sulphate constitute two of the most important pathways of metabolism of drugs, other foreign compounds and hormonal steroids2,3. Using 1-naphthol as a model phenolic substrate, normal peripheral lung tissue formed almost exclusively the sulphate ester conjugate, 1-naphthyl sulphate, whereas tumour tissue from squamous carcinomas from the same patients formed predominantly the glucuronic acid conjugate, 1-naphthyl glucuronide. Such major biochemical differences may be exploitable in the design of selectively toxic cancer chemotherapeutic agents.

  9. [Immunohistochemical Analysis of Krebs von den Lungen-6 (KL-6) Expression in Lung Tissue in Primary Lung Cancer Patients with High Serum KL-6 Levels].

    PubMed

    Yatsuyanagi, Eiji; Sato, Kazuhiro; Sato, Keisuke

    2015-09-01

    We investigated sialylated carbohydrate antigen( Krebs von den Lungen-6:KL-6) expression in lung tissue and correlation between the expression and serum KL-6 level in the patients with primary lung cancer. Thirty-four primary lung cancer patients with high serum KL-6 levels( >500 U/ml) were evaluated. A coexistence of interstitial pneumonia (IP) was histopathologically evaluated and an immunohistochemical staining using a mouse anti-human KL-6 antibody (mKL-6) was performed. A multiple regression analysis was also caluculated using a serum KL-6 level as a target variable and the histopathological and immunohistochemical factors (KL-6 expression in cancer tissue and IP tissue, coexistence of IP, tumor size, pathological staging) as descriptive variables. Twenty-two patients (64.7%) were histopathologically concomitant with IP. Cancer tissues were positively stained by mKL-6 in 32 patients (94.1%). Among them, 20 patients were concomitant with IP and all of their cancer tissues were more strongly stained by mKL-6 than IP tissues. Although considerable high rate of lung cancer patients might express the KL-6 in the cancer tissue, we could not reveal the relationship between the expression and serum KL-6 level by a multiple regression analysis. For revealing the mechanism of elevating serum KL-6 level in the patients with lung cancer, more detailed and powerful study is thought to be needed. PMID:26329623

  10. Molecular and histological changes in cerebral cortex and lung tissues under the effect of tramadol treatment.

    PubMed

    Awadalla, Eatemad A; Salah-Eldin, Alaa-Eldin

    2016-08-01

    Tramadol abuse is one of the most frequent health problems in Egypt and worldwide. In most cases, tramadol abused by men face a problem with premature ejaculation. Tramadol like other opioids induces a decrease in plasma antioxidant levels, which may reflect a failure of the antioxidant defense mechanism against oxidative damage. The present work aimed to study the possible deleterious effects of oral administration of tramadol on brain and lung tissues in rats. Twenty adult male albino rats were divided into two groups; a control administered with normal saline and tramadol-treated (40mg/kg b.w.) group for 20 successive days. At the end of experimental period, blood was collected and specimens from brains and lungs were taken for histopathological and molecular studies. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities were measured in serum of control and tramadol-treated groups. Brain and lung specimens were histopathological evaluated using light microscopy. The expression levels of apoptotic related genes; Bcl-2, Bax and Caspase-3 were study in brain and lung tissues using RT-PCR analysis. We recorded a significant increase MDA level, while antioxidant enzymes; GSH, SOD and CAT were significantly decreased after tramadol-treatment. The obtained results revealed that tramadol induced a remarkable histomorphological changes in rats' brains (cerebral cortex and hippocampus) and severe histopathological changes in rats' lung when compared to that of control. On molecular level, the expression of the pro-apoptotic Bax and Caspase-3 showed a significant increase whereas the anti-apoptotic Bcl-2 decreased markedly indicating that tramadol is harmful at cellular level and can induce apoptotic changes in brain tissues. Our data confirmed the risk of increased oxidative stress, neuronal and pulmonary damage due to tramadol abuse. Although tramadol is reported to be effective in pain management, its toxicity should

  11. Toward a comprehensive interpretation of intravital microscopy images in studies of lung tissue dynamics

    NASA Astrophysics Data System (ADS)

    Gaertner, Maria; Schirrmann, Kerstin; Schnabel, Christian; Meissner, Sven; Kertzscher, Ulrich; Kirsten, Lars; Koch, Edmund

    2015-06-01

    Intravital microscopy (IVM) is a well-established imaging technique for real-time monitoring of microscale lung tissue dynamics. Although accepted as a gold standard in respiratory research, its characteristic image features are scarcely understood, especially when trying to determine the actual position of alveolar walls. To allow correct interpretation of these images with respect to the true geometry of the lung parenchyma, we analyzed IVM data of alveoli in a mouse model in comparison with simultaneously acquired optical coherence tomography images. Several IVM characteristics, such as double ring structures or disappearing alveoli in regions of liquid filling, could be identified and related to the position of alveoli relative to each other. Utilizing a ray tracing approach based on an idealized geometry of the mouse lung parenchyma, two major reflection processes could be attributed to the IVM image formation: partial reflection and total internal reflection between adjacent alveoli. Considering the origin of the reflexes, a model was developed to determine the true position of alveolar walls within IVM images. These results allow thorough understanding of IVM data and may serve as a basis for the correction of alveolar sizes for more accurate quantitative analysis within future studies of lung tissue dynamics.

  12. Nonlinear histogram binning for quantitative analysis of lung tissue fibrosis in high-resolution CT data

    NASA Astrophysics Data System (ADS)

    Zavaletta, Vanessa A.; Bartholmai, Brian J.; Robb, Richard A.

    2007-03-01

    Diffuse lung diseases, such as idiopathic pulmonary fibrosis (IPF), can be characterized and quantified by analysis of volumetric high resolution CT scans of the lungs. These data sets typically have dimensions of 512 x 512 x 400. It is too subjective and labor intensive for a radiologist to analyze each slice and quantify regional abnormalities manually. Thus, computer aided techniques are necessary, particularly texture analysis techniques which classify various lung tissue types. Second and higher order statistics which relate the spatial variation of the intensity values are good discriminatory features for various textures. The intensity values in lung CT scans range between [-1024, 1024]. Calculation of second order statistics on this range is too computationally intensive so the data is typically binned between 16 or 32 gray levels. There are more effective ways of binning the gray level range to improve classification. An optimal and very efficient way to nonlinearly bin the histogram is to use a dynamic programming algorithm. The objective of this paper is to show that nonlinear binning using dynamic programming is computationally efficient and improves the discriminatory power of the second and higher order statistics for more accurate quantification of diffuse lung disease.

  13. Development of an inhalable, stimuli-responsive particulate system for delivery to deep lung tissue.

    PubMed

    Abbas, Yasmine; Azzazy, Hassan M E; Tammam, Salma; Lamprecht, Alf; Ali, Mohamed Ehab; Schmidt, Annette; Sollazzo, Silvio; Mathur, Sanjay

    2016-10-01

    Lung cancer, the deadliest solid tumor among all types of cancer, remains difficult to treat. This is a result of unavoidable exposure to carcinogens, poor diagnosis, the lack of targeted drug delivery platforms and limitations associated with delivery of drug to deep lung tissues. Development of a non-invasive, patient-convenient formula for the targeted delivery of chemotherapeutics to cancer in deep lung tissue is the aim of this study. The formulation consisted of inhalable polyvinylpyrrolidone (PVP)/maltodextrin (MD)-based microparticles (MPs) encapsulating chitosan (CS) nanoparticles (NPs) loaded with either drug only or drug and magnetic nanoparticles (MNPs). Drug release from CS NPs was enhanced with the aid of MNPs by a factor of 1.7 in response to external magnetic field. Preferential toxicity by CS NPs was shown towards tumor cells (A549) in comparison to cultured fibroblasts (L929). The prepared spray freeze dried (SFD) powders for CS NPs and CS MNPs were of the same size at ∼6μm. They had a fine particle fraction (FPF≤5.2μm) of 40-42% w/w and mass median aerodynamic diameter (MMAD) of 5-6μm as determined by the Next Generation Impactor (NGI). SFD-MPs of CS MNPs possess higher MMAD due to the high density associated with encapsulated MNPs. The developed formulation demonstrates several capabilities including tissue targeting, controlled drug release, and the possible imaging and diagnostic values (due to its MNPs content) and therefore represents an improved therapeutic platform for drug delivery to cancer in deep lung tissue. PMID:27244047

  14. Resolvin D1 prevents smoking-induced emphysema and promotes lung tissue regeneration

    PubMed Central

    Kim, Kang-Hyun; Park, Tai Sun; Kim, You-Sun; Lee, Jae Seung; Oh, Yeon-Mok; Lee, Sang-Do; Lee, Sei Won

    2016-01-01

    Purpose Emphysema is an irreversible disease that is characterized by destruction of lung tissue as a result of inflammation caused by smoking. Resolvin D1 (RvD1), derived from docosahexaenoic acid, is a novel lipid that resolves inflammation. The present study tested whether RvD1 prevents smoking-induced emphysema and promotes lung tissue regeneration. Materials and methods C57BL/6 mice, 8 weeks of age, were randomly divided into four groups: control, RvD1 only, smoking only, and smoking with RvD1 administration. Four different protocols were used to induce emphysema and administer RvD1: mice were exposed to smoking for 4 weeks with poly(I:C) or to smoking only for 24 weeks, and RvD1 was injected within the smoking exposure period to prevent regeneration or after completion of smoking exposure to assess regeneration. The mean linear intercept and inflammation scores were measured in the lung tissue, and inflammatory cells and cytokines were measured in the bronchoalveolar lavage fluid. Results Measurements of mean linear intercept showed that RvD1 significantly attenuated smoking-induced lung destruction in all emphysema models. RvD1 also reduced smoking-induced inflammatory cell infiltration, which causes the structural derangements observed in emphysema. In the 4-week prevention model, RvD1 reduced the smoking-induced increase in eosinophils and interleukin-6 in the bronchoalveolar lavage fluid. In the 24-week prevention model, RvD1 also reduced the increased neutrophils and total cell counts induced by smoking. Conclusion RvD1 attenuated smoking-induced emphysema in vivo by reducing inflammation and promoting tissue regeneration. This result suggests that RvD1 may be useful in the prevention and treatment of emphysema. PMID:27313451

  15. FOXP3+Treg/Th17 cell imbalance in lung tissues of mice with asthma

    PubMed Central

    Jiang, Hua; Wu, Xianbo; Zhu, Haiyan; Xie, Yiqiang; Tang, Songqi; Jiang, Yuji

    2015-01-01

    Immunocyte imbalances, particularly of Th1 and Th2 type helper T (Th) cells, have been implicated in the pathogenesis of chronic inflammatory diseases like asthma. Recent studies have suggested an important role for the balance between Th17 cells and FOXP3+ regulatory T cells (Treg). However, whether this balance is important in asthma remains unknown. This study sought to detect the populations of T cell subtypes (Th1, Th2, FOXP3+ Treg, Th17) in lung tissue of a mouse model of asthma to understand the significance of immunocyte balances in the disease. An asthma model was generated by sensitizing ten pathogen-free BALB/c mice using a standard ovalbumin challenge; ten other mice were challenged with PBS to serve as a control group. Total white cells and differential cell counts were determined in bronchoalveolar lavage fluid, and percentages of T cell subtypes were determined using flow cytometry. The severity of inflammation in lung tissue was evaluated in tissue sections, and airway hyperresponsiveness was assessed by unrestrained plethysmography. In mice with asthma, compared to those in the control group, total white cell, eosinophil, monocyte, and lymphocyte cell counts were higher, and lung inflammation and airway hyperresponsiveness were more severe (P<0.05), indicating that the model of asthma was successfully generated. Further, mice with asthma had higher percentages of Th2 and Th17 cells and lower percentages of Th1 and Foxp3+ Treg cells in lung tissue (P<0.05). Consequently, the ratios of Th1/Th2 cells and FOXP3+Treg/Th17 cells were higher in the asthma group (P<0.05). Thus, in addition to the imbalance of Th1/Th2 cells, an imbalance of FOXP3+Treg/Th17 cells may play an important role in the pathogenesis of asthma. PMID:26064325

  16. FOXP3(+)Treg/Th17 cell imbalance in lung tissues of mice with asthma.

    PubMed

    Jiang, Hua; Wu, Xianbo; Zhu, Haiyan; Xie, Yiqiang; Tang, Songqi; Jiang, Yuji

    2015-01-01

    Immunocyte imbalances, particularly of Th1 and Th2 type helper T (Th) cells, have been implicated in the pathogenesis of chronic inflammatory diseases like asthma. Recent studies have suggested an important role for the balance between Th17 cells and FOXP3(+) regulatory T cells (Treg). However, whether this balance is important in asthma remains unknown. This study sought to detect the populations of T cell subtypes (Th1, Th2, FOXP3(+) Treg, Th17) in lung tissue of a mouse model of asthma to understand the significance of immunocyte balances in the disease. An asthma model was generated by sensitizing ten pathogen-free BALB/c mice using a standard ovalbumin challenge; ten other mice were challenged with PBS to serve as a control group. Total white cells and differential cell counts were determined in bronchoalveolar lavage fluid, and percentages of T cell subtypes were determined using flow cytometry. The severity of inflammation in lung tissue was evaluated in tissue sections, and airway hyperresponsiveness was assessed by unrestrained plethysmography. In mice with asthma, compared to those in the control group, total white cell, eosinophil, monocyte, and lymphocyte cell counts were higher, and lung inflammation and airway hyperresponsiveness were more severe (P<0.05), indicating that the model of asthma was successfully generated. Further, mice with asthma had higher percentages of Th2 and Th17 cells and lower percentages of Th1 and Foxp3(+) Treg cells in lung tissue (P<0.05). Consequently, the ratios of Th1/Th2 cells and FOXP3(+)Treg/Th17 cells were higher in the asthma group (P<0.05). Thus, in addition to the imbalance of Th1/Th2 cells, an imbalance of FOXP3(+)Treg/Th17 cells may play an important role in the pathogenesis of asthma. PMID:26064325

  17. Three-dimensional simultaneous optical coherence tomography and confocal fluorescence microscopy for investigation of lung tissue

    NASA Astrophysics Data System (ADS)

    Gaertner, Maria; Cimalla, Peter; Meissner, Sven; Kuebler, Wolfgang M.; Koch, Edmund

    2012-07-01

    Although several strategies exist for a minimal-invasive treatment of patients with lung failure, the mortality rate of acute respiratory distress syndrome still reaches 30% at minimum. This striking number indicates the necessity of understanding lung dynamics on an alveolar level. To investigate the dynamical behavior on a microscale, we used three-dimensional geometrical and functional imaging to observe tissue parameters including alveolar size and length of embedded elastic fibers during ventilation. We established a combined optical coherence tomography (OCT) and confocal fluorescence microscopy system that is able to monitor the distension of alveolar tissue and elastin fibers simultaneously within three dimensions. The OCT system can laterally resolve a 4.9 μm line pair feature and has an approximately 11 μm full-width-half-maximum axial resolution in air. confocal fluorescence microscopy visualizes molecular properties of the tissue with a resolution of 0.75 μm (laterally), and 5.9 μm (axially) via fluorescence detection of the dye sulforhodamine B specifically binding to elastin. For system evaluation, we used a mouse model in situ to perform lung distension by application of different constant pressure values within the physiological regime. Our method enables the investigation of alveolar dynamics by helping to reveal basic processes emerging during artificial ventilation and breathing.

  18. Automated characterization of normal and pathologic lung tissue by topological texture analysis of multidetector CT

    NASA Astrophysics Data System (ADS)

    Boehm, H. F.; Fink, C.; Becker, C.; Reiser, M.

    2007-03-01

    Reliable and accurate methods for objective quantitative assessment of parenchymal alterations in the lung are necessary for diagnosis, treatment and follow-up of pulmonary diseases. Two major types of alterations are pulmonary emphysema and fibrosis, emphysema being characterized by abnormal enlargement of the air spaces distal to the terminal, nonrespiratory bronchiole, accompanied by destructive changes of the alveolar walls. The main characteristic of fibrosis is coursening of the interstitial fibers and compaction of the pulmonary tissue. With the ability to display anatomy free from superimposing structures and greater visual clarity, Multi-Detector-CT has shown to be more sensitive than the chest radiograph in identifying alterations of lung parenchyma. In automated evaluation of pulmonary CT-scans, quantitative image processing techniques are applied for objective evaluation of the data. A number of methods have been proposed in the past, most of which utilize simple densitometric tissue features based on the mean X-ray attenuation coefficients expressed in terms of Hounsfield Units [HU]. Due to partial volume effects, most of the density-based methodologies tend to fail, namely in cases, where emphysema and fibrosis occur within narrow spatial limits. In this study, we propose a methodology based upon the topological assessment of graylevel distribution in the 3D image data of lung tissue which provides a way of improving quantitative CT evaluation. Results are compared to the more established density-based methods.

  19. Diagnosis and prevalence of ovine pulmonary adenocarcinoma in lung tissues of naturally infected farm sheep

    PubMed Central

    Sonawane, Ganesh G.; Tripathi, Bhupendra Nath; Kumar, Rajiv; Kumar, Jyoti

    2016-01-01

    Aim: This study was aimed to detect ovine pulmonary adenocarcinoma (OPA) in sheep flocks affected with pulmonary disorders at organized farm. Materials and Methods: A total of 75 sheep died naturally were thoroughly examined for the lesions of OPA during necropsy. Tissue sections from affected portion of the lungs from each animal were collected aseptically and divided into two parts; one each for polymerase chain reaction (PCR) and another for histopathology. Results: On PCR examination of lung tissues, six sheep (8%) were found to be positive for JSRV. Two of them were 3-6 months of age and did not show clinical signs/gross lesions of OPA. Four adult sheep positive on PCR revealed characteristic lesions of OPA on gross and histopathological examination. Conclusion: In the absence of known specific antibody response to the infection with JSRV, there is no diagnostic serological test available. The PCR assay employed in this study on lung tissues, using primers based on the U3 region of the viral long terminal repeat for JSRV would be helpful in the screening of preclinical and clinical cases of OPA in sheep. PMID:27182131

  20. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD).

    PubMed

    Ohno, Yoshiharu; Koyama, Hisanobu; Yoshikawa, Takeshi; Seki, Shinichiro

    2015-12-01

    Involvement of the respiratory system is common in connective tissue diseases (CTDs), and the resultant lung injury can affect every part of the lung: the pleura, alveoli, interstitium, vasculature, lymphatic tissue, and large and/or small airways. Most of the parenchymal manifestations of CTD are similar to those found in interstitial lung diseases (ILDs), especially idiopathic interstitial pneumonias, and can be classified using the same system. Although there is some overlap, each CTD is associated with a characteristic pattern of pulmonary involvement. For this reason, thin-section CT as well as pulmonary function tests and serum markers are utilized for diagnosis, disease severity assessment, and therapeutic efficacy evaluation of ILD associated with CTD. In addition, newly developed pulmonary magnetic resonance imaging (MRI) procedures have been recommended as useful alternative imaging options for patients with CTD. This review article will (1) address radiological findings for chest radiography and conventional or thin-section CT currently used for six major types of CTD, rheumatoid arthritis, scleroderma (progressive systemic sclerosis), polymyositis/dermatomyositis, systemic lupus erythematosus, Sjögren syndrome and mixed connective tissue disease; (2) briefly deal with radiation dose reduction for thin-section CT examination; and (3) discuss clinically applicable or state-of-the-art MR imaging for CTD patients. PMID:26483318

  1. Expression of aquaporins in bronchial tissue and lung parenchyma of patients with chronic obstructive pulmonary disease

    PubMed Central

    2014-01-01

    Background Aquaporins AQP1 and AQP5 are highly expressed in the lung. Recent studies have shown that the expression of these proteins may be mechanistically involved in the airway inflammation and in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma of patients with COPD and COPD-resistant smokers. Methods Using a case–control design, we selected a group of 15 subjects with COPD and 15 resistant smokers (smokers without COPD) as a control, all of whom were undergoing lung resection surgery due to a lung neoplasm. We studied the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma by means of immunohistochemistry and reverse-transcription real-time polymerase chain reaction. Tissue expression of AQP1 and AQP5 was semi-quantitatively assessed in terms of intensity and expression by immunohistochemistry using a 4-point scale ranging from 0 (none) to 3 (maximum). Results There were no significant differences in gene expression between COPD patients and resistant smokers both in the bronchial tissue and in the lung parenchyma. However, AQP1 gene expression was 2.41-fold higher in the parenchyma of smokers with COPD compared to controls, whereas the AQP5 gene showed the opposite pattern, with a 7.75-fold higher expression in the bronchus of smokers with COPD compared with controls. AQP1 and AQP5 proteins were preferentially expressed in endothelial cells, showing a higher intensity for AQP1 (66.7% of cases with an intensity of 3, and 93.3% of subjects with an extension of 3 among patients with COPD). Subtle interstitial disease was associated with type II pneumocyte hyperplasia and an increased expression of AQP1. Conclusions This study provides pilot observations on the differences in AQP1 and AQP5 expression between COPD patients and COPD-resistant smokers. Our findings suggest a potential role for AQP1 in the

  2. MICRO DOSE ASESSMENT OF INHALED PARTICLES IN HUMAN LUNGS: A STEP CLOSER TOWARDS THE TARGET TISSUE DOSE

    EPA Science Inventory

    Rationale: Inhaled particles deposit inhomogeneously in the lung and this may result in excessive deposition dose at local regions of the lung, particularly at the anatomic sites of bifurcations and junctions of the airways, which in turn leads to injuries to the tissues and adve...

  3. Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

    SciTech Connect

    Rottmann, Joerg; Berbeco, Ross; Keall, Paul

    2013-09-15

    Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient.Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps.Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm.Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

  4. Immunohistochemical localization of LLC1 in human tissues and its limited expression in non-small cell lung cancer.

    PubMed

    Chandra, Vishal; Choi, Yong-Bock; Hwang, Hai-Li; Lee, Jeong-Hwa; Park, Seong-Yeol; Kim, Hyun-Kyoung; Poojan, Shiv; Koh, Jae-Soo; Kim, Han-Seong; Hong, Kyeong-Man

    2015-09-01

    We have shown both LLC1 expression in the lung epithelium by in situ hybridization and its inactivation in lung cancer by epigenetic modification. However, LLC1 protein's cellular localization or its role in normal lung or cancer tissues has not yet been evaluated. In the present study, a monoclonal antibody against recombinant LLC1 was produced, and immunohistochemical staining was performed on arrays including various human tissues, normal lung and non-small cell lung cancer (NSCLC) tissues for LLC1 localization. The immunohistochemical results showed LLC1 expression in the cilia of normal-airway epithelial cells and in the cytoplasm of type II pneumocytes in bronchiectatic patients, but no expression in most of the NSCLC tissues, which is consistent with our previous report positing LLC1 as a tumor suppressor. However, LLC1 over-expression in NSCLC cell lines NCI-H1299 and NCI-H23 did not show any change in proliferation or migration, which does not indicate any LLC1 tumor-suppressor role. As for the other human tissues, LLC1 was localized in renal tubular cells, pancreatic acinar cells, and epithelial cells of the stomach, duodenum, and gallbladder. In summary, our findings suggest that LLC1 is not a tumor suppressor, and that it is localized in the cilia of the normal lung epithelium but is absent in most NSCLC cases, probably due to the loss of cilia during lung carcinogenesis. PMID:25786037

  5. Prognostic significance of tissue miR-345 downregulation in non-small cell lung cancer

    PubMed Central

    Chen, Liming; Li, Xiaojie; Chen, Xiaojun

    2015-01-01

    Background: MiRNAs might function as oncogenes or tumor suppressor genes in the tumorigenesis process. Dysregulation of miR-345 is a frequent event in many types of human cancers. However, the tissue miR-345 expression level in non-small cell lung cancer (NSCLC) and its potential clinical significance remains unknown. Materials and methods: Real-time PCR was conducted to evaluate the expression level of miR-345 in NSCLC tissues as well as cell lines. Then the association between tissue miR-345 expression level and clinical outcome was investigated. Results: The expression level of miR-345 was significantly decreased in NSCLC tissues and cell lines compared with the controls (P<0.05; P<0.01). Tissue miR-345 expression level was associated with various clinicopathological parameters including LN metastasis (P=0.012), distant metastasis (P=0.007), TNM stage (P=0.008) and grade (P=0.030). In addition, the NSCLC patients in thelow tissue miR-345 expression group had significantly shorter 5-year overall survival time than those in the high tissue miR-345expression group (P=0.016). Multivariate analysis showed that tissue miR-345 was an independent risk factor for NSCLC (HR=3.921, 95% CI: 2.285-10.540; P=0.008). Conclusions: The expression level of miR-345 was reduced in NSCLC tissues and cell lines. Low tissue miR-345 expression was associated with progression and poor prognosis of NSCLC, indicating that tissue miR-345 may serve as a novel prognostic marker in NSCLC. PMID:26885027

  6. Quantifying Heterogeneity in Emphysema from High Resolution Computed Tomography: A Lung Tissue Research Consortium Study

    PubMed Central

    Yilmaz, Cuneyt; Dane, Dan M.; Patel, Nova C.; Hsia, Connie C.W.

    2012-01-01

    Rationale and Objective To quantify spatial distribution of emphysema using high-resolution computed tomography (HRCT), we applied semi-automated analysis with internal attenuation calibration to measure regional air volume, tissue volume, and fractional tissue volume (FTV=tissue/[air+tissue] volume) in well-characterized patients studied by the Lung Tissue Research Consortium (LTRC). Methods HRCT was obtained at supine end-inspiration and end-expiration, and prone end-inspiration from 31 patients with mild, moderate, severe, or very severe emphysema (stages II–V, FEV1>75%, 51–75%, 21–50% and ≤20% predicted, respectively). Control data were from 20 healthy non-smokers (stage I). Each lobe was analyzed separately. Heterogeneity of FTV was assessed from coefficients of variation (CV) within and among lobes, and the kurtosis and skewness of FTV histograms. Results In emphysema, lobar air volume increased up to 177% except in the right middle lobe. Lobar tissue volume increased up to 107% in mild-moderate stages then normalized in advanced stages. Normally, FTV was up to 82% higher in lower than upper lobes. In mild-moderate emphysema, lobar FTV increased by up to 74% above normal at supine inspiration. In severe emphysema FTV declined below normal in all lobes and positions in correlation with pulmonary function (p<0.05). Markers of FTV heterogeneity increased steadily with disease stage in correlation with pulmonary function (p<0.05); the pattern is distinct from that seen in interstitial lung disease (ILD). Conclusion CT-derived biomarkers differentiate the spatial patterns of emphysema distribution and heterogeneity from that in ILD. Early emphysema is associated with elevated tissue volume and FTV, consistent with hyperemia, inflammation or atelectasis. PMID:23122057

  7. A hypothesis on the mechanism of trauma of lung tissue subjected to impact load.

    PubMed

    Fung, Y C; Yen, R T; Tao, Z L; Liu, S Q

    1988-02-01

    When a compressive impact load is applied on the chest, as in automobile crash or bomb explosion, the lung may be injured and show evidences of edema and hemorrhage. Since soft tissues have good strength in compression, why does a compression wave cause edema? Our hypothesis is that tensile and shear stresses are induced in the alveolar wall on rebound from compression, and that the maximum principal stress (tensile) may exceed critical values for increased permeability of the epithelium to small solutes, or even fracture. Furthermore, small airways may collapse and trap gas in alveoli at a critical strain, causing traumatic atelectasis. The collapsed airways reopen at a higher strain after the wave passes, during which the expansion of the trapped gas will induce additional tension in the alveolar wall. To test this hypothesis, we made three new experiments: (1), measuring the effect of transient overstretch of the alveolar membrane on the rate of lung weight increase; (2) determining the critical pressure for reopening collapsed airways of rabbit lung subjected to cyclic compression and expansion; (3) cyclic compression of lung with trachea closed. We found that in isolated rabbit lung overstretching increases the rate of edema fluid formation, that the critical strain for airway reopening is higher than that for closing, and that these critical strains are strain-rate dependent, but independent of the state of the trachea, whether it is open or closed. Furthermore, a theoretical analysis is presented to show that the maximum principal (tensile) stress is of the same order of magnitude as the maximum initial compressive stress at certain localities of the lung.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3279269

  8. HOPE-fixation of lung tissue allows retrospective proteome and phosphoproteome studies.

    PubMed

    Shevchuk, Olga; Abidi, Nada; Klawonn, Frank; Wissing, Josef; Nimtz, Manfred; Kugler, Christian; Steinert, Michael; Goldmann, Torsten; Jänsch, Lothar

    2014-11-01

    Hepes-glutamic acid buffer-mediated organic solvent protection effect (HOPE)-fixation has been introduced as an alternative to formalin fixation of clinical samples. Beyond preservation of morphological structures for histology, HOPE-fixation was demonstrated to be compatible with recent methods for RNA and DNA sequencing. However, the suitability of HOPE-fixed materials for the inspection of proteomes by mass spectrometry so far remained undefined. This is of particular interest, since proteins constitute a prime resource for drug research and can give valuable insights into the activity status of signaling pathways. In this study, we extracted proteins from human lung tissue and tested HOPE-treated and snap-frozen tissues comparatively by proteome and phosphoproteome analyses. High confident data from accurate mass spectrometry allowed the identification of 2603 proteins and 3036 phosphorylation sites. HOPE-fixation did not hinder the representative extraction of proteins, and investigating their biochemical properties, covered subcellular localizations, and cellular processes revealed no bias caused by the type of fixation. In conclusion, proteome as well as phosphoproteome data of HOPE lung samples were qualitatively equivalent to results obtained from snap-frozen tissues. Thus, HOPE-treated tissues match clinical demands in both histology and retrospective proteome analyses of patient samples by proteomics. PMID:24702127

  9. A quantitative comparison analysis of diatoms in the lung tissues and the drowning medium as an indicator of drowning.

    PubMed

    Zhao, Jian; Ma, Yanbin; Liu, Chao; Wen, Jinfeng; Hu, Sunlin; Shi, He; Zhu, Lingyun

    2016-08-01

    The presence of diatoms in the lung tissues, internal organs and bone marrow is considered as the supportive evidence in the diagnosis of death by drowning. Generally, the diatoms detected in the lung tissues are regarded as insignificant since these diatoms can be detected in the lung tissues of the postmortem immersion bodies. In this study, we analyzed the relationships between the numbers of the diatoms in the lung tissues and the drowning medium. We made a comparison analysis between the diatoms in the lung tissues and the drowning medium using the ratio of diatom numbers in both samples (L/D ratio), utilizing Microwave Digestion - Vacuum Filtration - Automated Scanning Electron Microscopy method. Our data indicate that the L/D ratios in victims of the drowning group were higher than the postmortem immersion group. A higher L/D ratio provides valuable information about the cause of death in drowning victims. Quantitative diatom analysis in the lung tissues, especially combined with the diatom analysis of the drowning medium, provides supportive evidence in determining if a body recovered in water was due to drowning or not. PMID:27266652

  10. Evaluation of brachytherapy lung implant dose distributions from photon-emitting sources due to tissue heterogeneities

    SciTech Connect

    Yang Yun; Rivard, Mark J.

    2011-11-15

    Purpose: Photon-emitting brachytherapy sources are used for permanent implantation to treat lung cancer. However, the current brachytherapy dose calculation formalism assumes a homogeneous water medium without considering the influence of radiation scatter or tissue heterogeneities. The purpose of this study was to determine the dosimetric effects of tissue heterogeneities for permanent lung brachytherapy. Methods: The MCNP5 v1.40 radiation transport code was used for Monte Carlo (MC) simulations. Point sources with energies of 0.02, 0.03, 0.05, 0.1, 0.2, and 0.4 MeV were simulated to cover the range of pertinent brachytherapy energies and to glean dosimetric trends independent of specific radionuclide emissions. Source positions from postimplant CT scans of five patient implants were used for source coordinates, with dose normalized to 200 Gy at the center of each implant. With the presence of fibrosis (around the implant), cortical bone, lung, and healthy tissues, dose distributions and {sub PTV}DVH were calculated using the MCNP *FMESH4 tally and the NIST mass-energy absorption coefficients. This process was repeated upon replacing all tissues with water. For all photon energies, 10{sup 9} histories were simulated to achieve statistical errors (k = 1) typically of 1%. Results: The mean PTV doses calculated using tissue heterogeneities for all five patients changed (compared to dose to water) by only a few percent over the examined photon energy range, as did PTV dose at the implant center. The {sub PTV}V{sub 100} values were 81.2%, 90.0% (as normalized), 94.3%, 93.9%, 92.7%, and 92.2% for 0.02, 0.03, 0.05, 0.1, 0.2, and 0.4 MeV source photons, respectively. Relative to water, the maximum bone doses were higher by factors of 3.7, 5.1, 5.2, 2.4, 1.2, and 1.0 The maximum lung doses were about 0.98, 0.94, 0.91, 0.94, 0.97, and 0.99. Relative to water, the maximum healthy tissue doses at the mediastinal position were higher by factors of 9.8, 2.2, 1.3, 1.1, 1.1, and

  11. Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

    PubMed Central

    Shi, Jianxin; Marconett, Crystal N.; Duan, Jubao; Hyland, Paula L.; Li, Peng; Wang, Zhaoming; Wheeler, William; Zhou, Beiyun; Campan, Mihaela; Lee, Diane S.; Huang, Jing; Zhou, Weiyin; Triche, Tim; Amundadottir, Laufey; Warner, Andrew; Hutchinson, Amy; Chen, Po-Han; Chung, Brian S.I.; Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto; Bergen, Andrew W.; Freedman, Mathew; Siegmund, Kimberly D.; Berman, Benjamin P.; Borok, Zea; Chatterjee, Nilanjan; Tucker, Margaret A.; Caporaso, Neil E.; Chanock, Stephen J.; Laird-Offringa, Ite A.; Landi, Maria Teresa

    2014-01-01

    The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters, and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, 4 of the 5 established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome. PMID:24572595

  12. Histamine release by Western red cedar (Thuja plicata) from lung tissue in vitro

    PubMed Central

    Evans, Elizabeth; Nicholls, P. J.

    1974-01-01

    Evans, Elizabeth and Nicholls, P. J. (1974).British Journal of Industrial Medicine,31, 28-30. Histamine release by Western red cedar(Thuja plicata)from lung tissue in vitro. Various respiratory symptoms have previously been observed in workers exposed to dust from Western red cedar (Thuja plicata). Although an allergic basis for these effects has been proposed, the possibility that the dust may contain a pharmacologically active agent was investigated. Aqueous extracts of two samples of red cedar released significant amounts of histamine from pig and human lung in vitro. For one of these samples, using pig lung, a dose-response relation was found over a narrow range of concentrations. These dusts possessed the same order of histamine-releasing activity as a sample of cotton dust. Potassium cyanide reduced the release of histamine caused by low concentrations of Western red cedar. Similar effects of cyanide on the histamine-releasing activity of cotton dust and compound 48/80 were observed. It is possible that release of histamine in the lungs and upper respiratory tract occurs on inhalation of dust from Western red cedar and this may be a contributory factor to the development of respiratory symptoms in workers exposed to the dust of this wood. PMID:4132384

  13. Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology

    PubMed Central

    Massey, Veronica L.; Beier, Juliane I.; Ritzenthaler, Jeffrey D.; Roman, Jesse; Arteel, Gavin E.

    2015-01-01

    Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis. PMID:26437442

  14. Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.

    PubMed

    Witt, Leah J; Demchuk, Carley; Curran, James J; Strek, Mary E

    2016-02-01

    We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids. PMID:26762710

  15. High-Resolution Phase-Contrast Imaging of Submicron Particles in Unstained Lung Tissue

    NASA Astrophysics Data System (ADS)

    Schittny, J. C.; Barré, S. F.; Mokso, R.; Haberthür, D.; Semmler-Behnke, M.; Kreyling, W. G.; Tsuda, A.; Stampanoni, M.

    2011-09-01

    To access the risks and chances of deposition of submicron particles in the gas-exchange area of the lung, a precise three-dimensional (3D)-localization of the sites of deposition is essential—especially because local peaks of deposition are expected in the acinar tree and in individual alveoli. In this study we developed the workflow for such an investigation. We administered 200-nm gold particles to young adult rats by intratracheal instillation. After fixation and paraffin embedding, their lungs were imaged unstained using synchrotron radiation x-ray tomographic microscopy (SRXTM) at the beamline TOMCAT (Swiss Light Source, Villigen, Switzerland) at sample detector distances of 2.5 mm (absorption contrast) and of 52.5 mm (phase contrast). A segmentation based on a global threshold of grey levels was successfully done on absorption-contrast images for the gold and on the phase-contrast images for the tissue. The smallest spots containing gold possessed a size of 1-2 voxels of 370-nm side length. We conclude that a combination of phase and absorption contrast SRXTM imaging is necessary to obtain the correct segmentation of both tissue and gold particles. This method will be used for the 3D localization of deposited particles in the gas-exchange area of the lung.

  16. Development of a nonlinear fiber-optic spectrometer for human lung tissue exploration

    PubMed Central

    Peyrot, Donald A.; Lefort, Claire; Steffenhagen, Marie; Mansuryan, Tigran; Ducourthial, Guillaume; Abi-Haidar, Darine; Sandeau, Nicolas; Vever-Bizet, Christine; Kruglik, Sergei G.; Thiberville, Luc; Louradour, Frédéric; Bourg-Heckly, Geneviève

    2012-01-01

    Several major lung pathologies are characterized by early modifications of the extracellular matrix (ECM) fibrillar collagen and elastin network. We report here the development of a nonlinear fiber-optic spectrometer, compatible with an endoscopic use, primarily intended for the recording of second-harmonic generation (SHG) signal of collagen and two-photon excited fluorescence (2PEF) of both collagen and elastin. Fiber dispersion is accurately compensated by the use of a specific grism-pair stretcher, allowing laser pulse temporal width around 70 fs and excitation wavelength tunability from 790 to 900 nm. This spectrometer was used to investigate the excitation wavelength dependence (from 800 to 870 nm) of SHG and 2PEF spectra originating from ex vivo human lung tissue samples. The results were compared with spectral responses of collagen gel and elastin powder reference samples and also with data obtained using standard nonlinear microspectroscopy. The excitation-wavelength-tunable nonlinear fiber-optic spectrometer presented in this study allows performing nonlinear spectroscopy of human lung tissue ECM through the elastin 2PEF and the collagen SHG signals. This work opens the way to tunable excitation nonlinear endomicroscopy based on both distal scanning of a single optical fiber and proximal scanning of a fiber-optic bundle. PMID:22567579

  17. Lung cancer diagnosis and staging in the minimally invasive age with increasing demands for tissue analysis

    PubMed Central

    Costa, Daniel B.; Wright, Jeffrey; VanderLaan, Paul A.

    2015-01-01

    The diagnosis and staging of patients with lung cancer in recent decades has increasingly relied on minimally invasive tissue sampling techniques, such as endobronchial ultrasound (EBUS) or endoscopic ultrasound (EUS) needle aspiration, transbronchial biopsy, and transthoracic image guided core needle biopsy. These modalities have been shown to have low complication rates, and provide adequate cellular material for pathologic diagnosis and necessary ancillary molecular testing. As an important component to a multidisciplinary team approach in the care of patients with lung cancer, these minimally invasive modalities have proven invaluable for the rapid and safe acquisition of tissue used for the diagnosis, staging, and molecular testing of tumors to identify the best evidence-based treatment plan. The continuous evolution of the field of lung cancer staging and treatment has translated into improvements in survival and quality of life for patients. Although differences in clinical practice between academic and community hospital settings still exist, improvements in physician education and training as well as adoption of technological advancements should help narrow this gap going forward. PMID:26380180

  18. Arsenic Species in Scute (Shell Plate) and Lung Tissues of Desert Tortoises

    NASA Astrophysics Data System (ADS)

    Foster, A. L.; Berry, K.; Jacobson, E. R.; Rytuba, J. J.

    2009-12-01

    The desert tortoise (Gopherus agassizii) is federally listed as a threatened species, and its numbers have been in decline for at least two decades. Portions of protected desert tortoise habitats coincide with anthropogenic features such as historic mines and military bases that are potential sources of ingested or inhaled arsenic. Previous studies of necropsied desert tortoise specimens collected from the Mojave Desert have shown a statistically significant link between elevated tissue levels of arsenic (As) and the occurrence of clinical disease states. Synchrotron-based, microbeam X-ray absorption fine structure spectroscopy (XAFS) and X-ray fluorescence mapping (XRF) were the primary techniques used to identify As species in these tissues. Specimens have been analyzed from a mining-impacted area (Kelly-Rand Mining district, Kern County), and from sites on or adjacent to military bases (National Training Center, Ft Irwin, and Edwards AFB). XRF maps showed that scute sections sliced perpendicular to the exposed surface contain one or more diffuse bands of As(III) coordinated by oxygen instead of sulfur. This As(III) species is identical in all individuals, suggesting that it represents metabolized As. In contrast, the exterior surface and edges of scute sections contained As-rich particles of varying oxidation state and species, suggesting an exogenous origin. Particles contained reduced As in sulfides (Cu sulfide or arsenide) and As(V) in ferric sulfates and/or ferric arsenates. XAFS spectra of many As(V)-rich particles were close visual matches to spectra of known arsenic-bearing minerals or phases such as scorodite, jarosite, and arsenic adsorbed to iron (hydr)oxides. At least one, and more commonly 3-5 exogeneous As-rich particles were found in the formalin-preserved lung tissue sections examined, suggesting that such particles were relatively common. Pentavalent As was observed in forms similar to those encountered on scute sections. As(III) was observed in

  19. Early and late effects of prenatal corticosteroid treatment on the microRNA profiles of lung tissue in rats

    PubMed Central

    YU, HONG-REN; LI, SUNG-CHOU; TSENG, WAN-NING; TAIN, YOU-LIN; CHEN, CHIH-CHENG; SHEEN, JIUNN-MING; TIAO, MAO-MENG; KUO, HO-CHANG; HUANG, CHAO-CHENG; HSIEH, KAI-SHENG; HUANG, LI-TUNG

    2016-01-01

    Glucocorticoids have been administered to mothers at risk of premature delivery to induce maturation of preterm fetal lungs and prevent the development of respiratory distress syndrome. Micro (mi)RNAs serve various crucial functions in cell proliferation, differentiation and organ development; however, few studies have demonstrated an association between miRNAs and lung development. The aim of the present study was to investigate alterations in the miRNA profiles of rat lung tissue following prenatal glucocorticoid therapy for fetal lung development. The differences in miRNA expression profiles were compared between postnatal days 7 (D7) and 120 (D120) rat lung tissues, followed by validation using reverse transcription-quantitative polymerase chain reaction. The miRNA profiles of rat lung tissues following prenatal dexamethasone (DEX) therapy were also investigated. miRNAs with 2-fold changes were selected for further analysis. At D120, 6 upregulated and 6 downregulated miRNAs were detected, compared with D7. Among these differentially expressed miRNAs, miR-101-3p and miR-99b-5p were associated with the lowest and highest expressions of miRNA at D7, respectively. A limited impact on the miRNA profiles of rat lung tissues was observed following prenatal DEX treatment, which may help to further clarify the mechanisms underlying normal lung development. However, the results of the present study cannot entirely elucidate the effects of prenatal DEX treatment on the lung development of premature infants, and further studies investigating the impact of prenatal corticosteroids on fetal lung miRNA profiles are required. PMID:26997989

  20. A Case of Benign Metastasizing Leiomyoma with Multiple Metastasis to the Soft Tissue, Skeletal Muscle, Lung and Breast

    PubMed Central

    Jo, Ji Hoon; Lee, Jin Hwa; Kim, Dae Cheol; Kim, Sung Hyun; Kwon, Hyuk Chan; Kim, Jae Seok

    2006-01-01

    Benign metastasizing leiomyoma (BML) is composed of well-differentiated smooth muscle cells and dense connective tissue. BML affects middle-aged women who have had previous hysterectomies due to a histologically benign-appearing uterine leiomyoma. We report here on a case of BML from the uterine leiomyoma in a 39-year-old woman that involved the soft tissues, skeletal muscles, lungs and breasts. She underwent a hysterectomy for the uterine leiomyoma, double oophorectomy for hormonal ablation and lung wedge resection to confirm the diagnosis. The microscopic findings of the breast and lung tumor were similar to those of the benign uterine leiomyoma. Therefore, we consider that these lesions were breast and pulmonary metastases of the uterine leiomyoma. We report here on a rare case of benign metastasizing uterine leiomyoma that involved the soft tissue, skeletal muscles, lungs and breasts, and we include a review of the relevant literature. PMID:17017672

  1. TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections.

    PubMed

    Bailey, Daniel W; Wang, Iris Z; Lakeman, Tara; Hales, Lee D; Singh, Anurag K; Podgorsak, Matthew B

    2015-01-01

    This study compares lung dose distributions for two common techniques of total body photon irradiation (TBI) at extended source-to-surface distance calculated with, and without, tissue density correction (TDC). Lung dose correction factors as a function of lateral thorax separation are approximated for bilateral opposed TBI (supine), similar to those published for anteroposterior-posteroanterior (AP-PA) techniques in AAPM Report 17 (i.e., Task Group 29). 3D treatment plans were created retrospectively for 24 patients treated with bilateral TBI, and for whom CT data had been acquired from the head to the lower leg. These plans included bilateral opposed and AP-PA techniques- each with and without - TDC, using source-to-axis distance of 377 cm and largest possible field size. On average, bilateral TBI requires 40% more monitor units than AP-PA TBI due to increased separation (26% more for 23 MV). Calculation of midline thorax dose without TDC leads to dose underestimation of 17% on average (standard deviation, 4%) for bilateral 6 MV TBI, and 11% on average (standard deviation, 3%) for 23 MV. Lung dose correction factors (CF) are calculated as the ratio of midlung dose (with TDC) to midline thorax dose (without TDC). Bilateral CF generally increases with patient separation, though with high variability due to individual uniqueness of anatomy. Bilateral CF are 5% (standard deviation, 4%) higher than the same corrections calculated for AP-PA TBI in the 6 MV case, and 4% higher (standard deviation, 2%) for 23 MV. The maximum lung dose is much higher with bilateral TBI (up to 40% higher than prescribed, depending on patient anatomy) due to the absence of arm tissue blocking the anterior chest. Dose calculations for bilateral TBI without TDC are incorrect by up to 24% in the thorax for 6 MV and up to 16% for 23 MV. Bilateral lung CF may be calculated as 1.05 times the values published in Table 6 of AAPM Report 17, though a larger patient pool is necessary to better

  2. Cryopreservation and in vitro culture of primary cell types from lung tissue of a stranded pygmy sperm whale (Kogia breviceps).

    PubMed

    Annalaura Mancia; Spyropoulos, Demetri D; McFee, Wayne E; Newton, Danforth A; Baatz, John E

    2012-01-01

    Current models for in vitro studies of tissue function and physiology, including responses to hypoxia or environmental toxins, are limited and rely heavily on standard 2-dimensional (2-D) cultures with immortalized murine or human cell lines. To develop a new more powerful model system, we have pursued methods to establish and expand cultures of primary lung cell types and reconstituted tissues from marine mammals. What little is known about the physiology of the deep-sea diving pygmy sperm whale (PSW), Kogia breviceps, comes primarily from stranding events that occur along the coast of the southeastern United States. Thus, development of a method for preserving live tissues and retrieving live cells from deceased stranded individuals was initiated. This report documents successful cryopreservation of PSW lung tissue. We established in vitro cultures of primary lung cell types from tissue fragments that had been cryopreserved several months earlier at the stranding event. Dissociation of cryopreserved lung tissues readily provides a variety of primary cell types that, to varying degrees, can be expanded and further studied/manipulated in cell culture. In addition, PSW-specific molecular markers have been developed that permitted the monitoring of fibroblast, alveolar type II, and vascular endothelial cell types. Reconstitution of 3-D cultures of lung tissues with these cell types is now underway. This novel system may facilitate the development of rare or disease-specific lung tissue models (e.g., to test causes of PSW stranding events and lead to improved treatments for pulmonary hypertension or reperfusion injury in humans). Also, the establishment of a "living" tissue bank biorepository for rare/endangered species could serve multiple purposes as surrogates for freshly isolated samples. PMID:21501697

  3. Optimization of CT image reconstruction algorithms for the lung tissue research consortium (LTRC)

    NASA Astrophysics Data System (ADS)

    McCollough, Cynthia; Zhang, Jie; Bruesewitz, Michael; Bartholmai, Brian

    2006-03-01

    To create a repository of clinical data, CT images and tissue samples and to more clearly understand the pathogenetic features of pulmonary fibrosis and emphysema, the National Heart, Lung, and Blood Institute (NHLBI) launched a cooperative effort known as the Lung Tissue Resource Consortium (LTRC). The CT images for the LTRC effort must contain accurate CT numbers in order to characterize tissues, and must have high-spatial resolution to show fine anatomic structures. This study was performed to optimize the CT image reconstruction algorithms to achieve these criteria. Quantitative analyses of phantom and clinical images were conducted. The ACR CT accreditation phantom containing five regions of distinct CT attenuations (CT numbers of approximately -1000 HU, -80 HU, 0 HU, 130 HU and 900 HU), and a high-contrast spatial resolution test pattern, was scanned using CT systems from two manufacturers (General Electric (GE) Healthcare and Siemens Medical Solutions). Phantom images were reconstructed using all relevant reconstruction algorithms. Mean CT numbers and image noise (standard deviation) were measured and compared for the five materials. Clinical high-resolution chest CT images acquired on a GE CT system for a patient with diffuse lung disease were reconstructed using BONE and STANDARD algorithms and evaluated by a thoracic radiologist in terms of image quality and disease extent. The clinical BONE images were processed with a 3 x 3 x 3 median filter to simulate a thicker slice reconstructed in smoother algorithms, which have traditionally been proven to provide an accurate estimation of emphysema extent in the lungs. Using a threshold technique, the volume of emphysema (defined as the percentage of lung voxels having a CT number lower than -950 HU) was computed for the STANDARD, BONE, and BONE filtered. The CT numbers measured in the ACR CT Phantom images were accurate for all reconstruction kernels for both manufacturers. As expected, visual evaluation of the

  4. A mast cell secretagogue, compound 48/80, prevents the accumulation of hyaluronan in lung tissue injured by ionizing irradiation

    SciTech Connect

    Nilsson, K.; Bjermer, L.; Hellstroem, S.H.; Henriksson, R.; Haellgren, R. )

    1990-02-01

    Irradiation with a single dose of 30 Grey on the basal regions of the lungs of Sprague-Dawley rats induced a peribronchial and alveolar inflammation. Infiltration of mast cells in the edematous alveolar interstitial tissue and also in the peribronchial tissue were characteristic features of the lesion. The appearance of mast cells was already seen 4 wk after irradiation and by weeks 6 to 8 there was a heavy infiltration. The staining properties suggested that they were connective tissue-type mast cells. The infiltration of mast cells was paralleled by an accumulation of hyaluronan (hyaluronic acid) in the alveolar interstitial tissue 6 and 8 wk after irradiation. The recovery of hyaluronan (HA) during bronchoalveolar lavage (BAL) of the lungs also increased at this time. Treatment with a mast cell secretagogue, compound 48/80, induced a distinct reduction of granulated mast cells in the alveolar tissue. Regular treatment with compound 48/80 from the time of irradiation considerably reduced the HA recovery during BAL and the HA accumulation in the interstitial tissue but did not affect the interstitial infiltration of mononuclear cells and polymorphonuclear leukocytes. By contrast, an accumulation of HA in the alveolar interstitial space was induced when compound 48/80 was given not until mast cell infiltration of the lung had started. The effects of compound 48/80 indicate that the connective tissue response after lung irradiation is dependent on whether or not mast cell degranulation is induced before or after the mast cell infiltration of the alveolar tissue.

  5. Gene Expression Profiling of Lung Tissue of Rats Exposed to Lunar Dust Particles

    NASA Technical Reports Server (NTRS)

    Zhang, Ye; Feiveson, Alan H.; Lam, Chiu-Wing; Kidane, Yared H.; Ploutz-Snyder Robert; Yeshitla, Samrawit; Zalesak, Selina M.; Scully, Robert R.; Wu, Honglu; James, John T.

    2014-01-01

    The purpose of the study is to analyze the dynamics of global gene expression changes in the lung tissue of rats exposed to lunar dust particles. Multiple pathways and transcription factors were identified using the Ingenuity Pathway Analysis tool, showing the potential networks of these signaling regulations involved in lunar dust-induced prolonged proflammatory response and toxicity. The data presented in this study, for the first time, explores the molecular mechanisms of lunar dust induced toxicity. This work contributes not only to the risk assessment for future space exploration, but also to the understanding of the dust-induced toxicity to humans on earth.

  6. Asbestos content of lung tissue in patients with malignant peritoneal mesothelioma: A study of 42 cases.

    PubMed

    de Ridder, Gustaaf G; Kraynie, Alyssa; Pavlisko, Elizabeth N; Oury, Tim D; Roggli, Victor L

    2016-01-01

    Lung tissue from 42 peritoneal mesothelioma cases was analyzed by light microscopy and scanning electron microscopy/energy dispersive spectrometry. There were 34 men and 8 women with a mean age of 61 ± 10 years. Also, 17% of cases had histologically confirmed asbestosis, and 26% had only parietal pleural plaques. The asbestos body count exceeded our normal range in 22 of 42 cases (52%). Cases with asbestos-related pulmonary disease had higher fiber burdens than those without. The vast majority of fibers were commercial amphiboles (amosite with lesser amounts of crocidolite). These findings concur with previously published epidemiological observations. PMID:27281118

  7. Detection of Burkholderia cepacia DNA from artificially infected EDTA-blood and lung tissue comparing different DNA isolation methods.

    PubMed

    Merk, S; Meyer, H; Greiser-Wilke, I; Sprague, L D; Neubauer, H

    2006-08-01

    Bacterial DNA (Burkholderia cepacia) was prepared from artificially infected equine ethylenediaminetetraacetic acid (EDTA)-blood and lung tissue by using four standard methods (lysis buffer containing proteinase K, phenol/chloroform/isoamylalcohol-extraction, microwave-treatment, heat treatment) and six commercially available kits (Puregene, High Pure PCR Template Preparation Kit, InstaGene, QiaAmp Tissue Kit, DNAzol and Elu-Quik). After a subsequent polymerase chain reaction (PCR), their efficacy and sensitivity were compared. Concerning the detection limits, the simple lysis with a proteinase K-containing buffer led to the best results for EDTA-blood as well as for artificially infected lung tissue. PMID:16907960

  8. Identification and Characterization of Potential Biomarkers by Quantitative Tissue Proteomics of Primary Lung Adenocarcinoma.

    PubMed

    Hsu, Chiung-Hung; Hsu, Chia-Wei; Hsueh, Chuen; Wang, Chih-Liang; Wu, Yi-Cheng; Wu, Chih-Ching; Liu, Chin-Ching; Yu, Jau-Song; Chang, Yu-Sun; Yu, Chia-Jung

    2016-07-01

    Lung cancer is the leading cause of cancer-related death worldwide. Both diagnostic and prognostic biomarkers are urgently needed to increase patient survival. In this study, we identified/quantified 1763 proteins from paired adenocarcinoma (ADC) tissues with different extents of lymph node (LN) involvement using an iTRAQ-based quantitative proteomic analysis. Based on a bioinformatics analysis and literature search, we selected six candidates (ERO1L, PABPC4, RCC1, RPS25, NARS, and TARS) from a set of 133 proteins that presented a 1.5-fold increase in expression in ADC tumors without LN metastasis compared with adjacent normal tissues. These six proteins were further verified using immunohistochemical staining and Western blot analyses. The protein levels of these six candidates were higher in tumor tissues compared with adjacent normal tissues. The ERO1L and NARS levels were positively associated with LN metastasis. Importantly, ERO1L overexpression in patients with early-stage ADC was positively correlated with poor survival, suggesting that ERO1L overexpression in primary sites of early-stage cancer tissues indicates a high risk for cancer micrometastasis. Moreover, we found that knockdown of either ERO1L or NARS reduced the viability and migration ability of ADC cells. Our results collectively provide a potential biomarker data set for ADC diagnosis/prognosis and reveal novel roles of ERO1L and NARS in ADC progression. PMID:27161446

  9. Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue

    PubMed Central

    Fatykhova, Diana; Rabes, Anne; Machnik, Christoph; Guruprasad, Kunchur; Pache, Florence; Berg, Johanna; Toennies, Mario; Bauer, Torsten T.; Schneider, Paul; Schimek, Maria; Eggeling, Stephan; Mitchell, Timothy J.; Mitchell, Andrea M.; Hilker, Rolf; Hain, Torsten; Suttorp, Norbert; Hippenstiel, Stefan

    2015-01-01

    Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans. PMID:26317436

  10. Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue.

    PubMed

    Fatykhova, Diana; Rabes, Anne; Machnik, Christoph; Guruprasad, Kunchur; Pache, Florence; Berg, Johanna; Toennies, Mario; Bauer, Torsten T; Schneider, Paul; Schimek, Maria; Eggeling, Stephan; Mitchell, Timothy J; Mitchell, Andrea M; Hilker, Rolf; Hain, Torsten; Suttorp, Norbert; Hippenstiel, Stefan; Hocke, Andreas C; Opitz, Bastian

    2015-01-01

    Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans. PMID:26317436

  11. Automated Decellularization of Intact, Human-Sized Lungs for Tissue Engineering

    PubMed Central

    Price, Andrew P.; Godin, Lindsay M.; Domek, Alex; Cotter, Trevor; D'Cunha, Jonathan; Taylor, Doris A.

    2015-01-01

    We developed an automated system that can be used to decellularize whole human-sized organs and have shown lung as an example. Lungs from 20 to 30 kg pigs were excised en bloc with the trachea and decellularized with our established protocol of deionized water, detergents, sodium chloride, and porcine pancreatic DNase. A software program was written to control a valve manifold assembly that we built for selection and timing of decellularization fluid perfusion through the airway and the vasculature. This system was interfaced with a prototypic bioreactor chamber that was connected to another program, from a commercial source, which controlled the volume and flow pressure of fluids. Lung matrix that was decellularized by the automated method was compared to a manual method previously used by us and others. Automation resulted in more consistent acellular matrix preparations as demonstrated by measuring levels of DNA, hydroxyproline (collagen), elastin, laminin, and glycosaminoglycans. It also proved highly beneficial in saving time as the decellularization procedure was reduced from days down to just 24 h. Developing a rapid, controllable, automated system for production of reproducible matrices in a closed system is a major step forward in whole-organ tissue engineering. PMID:24826875

  12. Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue.

    PubMed

    Kerkelä, Erja; Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-07-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  13. Transient Proteolytic Modification of Mesenchymal Stromal Cells Increases Lung Clearance Rate and Targeting to Injured Tissue

    PubMed Central

    Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-01-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  14. The expression of P-selectin in inflammatory and non-inflammatory lung tissue.

    PubMed

    Ortmann, C; Brinkmann, B

    1997-01-01

    An initial attachment of leucocytes to blood vessel walls is mediated by selectins. A feature of adhesion mediated by P-selectin is the "rolling" of leucocytes on the endothelium. The time dependent expression of p-selectin in lung tissue was investigated in five groups of cases with different causes of death: carbon-monoxide and cyanide intoxication (n = 11), drowning (n = 5), hanging (n = 9), pneumonia (n = 13) and polytrauma with blunt thorax trauma (n = 14). In paraffin-embedded archival specimens immunostaining was achieved using an adapted APAAP-immunoperoxidase technique together with a wet autoclave method. P-selectin detection was scored by a semiquantitative method evaluating the intensity and incidence of positively stained endothelial cells. The distribution pattern of endothelial P-selectin of blood vessels in cases of pneumonia and septic shock were heterogenius and weak. In one case with lung contusion (survival time 3 h) moderate infiltrates of granulocytes were found near to septal and subpleural hemorrhages. In these inflammatory areas the positive endothelial immunostaining of small vessels was often weaker than in other lung segments or compared to the intensely stained platelets in corresponding vessels. PMID:9228566

  15. Cell structure and proliferative activity of organ cultures of normal embryonic lung tissue of mice resistant (C57BL) and predisposed (A) to lung tumors

    SciTech Connect

    Kolesnichenko, T.S.; Gor'kova, T.G.

    1985-08-01

    Local factors such as proliferative activity and the numerical ratio between epithelial and mesenchymal cells, and also the character of interaction between the tissue components in ontogeny may play an important role in the realization of sensitivity of mice of a particular line to the development of lung tumors. These characteristics of lung tissue in mice of lines A and C57BL are investigated under normal conditions and during induced carcinogenesis. Results are given of a comparative study of the relative numbers of epithelial and mesenchymal cells in organ cultures of embryonic lungs. /sup 3/H-thymidine was added to the cultures on the 14th day of the experiment in a concentration of 1 microCi/m1 medium. An autoradiographic study of the cultures was performed.

  16. Parametric and nonparametric nonlinear system identification of lung tissue strip mechanics.

    PubMed

    Yuan, H; Westwick, D T; Ingenito, E P; Lutchen, K R; Suki, B

    1999-01-01

    Lung parenchyma is a soft biological material composed of many interacting elements such as the interstitial cells, extracellular collagen-elastin fiber network, and proteoglycan ground substance. The mechanical behavior of this delicate structure is complex showing several mild but distinct types of nonlinearities and a fractal-like long memory stress relaxation characterized by a power-law function. To characterize tissue nonlinearity in the presence of such long memory, we investigated the robustness and predictive ability of several nonlinear system identification techniques on stress-strain data obtained from lung tissue strips with various input wave forms. We found that in general, for a mildly nonlinear system with long memory, a nonparametric nonlinear system identification in the frequency domain is preferred over time-domain techniques. More importantly, if a suitable parametric nonlinear model is available that captures the long memory of the system with only a few parameters, high predictive ability with substantially increased robustness can be achieved. The results provide evidence that the first-order kernel of the stress-strain relationship is consistent with a fractal-type long memory stress relaxation and the nonlinearity can be described as a Wiener-type nonlinear structure for displacements mimicking tidal breathing. PMID:10468239

  17. Gene Expression Profiling in Lung Tissues from Rat Exposed to Lunar Dust Particles

    NASA Technical Reports Server (NTRS)

    Zhang, Ye; Lam, Chiu-Wing; Zalesak, Selina M.; Kidane, Yared H.; Feiveson, Alan H.; Ploutz-Snyder, Robert; Scully, Robert R.; Williams, Kyle; Wu, Honglu; James, John T.

    2014-01-01

    The Moon's surface is covered by a layer of fine, reactive dust. Lunar dust contain about 1-2% of very fine dust (< 3 micron), that is respirable. The habitable area of any lunar landing vehicle and outpost would inevitably be contaminated with lunar dust that could pose a health risk. The purpose of the study is to analyze the dynamics of global gene expression changes in lung tissues from rats exposed to lunar dust particles. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.8, 21, and 61 mg/m(exp 3) of lunar dust. Five rats per group were euthanized 1 day, and 3 months after the last inhalation exposure. The total RNAs were isolated from lung tissues after being lavaged. The Agilent Rat GE v3 microarray was used to profile global gene expression (44K). The genes with significant expression changes are identified and the gene expression data were further analyzed using various statistical tools.

  18. Lung cancer in uranium miners: A tissue resource and pilot study. Final performance report

    SciTech Connect

    Samet, J.; Gilliland, F.D.

    1998-08-13

    This project incorporates two related research projects directed toward understanding respiratory carcinogenesis in radon-exposed former uranium miners. The first project involved a continuation of the tissue resource of lung cancer cases from former underground uranium miners and comparison cases from non-miners. The second project was a pilot study for a proposed longitudinal study of respiratory carcinogenesis in former uranium miners. The objectives including facilitating the investigation of molecular changes in radon exposed lung cancer cases, developing methods for prospectively studying clinical, cytologic, cytogenetic, and molecular changes in the multi-event process of respiratory carcinogenesis, and assessing the feasibility of recruiting former uranium miners into a longitudinal study that collected multiple biological specimens. A pilot study was conducted to determine whether blood collection, induced sputum, bronchial brushing, washings, and mucosal biopsies from participants at two of the hospitals could be included efficiently. A questionnaire was developed for the extended study and all protocols for specimen collection and tissue handling were completed. Resource utilization is in progress at ITRI and the methods have been developed to study molecular and cellular changes in exfoliated cells contained in sputum as well as susceptibility factors.

  19. Design, synthesis, and pharmacokinetic evaluation of a chemical delivery system for drug targeting to lung tissue.

    PubMed

    Saah, M; Wu, W M; Eberst, K; Marvanyos, E; Bodor, N

    1996-05-01

    We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy. PMID:8742941

  20. Global DNA methylation and PTEN hypermethylation alterations in lung tissues from human silicosis

    PubMed Central

    Zhang, Xianan; Jia, Xiaowei; Mei, Liangying; Zheng, Min; Yu, Chen

    2016-01-01

    Background Silicosis is a respiratory disease caused by long-term silica dust exposure. Our previous study has demonstrated that silica mediates the activation of phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/serine or threonine kinase (AKT)/mitogen-activated protein kinases (MAPK)/AP-1 pathway in human embryo lung fibroblasts (HELFs). The purpose of this study is to identify genome-wide aberrant DNA methylation profiling in lung tissues from silicosis patients. Methods We performed Illumina Human Methylation 450K Beadchip arrays to investigate the methylation alteration in formalin-fixed, paraffin-embedded (FFPE) lung specimens, immunohistochemistry to detect the level of c-Jun and PTEN proteins; methylation specific PCR (MS-PCR) to identify PTEN and c-Jun promoter methylation in HELFs. Results We found 86,770 CpG sites and 79,660 CpG sites significantly differed in methylation status in early-stage and advanced-stage compared with GEO normal lung methylation data. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the methylated status of MAPK signaling pathway was considered changed. The number of PTEN and c-Jun CpG promoter methylated-sites were increased in advanced-stage. Early-stage showed the positive expression of c-Jun and PTEN protein and negative or mild expression in advanced-stage. PTEN promoter was no differentially methylated and c-Jun promoter differed at 12 and 24 h in HELFs. Conclusions Abnormal DNA methylation on genome-scale was implicated in silicosis, and PTEN promoter hypermethylation might be associated with decrease of PTEN protein.

  1. Epigenetic clustering of lung adenocarcinomas based on DNA methylation profiles in adjacent lung tissue: Its correlation with smoking history and chronic obstructive pulmonary disease.

    PubMed

    Sato, Takashi; Arai, Eri; Kohno, Takashi; Takahashi, Yoriko; Miyata, Sayaka; Tsuta, Koji; Watanabe, Shun-ichi; Soejima, Kenzo; Betsuyaku, Tomoko; Kanai, Yae

    2014-07-15

    The aim of this study was to clarify the significance of DNA methylation alterations during lung carcinogenesis. Infinium assay was performed using 139 paired samples of non-cancerous lung tissue (N) and tumorous tissue (T) from a learning cohort of patients with lung adenocarcinomas (LADCs). Fifty paired N and T samples from a validation cohort were also analyzed. DNA methylation alterations on 1,928 probes occurred in N samples relative to normal lung tissue from patients without primary lung tumors, and were inherited by, or strengthened in, T samples. Unsupervised hierarchical clustering using DNA methylation levels in N samples on all 26,447 probes subclustered patients into Cluster I (n = 32), Cluster II (n = 35) and Cluster III (n = 72). LADCs in Cluster I developed from the inflammatory background in chronic obstructive pulmonary disease (COPD) in heavy smokers and were locally invasive. Most patients in Cluster II were non-smokers and had a favorable outcome. LADCs in Cluster III developed in light smokers were most aggressive (frequently showing lymphatic and blood vessel invasion, lymph node metastasis and an advanced pathological stage), and had a poor outcome. DNA methylation levels of hallmark genes for each cluster, such as IRX2, HOXD8, SPARCL1, RGS5 and EI24, were again correlated with clinicopathological characteristics in the validation cohort. DNA methylation profiles reflecting carcinogenetic factors such as smoking and COPD appear to be established in non-cancerous lung tissue from patients with LADCs and may determine the aggressiveness of tumors developing in individual patients, and thus patient outcome. PMID:24921089

  2. Epigenetic clustering of lung adenocarcinomas based on DNA methylation profiles in adjacent lung tissue: Its correlation with smoking history and chronic obstructive pulmonary disease

    PubMed Central

    Sato, Takashi; Arai, Eri; Kohno, Takashi; Takahashi, Yoriko; Miyata, Sayaka; Tsuta, Koji; Watanabe, Shun-ichi; Soejima, Kenzo; Betsuyaku, Tomoko; Kanai, Yae

    2014-01-01

    The aim of this study was to clarify the significance of DNA methylation alterations during lung carcinogenesis. Infinium assay was performed using 139 paired samples of non-cancerous lung tissue (N) and tumorous tissue (T) from a learning cohort of patients with lung adenocarcinomas (LADCs). Fifty paired N and T samples from a validation cohort were also analyzed. DNA methylation alterations on 1,928 probes occurred in N samples relative to normal lung tissue from patients without primary lung tumors, and were inherited by, or strengthened in, T samples. Unsupervised hierarchical clustering using DNA methylation levels in N samples on all 26,447 probes subclustered patients into Cluster I (n = 32), Cluster II (n = 35) and Cluster III (n = 72). LADCs in Cluster I developed from the inflammatory background in chronic obstructive pulmonary disease (COPD) in heavy smokers and were locally invasive. Most patients in Cluster II were non-smokers and had a favorable outcome. LADCs in Cluster III developed in light smokers were most aggressive (frequently showing lymphatic and blood vessel invasion, lymph node metastasis and an advanced pathological stage), and had a poor outcome. DNA methylation levels of hallmark genes for each cluster, such as IRX2, HOXD8, SPARCL1, RGS5 and EI24, were again correlated with clinicopathological characteristics in the validation cohort. DNA methylation profiles reflecting carcinogenetic factors such as smoking and COPD appear to be established in non-cancerous lung tissue from patients with LADCs and may determine the aggressiveness of tumors developing in individual patients, and thus patient outcome. PMID:24921089

  3. Lung tissue proteomics identifies elevated transglutaminase 2 levels in stable chronic obstructive pulmonary disease.

    PubMed

    Ohlmeier, Steffen; Nieminen, Pentti; Gao, Jing; Kanerva, Tinja; Rönty, Mikko; Toljamo, Tuula; Bergmann, Ulrich; Mazur, Witold; Pulkkinen, Ville

    2016-06-01

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by irreversible airflow limitation. Cigarette smoking represents the main risk factor, but the specific mechanisms of COPD are not completely understood. Our aim was to identify COPD-specific proteomic changes involved in disease onset and severity. A comparative proteomic analysis of 51 lung tissues from nonsmokers, smokers, smokers with mild to moderate (stage I-II) COPD, severe to very severe COPD (stage III-IV), and patients with α-1-antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF) was performed by cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry. Selected COPD-specific changes were validated by immunoblotting and further by ELISA in 120 induced sputum and plasma samples from nonsmokers, smokers, and patients with COPD (stage I-III). Altogether 82 altered proteins were identified comprising COPD-, AATD-, and IPF-specific, overlapping, and unspecific changes. Cathepsin D (CTSD), dihydropyrimidinase-related protein 2 (DPYSL2), transglutaminase 2 (TGM2), and tripeptidyl-peptidase 1 (TPP1) were validated as COPD-specific. TGM2 was not associated with smoking and correlated with COPD severity in lung tissue. TGM2 levels in sputum and plasma were elevated in patients with COPD (stage II-III) and correlated with lung function. In conclusion, new proteins related to COPD onset and severity could be identified with TGM2 being a novel potential diagnostic and therapeutic target for COPD. Further studies in carefully characterized cohorts are required to validate the identified changes. PMID:27084846

  4. Mechanical Forces Accelerate Collagen Digestion by Bacterial Collagenase in Lung Tissue Strips

    PubMed Central

    Yi, Eunice; Sato, Susumu; Takahashi, Ayuko; Parameswaran, Harikrishnan; Blute, Todd A.; Bartolák-Suki, Erzsébet; Suki, Béla

    2016-01-01

    Most tissues in the body are under mechanical tension, and while enzymes mediate many cellular and extracellular processes, the effects of mechanical forces on enzyme reactions in the native extracellular matrix (ECM) are not fully understood. We hypothesized that physiological levels of mechanical forces are capable of modifying the activity of collagenase, a key remodeling enzyme of the ECM. To test this, lung tissue Young's modulus and a nonlinearity index characterizing the shape of the stress-strain curve were measured in the presence of bacterial collagenase under static uniaxial strain of 0, 20, 40, and 80%, as well as during cyclic mechanical loading with strain amplitudes of ±10 or ±20% superimposed on 40% static strain, and frequencies of 0.1 or 1 Hz. Confocal and electron microscopy was used to determine and quantify changes in ECM structure. Generally, mechanical loading increased the effects of enzyme activity characterized by an irreversible decline in stiffness and tissue deterioration seen on both confocal and electron microscopic images. However, a static strain of 20% provided protection against digestion compared to both higher and lower strains. The decline in stiffness during digestion positively correlated with the increase in equivalent alveolar diameters and negatively correlated with the nonlinearity index. These results suggest that the decline in stiffness results from rupture of collagen followed by load transfer and subsequent rupture of alveolar walls. This study may provide new understanding of the role of collagen degradation in general tissue remodeling and disease progression. PMID:27462275

  5. Gene expression profile of oxidative stress and antioxidant defense in lung tissue of patients exposed to sulfur mustard.

    PubMed

    Tahmasbpour, Eisa; Ghanei, Mostafa; Qazvini, Ali; Vahedi, Ensieh; Panahi, Yunes

    2016-04-01

    Sulfur mustard (SM) is a potent alkylating agent that targets several organs, especially lung tissue. Although pathological effects of SM on mustard lung have been widely considered, molecular and cellular mechanisms for these pathologies are poorly understood. We investigated changes in expression of genes related to oxidative stress (OS) and antioxidant defense caused by SM in lung tissue of patients. We performed gene expression profiling of OS and antioxidant defense in lung tissue samples from healthy controls (n=5) and SM-exposed patients (n=6). Changes in gene expression were measured using a 96-well RT(2) Profiler ™PCR Array: Human Oxidative Stress and Antioxidant Defense, which arrayed 84 genes functionally involved in cellular OS response. 47 (55.95%) genes were found to be significantly upregulated in patients with mustard lung compared with controls (p<0.05), whereas 7 (8.33%) genes were significantly downregulated (p<0.05). Among the most upregulated genes were OS responsive-1 (OXSR1), forkhead box M1 (FOXM1), and glutathione peroxidase-2 (GPX2), while metallothionein-3 (MT3) and glutathione reductase (GSR) were the most downregulated genes. Expression of hypoxia-induced genes (CYGB and MB), antioxidants and reactive oxygen species (ROS)-producing genes were significantly altered, suggesting an increased oxidative damage in mustard lungs. Mustard lungs were characterized by hypoxia, massive production of ROS, OS, disruption of epithelial cells, surfactant dysfunction, as well as increased risk of lung cancer and pulmonary fibrosis. Oxidative stress induced by ROS is the major mechanism for direct effect of SM exposure on respiratory system. Antioxidant treatment may improve the main features of mustard lungs. PMID:27085470

  6. Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

    PubMed Central

    Meireles, Sibele I.; Esteves, Gustavo H.; Hirata, Roberto; Peri, Suraj; Devarajan, Karthik; Slifker, Michael; Mosier, Stacy L.; Peng, Jing; Vadhanam, Manicka V.; Hurst, Harrell E.; Neves, E. Jordao; Reis, Luiz F.; Gairola, C. Gary; Gupta, Ramesh C.; Clapper, Margie L.

    2010-01-01

    Lung cancer is the leading cause of cancer deaths in the U.S., surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/day; 5 days/wk for 3, 8 and 20 wk). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15 K cDNA microarray. Cytochrome P450 1b1 (Cyp1b1), a Phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17β-estradiol, was modulated to the greatest extent following smoke exposure. A panel of 10 genes was found to be differentially expressed in control and smoke-exposed lung tissue at 3, 8 and 20 wk (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure including estrogen metabolism. In addition, 17β-estradiol was detected within murine lung tissue by gas chromatography coupled mass spectrometry and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of 17β-estradiol within lung tissue when combined with the modulation of Cyp1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer. PMID:20515954

  7. Open lung ventilation in neurosurgery: an update on brain tissue oxygenation.

    PubMed

    Wolf, S; Plev, D V; Trost, H A; Lumenta, C B

    2005-01-01

    Recently, we showed the feasibility of ventilating neurosurgical patients with acute intracranial pathology and concomitant acute respiratory distress syndrome (ARDS) according the so-called Open Lung approach. This technique consists of low tidal volume, elevated positive expiratory pressure (PEEP) level and initial recruitment maneuvers to open up collapsed alveoli. In this report, we focus on our experience to guide recruitment with brain tissue oxygenation (pbrO2) probes. We studied recruitment maneuvers in thirteen patients with ARDS and acute brain injury such as subarachnoid hemorrhage and traumatic brain injury. A pbrO2 probe was implanted in brain tissue at risk for hypoxia. Recruitment maneuvers were performed at an inspired oxygen frcation (FiO2) of 1.0 and a PEEP level of 30 40 cmH2O for 40 seconds. The mean FiO2 necessary for normoxemia could be decreased from 0.85 +/- 0.17 before recruitment to 0.55 +/- 0.12 after 24 hours, while mean PbrO2 (24.6 mmHg before recruitment) did not change. At a mean of 17 minutes after the first recruitment maneuver, PbrO2 showed peak a value of 35.6 +/- 16.6 mmHg, reflecting improvement in arterial oxygenation at an FiO2 of 1.0. Brain tissue oxygenation monitoring provides a useful adjunct to estimate the effects of recruitment maneuvers and ventilator settings in neurosurgical patients with acute lung injury. PMID:16463830

  8. NOTCH1, HIF1A and Other Cancer-Related Proteins in Lung Tissue from Uranium Miners—Variation by Occupational Exposure and Subtype of Lung Cancer

    PubMed Central

    Pesch, Beate; Casjens, Swaantje; Stricker, Ingo; Westerwick, Daniela; Taeger, Dirk; Rabstein, Sylvia; Wiethege, Thorsten; Tannapfel, Andrea; Brüning, Thomas; Johnen, Georg

    2012-01-01

    Background Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. Methodology/Principal Findings Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (rs). Occupational exposure was associated with an up-regulation of NOTCH1 (radon rs = 0.18, 95% CI 0.02–0.33; arsenic: rs = 0.23, 95% CI 0.07–0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. Conclusions/Significance These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate. PMID:23028920

  9. Lung Motion Model Validation Experiments, Free-Breathing Tissue Densitometry, and Ventilation Mapping using Fast Helical CT Imaging

    NASA Astrophysics Data System (ADS)

    Dou, Hsiang-Tai

    The uncertainties due to respiratory motion present significant challenges to accurate characterization of cancerous tissues both in terms of imaging and treatment. Currently available clinical lung imaging techniques are subject to inferior image quality and incorrect motion estimation, with consequences that can systematically impact the downstream treatment delivery and outcome. The main objective of this thesis is the development of the techniques of fast helical computed tomography (CT) imaging and deformable image registration for the radiotherapy applications in accurate breathing motion modeling, lung tissue density modeling and ventilation imaging. Fast helical CT scanning was performed on 64-slice CT scanner using the shortest available gantry rotation time and largest pitch value such that scanning of the thorax region amounts to just two seconds, which is less than typical breathing cycle in humans. The scanning was conducted under free breathing condition. Any portion of the lung anatomy undergoing such scanning protocol would be irradiated for only a quarter second, effectively removing any motion induced image artifacts. The resulting CT data were pristine volumetric images that record the lung tissue position and density in a fraction of the breathing cycle. Following our developed protocol, multiple fast helical CT scans were acquired to sample the tissue positions in different breathing states. To measure the tissue displacement, deformable image registration was performed that registers the non-reference images to the reference one. In modeling breathing motion, external breathing surrogate signal was recorded synchronously with the CT image slices. This allowed for the tissue-specific displacement to be modeled as parametrization of the recorded breathing signal using the 5D lung motion model. To assess the accuracy of the motion model in describing tissue position change, the model was used to simulate the original high-pitch helical CT scan

  10. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    PubMed

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury. PMID:25815693

  11. Synergistically increased ILC2 and Th9 cells in lung tissue jointly promote the pathological process of asthma in mice.

    PubMed

    Ying, Xinyu; Su, Zhaoliang; Bie, Qingli; Zhang, Pan; Yang, Huijian; Wu, Yumin; Xu, Yunyun; Wu, Jing; Zhang, Mengying; Wang, Shengjun; Xu, Huaxi

    2016-06-01

    In recent years, T helper (Th) 9 cells have been demonstrated to be key mediators in immune responses in asthmatic lungs, and innate lymphoid cells 2 (ILC2s) have been described as a novel type of innate immunocyte with the ability to enhance immunoglobulin E (IgE) production. However, the interaction between ILC2s and Th9 cells in the pulmonary system of a mouse model of asthma remains to be elucidated. In the present study, the response state of lung tissue with regards to Th9 and ILC2s in a mouse model of asthma was investigated by detecting Th9‑ and ILC2‑associated cytokine receptors. The present study also investigated the association between the expression levels of the cytokine receptors in lung tissue samples and the IgE levels in sera samples from mouse models of asthma. Results from the present study demonstrated that the frequency of ILC2s and Th9 cells was significantly increased in the lung tissue samples, indicating that a Th2-type immune response had occurred. In addition, high mRNA expression levels of RAR‑related orphan receptor α, interleukin 1 receptor‑like 1, transcription factor PU.1 and interleukin (IL)‑9 were observed. Furthermore, IL‑5Rα, IL‑13Rα2 and high‑affinity IgE receptor were increased in mouse models of asthma, and a positive association was observed between the expression levels of ILC2‑ or Th9‑associated receptors in tissue samples and IgE levels in the sera. This indicated that ILC2s and Th9 were in a state of polarization and may promote each other in the lung tissue of mouse models of asthma, and that the lung tissue was responding to the two types of cells via increased expression of receptors. PMID:27109139

  12. Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

    PubMed Central

    Liu, Dongdong; Mao, Pu; Huang, Yongbo; Liu, Yiting; Liu, Xiaoqing; Pang, Xiaoqing; Li, Yimin

    2014-01-01

    Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI. PMID:25024510

  13. Lung Motion Model Validation Experiments, Free-Breathing Tissue Densitometry, and Ventilation Mapping using Fast Helical CT Imaging

    NASA Astrophysics Data System (ADS)

    Dou, Hsiang-Tai

    The uncertainties due to respiratory motion present significant challenges to accurate characterization of cancerous tissues both in terms of imaging and treatment. Currently available clinical lung imaging techniques are subject to inferior image quality and incorrect motion estimation, with consequences that can systematically impact the downstream treatment delivery and outcome. The main objective of this thesis is the development of the techniques of fast helical computed tomography (CT) imaging and deformable image registration for the radiotherapy applications in accurate breathing motion modeling, lung tissue density modeling and ventilation imaging. Fast helical CT scanning was performed on 64-slice CT scanner using the shortest available gantry rotation time and largest pitch value such that scanning of the thorax region amounts to just two seconds, which is less than typical breathing cycle in humans. The scanning was conducted under free breathing condition. Any portion of the lung anatomy undergoing such scanning protocol would be irradiated for only a quarter second, effectively removing any motion induced image artifacts. The resulting CT data were pristine volumetric images that record the lung tissue position and density in a fraction of the breathing cycle. Following our developed protocol, multiple fast helical CT scans were acquired to sample the tissue positions in different breathing states. To measure the tissue displacement, deformable image registration was performed that registers the non-reference images to the reference one. In modeling breathing motion, external breathing surrogate signal was recorded synchronously with the CT image slices. This allowed for the tissue-specific displacement to be modeled as parametrization of the recorded breathing signal using the 5D lung motion model. To assess the accuracy of the motion model in describing tissue position change, the model was used to simulate the original high-pitch helical CT scan

  14. Metallic artifact mitigation and organ-constrained tissue assignment for Monte Carlo calculations of permanent implant lung brachytherapy

    SciTech Connect

    Sutherland, J. G. H.; Miksys, N.; Thomson, R. M.; Furutani, K. M.

    2014-01-15

    Purpose: To investigate methods of generating accurate patient-specific computational phantoms for the Monte Carlo calculation of lung brachytherapy patient dose distributions. Methods: Four metallic artifact mitigation methods are applied to six lung brachytherapy patient computed tomography (CT) images: simple threshold replacement (STR) identifies high CT values in the vicinity of the seeds and replaces them with estimated true values; fan beam virtual sinogram replaces artifact-affected values in a virtual sinogram and performs a filtered back-projection to generate a corrected image; 3D median filter replaces voxel values that differ from the median value in a region of interest surrounding the voxel and then applies a second filter to reduce noise; and a combination of fan beam virtual sinogram and STR. Computational phantoms are generated from artifact-corrected and uncorrected images using several tissue assignment schemes: both lung-contour constrained and unconstrained global schemes are considered. Voxel mass densities are assigned based on voxel CT number or using the nominal tissue mass densities. Dose distributions are calculated using the EGSnrc user-code BrachyDose for{sup 125}I, {sup 103}Pd, and {sup 131}Cs seeds and are compared directly as well as through dose volume histograms and dose metrics for target volumes surrounding surgical sutures. Results: Metallic artifact mitigation techniques vary in ability to reduce artifacts while preserving tissue detail. Notably, images corrected with the fan beam virtual sinogram have reduced artifacts but residual artifacts near sources remain requiring additional use of STR; the 3D median filter removes artifacts but simultaneously removes detail in lung and bone. Doses vary considerably between computational phantoms with the largest differences arising from artifact-affected voxels assigned to bone in the vicinity of the seeds. Consequently, when metallic artifact reduction and constrained tissue

  15. Regional Mapping of Gas Uptake by Blood and Tissue in the Human Lung using Hyperpolarized Xenon-129 MRI

    PubMed Central

    Qing, Kun; Ruppert, Kai; Jiang, Yun; Mata, Jaime F.; Miller, G. Wilson; Shim, Y. Michael; Wang, Chengbo; Ruset, Iulian C.; Hersman, F. William; Altes, Talissa A.; Mugler, John P.

    2013-01-01

    Purpose To develop a breath-hold acquisition for regional mapping of ventilation and the fractions of hyperpolarized xenon-129 (Xe129) dissolved in tissue (lung parenchyma and plasma) and red blood cells (RBCs), and to perform an exploratory study to characterize data obtained in human subjects. Materials and Methods A three-dimensional, multi-echo, radial-trajectory pulse sequence was developed to obtain ventilation (gaseous Xe129), tissue and RBC images in healthy subjects, smokers and asthmatics. Signal ratios (total dissolved Xe129 to gas, tissue-to-gas, RBC-to-gas and RBC-to-tissue) were calculated from the images for quantitative comparison. Results Healthy subjects demonstrated generally uniform values within coronal slices, and a gradient in values along the anterior-to-posterior direction. In contrast, images and associated ratio maps in smokers and asthmatics were generally heterogeneous and exhibited values mostly lower than those in healthy subjects. Whole-lung values of total dissolved Xe129 to gas, tissue-to-gas, and RBC-to-gas ratios in healthy subjects were significantly larger than those in diseased subjects. Conclusion Regional maps of tissue and RBC fractions of dissolved Xe129 were obtained from a short breath-hold acquisition, well tolerated by healthy volunteers and subjects with obstructive lung disease. Marked differences were observed in spatial distributions and overall amounts of Xe129 dissolved in tissue and RBCs among healthy subjects, smokers and asthmatics. PMID:23681559

  16. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome.

    PubMed

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Omodeo Salè, Fausta; Van den Steen, Philippe E; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  17. Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage.

    PubMed

    Hsieh, Ya-Ching; Frink, Michael; Hsieh, Chi-Hsun; Choudhry, Mashkoor A; Schwacha, Martin G; Bland, Kirby I; Chaudry, Irshad H

    2007-05-01

    Although studies have shown that 17beta-estradiol (E(2)) prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which E(2) inhibits neutrophil transmigration remains unknown. Macrophage migration inhibitory factor (MIF) is thought to play a central role in exacerbation of inflammation and is associated with lung injury. MIF regulates the inflammatory response through modulation of Toll-like receptor 4 (TLR4). Activation of TLR4 results in the release of proinflammatory cytokines and chemokines, which induce neutrophil infiltration and subsequent tissue damage. We hypothesized that E(2) mediates its salutary effects in the lung following trauma-hemorrhage via negative regulation of MIF and modulation of TLR4 and cytokine-induced chemotaxis. C3H/HeOuJ mice were subjected to trauma-hemorrhage (mean blood pressure 35 +/- 5 mmHg for approximately 90 min, then resuscitation) or sham operation. Mice received vehicle, E(2), or E(2) in combination with recombinant mouse MIF protein (rMIF). Trauma-hemorrhage increased lung MIF and TLR4 protein levels as well as lung and systemic levels of cytokines/chemokines. Treatment of animals with E(2) following trauma-hemorrhage prevented these changes. However, administration of rMIF protein with E(2) abolished the E(2)-mediated decrease in lung TLR4 levels, lung and plasma levels of IL-6, TNF-alpha, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine (KC). Administration of rMIF protein also prevented E(2)-mediated reduction in neutrophil influx and tissue damage in the lungs following trauma-hemorrhage. These results suggest that the protective effects of E(2) on lung injury following trauma-hemorrhage are mediated via downregulation of lung MIF and TLR4-induced cytokine/chemokine production. PMID:17277045

  18. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome

    PubMed Central

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  19. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis.

    PubMed

    Nuovo, Gerard J; Hagood, James S; Magro, Cynthia M; Chin, Nena; Kapil, Rubina; Davis, Luke; Marsh, Clay B; Folcik, Virginia A

    2012-03-01

    We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68(+) and CD80(+) cells and significantly fewer CD3(+), CD4(+), and CD45RO(+) cells in areas of relatively (histologically) normal lung in biopsy samples from idiopathic pulmonary fibrosis patients compared with controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, chemokine receptor 6 (CCR6), S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared with histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3(+) T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for forkhead box p3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating

  20. Differential protein folding and chemical changes in lung tissues exposed to asbestos or particulates.

    PubMed

    Pascolo, Lorella; Borelli, Violetta; Canzonieri, Vincenzo; Gianoncelli, Alessandra; Birarda, Giovanni; Bedolla, Diana E; Salomé, Murielle; Vaccari, Lisa; Calligaro, Carla; Cotte, Marine; Hesse, Bernhard; Luisi, Fernando; Zabucchi, Giuliano; Melato, Mauro; Rizzardi, Clara

    2015-01-01

    Environmental and occupational inhalants may induce a large number of pulmonary diseases, with asbestos exposure being the most risky. The mechanisms are clearly related to chemical composition and physical and surface properties of materials. A combination of X-ray fluorescence (μXRF) and Fourier Transform InfraRed (μFTIR) microscopy was used to chemically characterize and compare asbestos bodies versus environmental particulates (anthracosis) in lung tissues from asbestos exposed and control patients. μXRF analyses revealed heterogeneously aggregated particles in the anthracotic structures, containing mainly Si, K, Al and Fe. Both asbestos and particulates alter lung iron homeostasis, with a more marked effect in asbestos exposure. μFTIR analyses revealed abundant proteins on asbestos bodies but not on anthracotic particles. Most importantly, the analyses demonstrated that the asbestos coating proteins contain high levels of β-sheet structures. The occurrence of conformational changes in the proteic component of the asbestos coating provides new insights into long-term asbestos effects. PMID:26159651

  1. Differential protein folding and chemical changes in lung tissues exposed to asbestos or particulates

    PubMed Central

    Pascolo, Lorella; Borelli, Violetta; Canzonieri, Vincenzo; Gianoncelli, Alessandra; Birarda, Giovanni; Bedolla, Diana E.; Salomé, Murielle; Vaccari, Lisa; Calligaro, Carla; Cotte, Marine; Hesse, Bernhard; Luisi, Fernando; Zabucchi, Giuliano; Melato, Mauro; Rizzardi, Clara

    2015-01-01

    Environmental and occupational inhalants may induce a large number of pulmonary diseases, with asbestos exposure being the most risky. The mechanisms are clearly related to chemical composition and physical and surface properties of materials. A combination of X-ray fluorescence (μXRF) and Fourier Transform InfraRed (μFTIR) microscopy was used to chemically characterize and compare asbestos bodies versus environmental particulates (anthracosis) in lung tissues from asbestos exposed and control patients. μXRF analyses revealed heterogeneously aggregated particles in the anthracotic structures, containing mainly Si, K, Al and Fe. Both asbestos and particulates alter lung iron homeostasis, with a more marked effect in asbestos exposure. μFTIR analyses revealed abundant proteins on asbestos bodies but not on anthracotic particles. Most importantly, the analyses demonstrated that the asbestos coating proteins contain high levels of β-sheet structures. The occurrence of conformational changes in the proteic component of the asbestos coating provides new insights into long-term asbestos effects. PMID:26159651

  2. Proteomic Study of Differential Protein Expression in Mouse Lung Tissues after Aerosolized Ricin Poisoning

    PubMed Central

    Guo, Zhendong; Han, Chao; Du, Jiajun; Zhao, Siyan; Fu, Yingying; Zheng, Guanyu; Sun, Yucheng; Zhang, Yi; Liu, Wensen; Wan, Jiayu; Qian, Jun; Liu, Linna

    2014-01-01

    Ricin is one of the most poisonous natural toxins from plants and is classified as a Class B biological threat pathogen by the Centers for Disease Control and Prevention (CDC) of U.S.A. Ricin exposure can occur through oral or aerosol routes. Ricin poisoning has a rapid onset and a short incubation period. There is no effective treatment for ricin poisoning. In this study, an aerosolized ricin-exposed mouse model was developed and the pathology was investigated. The protein expression profile in the ricin-poisoned mouse lung tissue was analyzed using proteomic techniques to determine the proteins that were closely related to the toxicity of ricin. 2D gel electrophoresis, mass spectrometry and subsequent biological functional analysis revealed that six proteins including Apoa1 apolipoprotein, Ywhaz 14-3-3 protein, Prdx6 Uncharacterized Protein, Selenium-binding protein 1, HMGB1, and DPYL-2, were highly related to ricin poisoning. PMID:24786090

  3. Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung

    PubMed Central

    Hwang, Ji Young; Randall, Troy D.; Silva-Sanchez, Aaron

    2016-01-01

    Following pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as inducible Bronchus-Associated Lymphoid Tissue (iBALT). Like conventional lymphoid organs, areas of iBALT have segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels. After inflammation is resolved, iBALT is maintained for months, independently of inflammation. Once iBALT is formed, it participates in immune responses to pulmonary antigens, including those that are unrelated to the iBALT-initiating antigen, and often alters the clinical course of disease. However, the mechanisms that govern immune responses in iBALT and determine how iBALT impacts local and systemic immunity are poorly understood. Here, we review our current understanding of iBALT formation and discuss how iBALT participates in pulmonary immunity. PMID:27446088

  4. LARGE SCALE ISOLATION AND PURIFICATION OF SOLUBLE RAGE FROM LUNG TISSUE

    PubMed Central

    Englert, Judson M.; Ramsgaard, Lasse; Valnickova, Zuzana; Enghild, Jan J.; Oury, Tim D.

    2008-01-01

    The receptor for advanced glycation end-products (RAGE) has been implicated in numerous disease processes including: atherosclerosis, diabetic nephropathy, impaired wound healing, and neuropathy to name a few. Treatment of animals with a soluble isoform of the receptor (sRAGE) has been shown to prevent and even reverse many disease processes. Isolating large quantities of pure sRAGE for in vitro and in vivo studies has hindered its development as a therapeutic strategy in other RAGE mediated diseases that require long-term therapy. This article provides an improvement in both yield and detail of a previously published method to obtain 10 mg of pure, endotoxin free sRAGE from 65 g of lung tissue. PMID:18558495

  5. Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease.

    PubMed

    Li, Xue-Ren; Peng, Shou-Chun; Wei, Lu-Qing

    2015-01-01

    Here, we reported two cases of nonspecific interstitial pneumonia overlap organizing pneumonia (NSIP/OP) with lung-dominant connective tissue disease (LD-ILD). The first case is a patient with hands of chapped skin, right-sided pleuritic chest discomfort, weakness, positive ANA and antibodies to Ro/SS-A (+++) and Ro-52 (++). In the second case, there were Reynaud's disease, and nucleolus-ANA increased (1:800). Chest high resolution CT scan in both cases showed ground-glass opacifications, predominantly in basal and subpleural region and the pathologic manifestation were correlated with NSIP/OP, which were previously discovered in Sjogren syndrome, PM/DM and other rheumatic diseases. The two cases of NSIP/OP with LD-CTD we reported expand disease spectrum of NSIP/OP pathological types in ILD. However, it is necessary to process large-scale studies. PMID:26617847

  6. Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

    PubMed Central

    Mairpady Shambat, Srikanth; Chen, Puran; Nguyen Hoang, Anh Thu; Bergsten, Helena; Vandenesch, Francois; Siemens, Nikolai; Lina, Gerard; Monk, Ian R.; Foster, Timothy J.; Arakere, Gayathri; Svensson, Mattias; Norrby-Teglund, Anna

    2015-01-01

    ABSTRACT Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human

  7. Development of an Ex Vivo Tissue Platform To Study the Human Lung Response to Coxiella burnetii.

    PubMed

    Graham, Joseph G; Winchell, Caylin G; Kurten, Richard C; Voth, Daniel E

    2016-05-01

    Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, an acute debilitating flu-like illness that can also present as chronic endocarditis. Disease typically occurs following inhalation of contaminated aerosols, resulting in an initial pulmonary infection. In human cells, C. burnetii generates a replication niche termed the parasitophorous vacuole (PV) by directing fusion with autophagosomes and lysosomes. C. burnetii requires this lysosomal environment for replication and uses a Dot/Icm type IV secretion system to generate the large PV. However, we do not understand how C. burnetii evades the intracellular immune surveillance that triggers an inflammatory response. We recently characterized human alveolar macrophage (hAM) infection in vitro and found that avirulent C. burnetii triggers sustained interleukin-1β (IL-1β) production. Here, we evaluated infection of ex vivo human lung tissue, defining a valuable approach for characterizing C. burnetii interactions with a human host. Within whole lung tissue, C. burnetii preferentially replicated in hAMs. Additionally, IL-1β production correlated with formation of an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)-dependent inflammasome in response to infection. We also assessed potential activation of a human-specific noncanonical inflammasome and found that caspase-4 and caspase-5 are processed during infection. Interestingly, although inflammasome activation is closely linked to pyroptosis, lytic cell death did not occur following C. burnetii-triggered inflammasome activation, indicating an atypical response after intracellular detection. Together, these studies provide a novel platform for studying the human innate immune response to C. burnetii. PMID:26902725

  8. Expression of Toll-like receptor 9 (TLR9) in the lungs and lymphoid tissue of pigs.

    PubMed

    Kuzemtseva, Liudmila; Pérez, Mónica; Mateu, Enric; Segalés, Joaquim; Darwich, Laila

    2015-02-01

    The pattern of distribution of Toll-like receptor 9 (TLR9) in different tissues varies between species. The aim of the present study was to describe the distribution of TLR9 expression in selected tissues and organs of healthy pigs at 3 weeks and 3 months of age. Representative formalin-fixed samples of lung, thymus and secondary lymphoid tissues were evaluated by immunohistochemistry. TLR9 positive staining was observed in epithelial cells, vascular endothelium and myoepithelial-like cells, as well as in cells of the alveolar septa of the lung. Antigen presenting cells of perifollicular zones (interdigitating, macrophage and dendritic-like cells) of the Peyer's patches, lymph nodes, spleen and thymus were also immunoreactive for TLR9. No differences were seen in TLR9 protein expression in tissues from the two age groups. PMID:25576141

  9. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts.

    PubMed

    Lama, Vibha N; Smith, Lisa; Badri, Linda; Flint, Andrew; Andrei, Adin-Cristian; Murray, Susan; Wang, Zhuo; Liao, Hui; Toews, Galen B; Krebsbach, Paul H; Peters-Golden, Marc; Pinsky, David J; Martinez, Fernando J; Thannickal, Victor J

    2007-04-01

    The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% +/- 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ. PMID:17347686

  10. Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue.

    PubMed

    Prado, Charlotte; Kazi, Abdul; Bennett, Alexander; MacVittie, Thomas; Prado, Karl

    2015-11-01

    Multi-organ dose evaluations and the effects of heterogeneous tissue dose calculations have been retrospectively evaluated following irradiation to the whole thorax and lung in non-human primates (NHP). A clinical-based approach was established to evaluate actual doses received in the heart and lungs during whole thorax lung irradiation. Anatomical structure and organ densities have been introduced in the calculations to show the effects of dose distribution through heterogeneous tissue. Mean organ doses received by non-human primates undergoing whole thorax lung irradiations were calculated using a treatment planning system that is routinely used in clinical radiation oncology. The doses received by non-human primates irradiated following conventional dose calculations have been retrospectively reconstructed using computerized tomography-based, heterogeneity-corrected dose calculations. The use of dose volume descriptors for irradiation to organs at risk and tissue exposed to radiation is introduced. Mean and partial-volume doses to lung and heart are presented and contrasted. The importance of exact dose definitions is highlighted, and the relevance of precise dosimetry to establish organ-specific dose response relationships in NHP models of acute and delayed effects of acute radiation exposure is emphasized. PMID:26425898

  11. Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy.

    PubMed

    Rangel, M P; de Sá, V K; Martins, V; Martins, J R M; Parra, E R; Mendes, A; Andrade, P C; Reis, R M; Longatto-Filho, A; Oliveira, C Z; Takagaki, T; Carraro, D M; Nader, H B; Capelozzi, V L

    2015-06-01

    Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology. PMID:25992645

  12. Two-color widefield fluorescence microendoscopy enables multiplexed molecular imaging in the alveolar space of human lung tissue

    NASA Astrophysics Data System (ADS)

    Krstajić, Nikola; Akram, Ahsan R.; Choudhary, Tushar R.; McDonald, Neil; Tanner, Michael G.; Pedretti, Ettore; Dalgarno, Paul A.; Scholefield, Emma; Girkin, John M.; Moore, Anne; Bradley, Mark; Dhaliwal, Kevin

    2016-04-01

    We demonstrate a fast two-color widefield fluorescence microendoscopy system capable of simultaneously detecting several disease targets in intact human ex vivo lung tissue. We characterize the system for light throughput from the excitation light emitting diodes, fluorescence collection efficiency, and chromatic focal shifts. We demonstrate the effectiveness of the instrument by imaging bacteria (Pseudomonas aeruginosa) in ex vivo human lung tissue. We describe a mechanism of bacterial detection through the fiber bundle that uses blinking effects of bacteria as they move in front of the fiber core providing detection of objects smaller than the fiber core and cladding (˜3 μm). This effectively increases the measured spatial resolution of 4 μm. We show simultaneous imaging of neutrophils, monocytes, and fungus (Aspergillus fumigatus) in ex vivo human lung tissue. The instrument has 10 nM and 50 nM sensitivity for fluorescein and Cy5 solutions, respectively. Lung tissue autofluorescence remains visible at up to 200 fps camera acquisition rate. The optical system lends itself to clinical translation due to high-fluorescence sensitivity, simplicity, and the ability to multiplex several pathological molecular imaging targets simultaneously.

  13. ON BENZO[A]PYRENE DERIVED DNA ADDUCTS FORMED IN LUNG TISSUE OF MICE

    EPA Science Inventory

    On Benzo [a] pyrene Derived DNA Adducts Formed in Lung Tissue of Mice
    The previously identified major DNA adducts of benzo[a]pyrene (BP) in vitro and in vivo are the stable and unstable adducts formed by reaction of the bay-region diol epoxide of BP (BPDE) and BP radical catio...

  14. Elemental analysis of lung tissue particles and intracellular iron content of alveolar macrophages in pulmonary alveolar proteinosis

    PubMed Central

    2011-01-01

    Background Pulmonary alveolar proteinosis (PAP) is a rare disease occurred by idiopathic (autoimmune) or secondary to particle inhalation. The in-air microparticle induced X-ray emission (in-air micro-PIXE) system performs elemental analysis of materials by irradiation with a proton microbeam, and allows visualization of the spatial distribution and quantitation of various elements with very low background noise. The aim of this study was to assess the secondary PAP due to inhalation of harmful particles by employing in-air micro-PIXE analysis for particles and intracellular iron in parafin-embedded lung tissue specimens obtained from a PAP patient comparing with normal lung tissue from a non-PAP patient. The iron inside alveolar macrophages was stained with Berlin blue, and its distribution was compared with that on micro-PIXE images. Results The elements composing particles and their locations in the PAP specimens could be identified by in-air micro-PIXE analysis, with magnesium (Mg), aluminum (Al), silicon (Si), phosphorus (P), sulfur (S), scandium (Sc), potassium (K), calcium (Ca), titanium (Ti), chromium (Cr), copper (Cu), manganase (Mn), iron (Fe), and zinc (Zn) being detected. Si was the major component of the particles. Serial sections stained by Berlin blue revealed accumulation of sideromacrophages that had phagocytosed the particles. The intracellular iron content of alveolar macrophage from the surfactant-rich area in PAP was higher than normal lung tissue in control lung by both in-air micro-PIXE analysis and Berlin blue staining. Conclusion The present study demonstrated the efficacy of in-air micro-PIXE for analyzing the distribution and composition of lung particles. The intracellular iron content of single cells was determined by simultaneous two-dimensional and elemental analysis of paraffin-embedded lung tissue sections. The results suggest that secondary PAP is associated with exposure to inhaled particles and accumulation of iron in alveolar

  15. Extracellular matrix structure and tissue stiffness control postnatal lung development through the lipoprotein receptor-related protein 5/Tie2 signaling system.

    PubMed

    Mammoto, Tadanori; Jiang, Elisabeth; Jiang, Amanda; Mammoto, Akiko

    2013-12-01

    Physical properties of the tissues and remodeling of extracellular matrix (ECM) play an important role in organ development. Recently, we have reported that low-density lipoprotein receptor-related protein (LRP) 5/Tie2 signaling controls postnatal lung development by modulating angiogenesis. Here we show that tissue stiffness modulated by the ECM cross-linking enzyme, lysyl oxidase (LOX), regulates postnatal lung development through LRP5-Tie2 signaling. The expression of LRP5 and Tie2 is up-regulated twofold in lung microvascular endothelial cells when cultured on stiff matrix compared to those cultured on soft matrix in vitro. LOX inhibitor, β-aminopropionitrile, disrupts lung ECM (collagen I, III, and VI, and elastin) structures, softens neonatal mouse lung tissue by 20%, and down-regulates the expression of LRP5 and Tie2 by 20 and 60%, respectively, which leads to the inhibition of postnatal lung development (30% increase in mean linear intercept, 1.5-fold increase in air space area). Importantly, hyperoxia treatment (Postnatal Days 1-10) disrupts ECM structure and stiffens mouse lung tissue by up-regulating LOX activity, thereby increasing LRP5 and Tie2 expression and deregulating alveolar morphogenesis in neonatal mice, which is attenuated by inhibiting LOX activity. These findings suggest that appropriate physical properties of lung tissue are necessary for physiological postnatal lung development, and deregulation of this mechanism contributes to postnatal lung developmental disorders, such as bronchopulmonary dysplasia. PMID:23841513

  16. Hair growth promoting potential of phospholipids purified from porcine lung tissues.

    PubMed

    Choi, Seong-Hyun; Moon, Jeong-Su; Jeon, Byung-Suk; Jeon, Yeon-Jeong; Yoon, Byung-Il; Lim, Chang-Jin

    2015-03-01

    BP201, porcine lung tissue-derived phospholipids, consists of phosphatidylcholine as a major phospholipid species. BP201 promoted hair growth after application onto the shaved backs of BALB/c and C3H mice. Its effect was enhanced when applied together with minoxidil (MNX) in C3H mice. When the tissue specimens prepared from the shaved skins of BP201-treated and control mice were microscopically examined, the total numbers of hair follicles in both anagen and telogen phases of BP201-treated mice were significantly higher than those of control mice. The numbers of hair follicles in the anagen phase of BP201-treated mice were also higher than those of control mice. In combination with MNX, BP201 further increased the total number of hair follicles, but did not alter the percentage of hair follicles in the anagenic phase. BP201 also increased the proliferation of human hair follicle dermal papilla cells. Collectively, BP201 possesses hair growth promoting potential, which would suggest its use singly or in combination for hair growth products. PMID:25767686

  17. Hair Growth Promoting Potential of Phospholipids Purified from Porcine Lung Tissues

    PubMed Central

    Choi, Seong-Hyun; Moon, Jeong-Su; Jeon, Byung-Suk; Jeon, Yeon-Jeong; Yoon, Byung-Il; Lim, Chang-Jin

    2015-01-01

    BP201, porcine lung tissue-derived phospholipids, consists of phosphatidylcholine as a major phospholipid species. BP201 promoted hair growth after application onto the shaved backs of BALB/c and C3H mice. Its effect was enhanced when applied together with minoxidil (MNX) in C3H mice. When the tissue specimens prepared from the shaved skins of BP201-treated and control mice were microscopically examined, the total numbers of hair follicles in both anagen and telogen phases of BP201-treated mice were significantly higher than those of control mice. The numbers of hair follicles in the anagen phase of BP201-treated mice were also higher than those of control mice. In combination with MNX, BP201 further increased the total number of hair follicles, but did not alter the percentage of hair follicles in the anagenic phase. BP201 also increased the proliferation of human hair follicle dermal papilla cells. Collectively, BP201 possesses hair growth promoting potential, which would suggest its use singly or in combination for hair growth products. PMID:25767686

  18. Improved correction for the tissue fraction effect in lung PET/CT imaging

    NASA Astrophysics Data System (ADS)

    Holman, Beverley F.; Cuplov, Vesna; Millner, Lynn; Hutton, Brian F.; Maher, Toby M.; Groves, Ashley M.; Thielemans, Kris

    2015-09-01

    Recently, there has been an increased interest in imaging different pulmonary disorders using PET techniques. Previous work has shown, for static PET/CT, that air content in the lung influences reconstructed image values and that it is vital to correct for this ‘tissue fraction effect’ (TFE). In this paper, we extend this work to include the blood component and also investigate the TFE in dynamic imaging. CT imaging and PET kinetic modelling are used to determine fractional air and blood voxel volumes in six patients with idiopathic pulmonary fibrosis. These values are used to illustrate best and worst case scenarios when interpreting images without correcting for the TFE. In addition, the fractional volumes were used to determine correction factors for the SUV and the kinetic parameters. These were then applied to the patient images. The kinetic parameters K1 and Ki along with the static parameter SUV were all found to be affected by the TFE with both air and blood providing a significant contribution to the errors. Without corrections, errors range from 34-80% in the best case and 29-96% in the worst case. In the patient data, without correcting for the TFE, regions of high density (fibrosis) appeared to have a higher uptake than lower density (normal appearing tissue), however this was reversed after air and blood correction. The proposed correction methods are vital for quantitative and relative accuracy. Without these corrections, images may be misinterpreted.

  19. Retention patterns of asbestos fibres in lung tissue among asbestos cement workers.

    PubMed Central

    Albin, M; Pooley, F D; Strömberg, U; Attewell, R; Mitha, R; Johansson, L; Welinder, H

    1994-01-01

    Retention patterns in lung tissue (determined by transmission electron microscopy and energy dispersive spectrometry) of chrysotile, tremolite, and crocidolite fibres were analysed in 69 dead asbestos cement workers and 96 referents. There was an accumulation of tremolite with time of employment. Among workers who died within three years of the end of exposure, the 13 with high tremolite concentrations had a significantly longer duration of exposure than seven in a low to intermediate category (medians 32 v 20 years; p = 0.018, one sided). Crocidolite showed similar patterns of accumulation. In workers who died more than three years after the end of exposure, there were no correlations between concentrations of amphibole fibres and time between the end of exposure and death. Chrysotile concentrations among workers who died shortly after the end of exposure were higher than among the referents (median difference in concentrations 13 million fibres (f)/g dry weight; p = 0.033, one sided). No quantitative differences in exposure (duration or intensity) could be shown between workers with high and low to intermediate concentrations. Interestingly, all seven workers who had had a high intensity at the end of exposure (> 2.5 f/ml), had low to intermediate chrysotile concentrations at death, whereas those with low exposure were evenly distributed (31 subjects in both concentration categories); hence, there was a dependence between last intensity of exposure and chrysotile concentration (p = 0.014). Among 14 workers with a high average intensity of exposure, both those (n = 5) with high tissue concentrations of chrysotile and those (n = 10) with high tissue concentrations of tremolite fibres had more pronounced fibrosis than those with low to intermediate concentrations (median fibrosis grades for chrysotile: 2 v 1, p = 0.021; for tremolite: 2 v 0.5, p = 0.012). Additionally, workers who died shortly after the end of exposure with high concentrations of chrysotile and

  20. Retention patterns of asbestos fibres in lung tissue among asbestos cement workers.

    PubMed

    Albin, M; Pooley, F D; Strömberg, U; Attewell, R; Mitha, R; Johansson, L; Welinder, H

    1994-03-01

    Retention patterns in lung tissue (determined by transmission electron microscopy and energy dispersive spectrometry) of chrysotile, tremolite, and crocidolite fibres were analysed in 69 dead asbestos cement workers and 96 referents. There was an accumulation of tremolite with time of employment. Among workers who died within three years of the end of exposure, the 13 with high tremolite concentrations had a significantly longer duration of exposure than seven in a low to intermediate category (medians 32 v 20 years; p = 0.018, one sided). Crocidolite showed similar patterns of accumulation. In workers who died more than three years after the end of exposure, there were no correlations between concentrations of amphibole fibres and time between the end of exposure and death. Chrysotile concentrations among workers who died shortly after the end of exposure were higher than among the referents (median difference in concentrations 13 million fibres (f)/g dry weight; p = 0.033, one sided). No quantitative differences in exposure (duration or intensity) could be shown between workers with high and low to intermediate concentrations. Interestingly, all seven workers who had had a high intensity at the end of exposure (> 2.5 f/ml), had low to intermediate chrysotile concentrations at death, whereas those with low exposure were evenly distributed (31 subjects in both concentration categories); hence, there was a dependence between last intensity of exposure and chrysotile concentration (p = 0.014). Among 14 workers with a high average intensity of exposure, both those (n = 5) with high tissue concentrations of chrysotile and those (n = 10) with high tissue concentrations of tremolite fibres had more pronounced fibrosis than those with low to intermediate concentrations (median fibrosis grades for chrysotile: 2 v 1, p = 0.021; for tremolite: 2 v 0.5, p = 0.012). Additionally, workers who died shortly after the end of exposure with high concentrations of chrysotile and

  1. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

    PubMed Central

    2012-01-01

    Background Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Methods Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. Results MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Conclusions Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors. PMID

  2. Radiation-Induced Oxidative Stress at Out-of-Field Lung Tissues after Pelvis Irradiation in Rats

    PubMed Central

    Najafi, Masoud; Fardid, Reza; Takhshid, Mohammad Ali; Mosleh-Shirazi, Mohammad Amin; Rezaeyan, Abol-Hassan; Salajegheh, Ashkan

    2016-01-01

    Objective The out-of-field/non-target effect is one of the most important phenomena of ionizing radiation that leads to molecular and cellular damage to distant non-irradiated tissues. The most important concern about this phenomenon is carcinogenesis many years after radiation treatment. In vivo mechanisms and consequences of this phenomenon are not known completely. Therefore, this study aimed to evaluate the oxidative damages to out-of-field lung tissues 24 and 72 hours after pelvic irradiation in rats. Materials and Methods In this experimentalinterventional study, Sprague-Dawleymale rats (n=49) were divided into seven groups (n=7/each group), including two groups of pelvis- exposed rats (out-of-field groups), two groups of whole bodyexposed rats (scatter groups), two groups of lung-exposed rats (direct irradiation groups), and one control sham group. Out- of-field groups were irradiated at a 2×2 cm area in the pelvis region with 3 Gy using 1.25 MeV cobalt-60 gamma-ray source, and subsequently, malondialdehyde (MDA) and glutathione (GSH) levels as well as superoxide dismutase (SOD) activity in out-of-field lung tissues were measured. Results were compared to direct irradiation, control and scatter groups at 24 and 72 hours after exposure. Data were analyzed using Mann-Whitney U test. Results SOD activity decreased in out-of-field lung tissue 24 and 72 hours after irradiation as compared with the controls and scatter groups. GSH level decreased 24 hours after exposure and increased 72 hours after exposure in the out-of-field groups as compared with the scatter groups. MDA level in out-of-field groups only increased 24 hours after irradiation. Conclusion Pelvis irradiation induced oxidative damage in distant lung tissue that led to a dramatic decrease in SOD activity. This oxidative stress was remarkable, but it was less durable as compared to direct irradiation. PMID:27602315

  3. Real-Time, In Vivo Determination of Dynamic Changes in Lung and Heart Tissue Oxygenation Using EPR Oximetry

    PubMed Central

    Rivera, Brian K.; Naidu, Shan K.; Subramanian, Kamal; Joseph, Matthew; Hou, Huagang; Khan, Nadeem; Swartz, Harold M.

    2015-01-01

    The use of electron paramagnetic resonance (EPR) oximetry for oxygen measurements in deep tissues (>1 cm) is challenging due to the limited penetration depth of the microwave energy. To overcome this limitation, implantable resonators, having a small (0 5 mm diameter) sensory loop containing the oxygen-sensing paramagnetic material connected by a pair of twisted copper wire to a coupling loop (8–10 mm diameter), have been developed, which enable repeated measurements of deep-tissue oxygen levels (pO2, partial pressure of oxygen) in the brain and tumors of rodents. In this study, we have demonstrated the feasibility of measuring dynamic changes in pO2 in the heart and lung of rats using deep-tissue implantable oxygen sensors. The sensory loop of the resonator contained lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) crystals embedded in polydimethylsiloxane (PDMS) polymer and was implanted in the myocardial tissue or lung pleura. The external coupling loop was secured subcutaneously above chest. The rats were exposed to different breathing gas mixtures while undergoing EPR measurements. The results demonstrated that implantable oxygen sensors provide reliable measurements of pO2 in deep tissues such as heart and lung under adverse conditions of cardiac and respiratory motions. PMID:24729218

  4. Assessment of the effects of ultrasound-mediated glucose on permeability of normal, benign, and cancerous human lung tissues with the Fourier-domain optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Wei, Huajiang; Wu, Guoyong; Guo, Zhouyi; Yang, Hongqin; He, Yonghong; Xie, Shusen; Guo, Xiao

    2012-11-01

    The objective of this study was to evaluate the effects of ultrasound-mediated analyte diffusion on permeability of normal, benign, and cancerous human lung tissue in vitro and to find more effective sonophoretic (SP) delivery in combination with the optical clearing agents (OCAs) method to distinguish normal and diseased lung tissues. The permeability coefficients of SP in combination with OCAs diffusion in lung tissue were measured with Fourier-domain optical coherence tomography (FD-OCT). 30% glucose and SP with a frequency of 1 MHz and an intensity of 0.80 W/cm2 over a 3 cm probe was simultaneously applied for 15 min. Experimental results show that the mean permeability coefficients of 30% glucose/SP were found to be (2.01±0.21)×10-5 cm/s from normal lung (NL) tissue, (2.75±0.28)×10-5 cm/s from lung benign granulomatosis (LBG) tissue, (4.53±0.49)×10-5 cm/s from lung adenocarcinoma tumor (LAT) tissue, and (5.81±0.62)×10-5 cm/s from lung squamous cell carcinoma (LSCC) tissue, respectively. The permeability coefficients of 30% glucose/SP increase approximately 36.8%, 125.4%, and 189.1% for the LBG, LAT, and LSCC tissue compared with that for the NL tissue, respectively. There were statistically significant differences in permeability coefficients of 30% glucose/SP between LBG and NL tissue (p<0.05), between LAT and NL tissue (p<0.05), and between LSCC and NL tissue (p<0.05). The results suggest that the OCT functional imaging technique to combine an ultrasound-OCAs combination method could become a powerful tool in early diagnosis and monitoring of changed microstructure of pathologic human lung tissue.

  5. Thermal Ablation of Lung Tissue: In Vivo Experimental Comparison of Microwave and Radiofrequency

    SciTech Connect

    Crocetti, Laura Bozzi, Elena; Faviana, Pinuccia; Cioni, Dania; Della Pina, Clotilde; Sbrana, Alberto; Fontanini, Gabriella; Lencioni, Riccardo

    2010-08-15

    This study was designed to compare feasibility, safety, and effectiveness of microwave (MW) ablation versus radiofrequency (RF) ablation of lung tissue in a rabbit model. Twenty New Zealand White rabbits were submitted to MW (n = 10, group A) or RF ablation (n = 10, group B). The procedures were performed with a prototype MW ablation device with a 1.6-cm radiating section antenna (Valleylab MW Ablation System) and with a 2-cm exposed-tip RF electrode (Cool-tip RF Ablation System). At immediate computed tomography increase in density, maximum diameters (D1-D3) of ablation zones were measured and ablation volume was calculated. Histopathologic assessment was performed 3 and 7 days after the procedure. Technical success was achieved in nine of 10 rabbits in each group. One death occurred in group B. Complications included pneumothorax (group A, n = 4; group B, n = 4), abscess (group A, n = 1; group B, n = 1), and thoracic wall burn (group A, n = 4). No significant differences were demonstrated in attenuation increase (P = 0.73), dimensions (P = 0.28, 0.86, 0.06, respectively, comparing D1-D3) and volume (P = 0.17). At histopathology, ablation zones were similar, with septal necrosis, edema, hemorrhage, and peripheral lymphocytic infiltrate. Complete thrombosis of more than 90% of vessels up to 2 mm in diameter was depicted at the periphery of the ablation zone in group A specimens. In group B specimens, complete thrombosis was depicted in 20% of vessels. Feasibility and safety of MW and RF ablation are similar in a lung rabbit model. MW ablation produces a greater damage to peripheral small vessels inducing thrombosis.

  6. Low levels of tissue factor lead to alveolar hemorrhage, potentiating murine acute lung injury and oxidative stress

    PubMed Central

    Bastarache, J.A.; Sebag, S. C.; Clune, J.K.; Grove, B.S.; Lawson, W.E.; Janz, D. R.; Roberts, L. J.; Dworski, R; Mackman, N.; Ware, L. B.

    2013-01-01

    Background Systemic blockade of Tissue Factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. Hypothesis We used mice with complete knockout of mouse TF and low levels (~1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. Methods LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal (IT) injection and studied at 24 hours. Results Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4 × 105 WT LPS versus 3.3 × 105 LTF LPS, p=0.947) and protein (493 μg/ml WT LPS versus 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS versus LTF LPS) and histology compared to wild type mice. LTF mice also had increased hemorrhage and free hemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F2-Isoprostanes and Isofurans). Conclusions These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar hemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit tissue factor may be deleterious in patients with ALI. PMID:23033361

  7. Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

    PubMed Central

    Pott, F; Stöber, W

    1983-01-01

    Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is

  8. Effects of Nigella sativa seed extract on ameliorating lung tissue damage in rats after experimental pulmonary aspirations.

    PubMed

    Kanter, Mehmet

    2009-01-01

    Aspiration of gastric contents can cause serious lung injury, although the mechanisms of pulmonary damage are still not clear and means of amelioration of the pulmonary damage have been little investigated. The black cumin seed, Nigella sativa L. (NS) has been shown to have specific health benefits and the aim of the current study was to investigate the possible beneficial effects of NS on experimental lung injury in male Wistar rats after pulmonary aspiration of different materials. The rats were randomly allotted into one of six experimental groups (n=7 per group): (1) saline control, (2) saline+NS treated, (3) Pulmocare (a specialized nutritional supplement given to pulmonary patients), (4) Pulmocare+NS treated, (5) hydrochloric acid, (6) hydrochloric acid+NS treated. The saline, Pulmocare and hydrochloric acid were injected into the lungs in a volume of 2 ml/kg. The rats received daily oral doses of NS volatile oil (400mg/kg body weight) by means of intragastric intubation for 7 days starting immediately after the pulmonary aspiration of the materials. After 7 days, the rats were sacrificed and tissue samples from both lungs were taken for histopathological investigation. To date, no similar study investigating the potential for NS treatment to protect against lung injury after pulmonary aspiration of materials has been reported. Our study showed that NS treatment inhibits the inflammatory pulmonary responses, reducing significantly (p<0.05) peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar macrophages, interstitial fibrosis, granuloma and necrosis formation in different pulmonary aspiration models. Our data indicate a significant reduction in the activity of inducible nitric oxide synthase (iNOS) and a rise in surfactant protein D in lung tissue of different pulmonary aspiration models after NS therapy. Based on our results, we conclude that NS treatment might be beneficial in lung injury and

  9. Buffer optimization for high resolution of human lung cancer tissue proteins by two-dimensional gel electrophoresis.

    PubMed

    Lee, Kibeom; Pi, Kyungbae; Lee, Keeman

    2009-01-01

    A problem in proteomic analysis of lung cancer tissue is the presence of complex components of different histological backgrounds (squamous cell carcinoma, small cell lung carcinoma, and adenocarcinoma). The efficient solubilization of protein components before two-dimensional electrophoresis (2-DE) is a very critical. Poor solubilization has been associated with a failure to detect proteins and diffuse, streaked and/or trailing protein spots. Here, we have optimized the solubilization of human lung cancer tissue to increase protein resolution. Isoelectric focusing (IEF) rehydration buffer containing a thiourea-urea mixture provided superior resolution, whereas a buffer without thiourea yielded consistently poor results. In addition, IEF rehydration buffers containing CHAPS and DTT gave superior resolution, whereas buffers containing Nonidet P-40 (NP-40) and/or Triton X-100 did not. A tributylphosphine-containing buffer gave consistently poor results. Using optimized conditions, we used 2-D gel analysis of human lung cancer tissue to identify 11 differentially-expressed protein spots by MALDI-mass spectrometry. This study provides a methodological tool to study the complex mammalian proteomes. PMID:18800191

  10. MicroRNA Profile of Lung Tumor Tissues Is Associated with a High Risk Plasma miRNA Signature.

    PubMed

    Fortunato, Orazio; Verri, Carla; Pastorino, Ugo; Sozzi, Gabriella; Boeri, Mattia

    2016-01-01

    Lung cancer is the most common cause of cancer deaths worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression. Many studies have reported that alterations in miRNA expression are involved in several human tumors. We have previously identified a circulating miRNA signature classifier (MSC) able to discriminate lung cancer with more aggressive features. In the present work, microarray miRNA profiling of tumor tissues collected from 19 lung cancer patients with an available MSC result were perform in order to find a possible association between miRNA expression and the MSC risk level. Eleven tissue mature miRNAs and six miRNA precursors were observed to be associated with the plasma MSC risk level of patients. Not one of these miRNAs was included in the MSC algorithm. A pathway enrichment analysis revealed a role of these miRNA in the main pathways determining lung cancer aggressiveness. Overall, these findings add to the knowledge that tissue and plasma miRNAs behave as excellent diagnostic and prognostic biomarkers, which may find rapid application in clinical settings. PMID:27600084

  11. Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats.

    PubMed

    Ebrahimi, Ammar; Kardar, Gholam Ali; Teimoori-Toolabi, Ladan; Toolabi, LadanTeimoori; Ghanbari, Hossein; Sadroddiny, Esmaeil

    2016-01-15

    Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. PMID:26506443

  12. Use of human lung tissue for studies of structural changes associated with chronic ozone exposure: Opportunities and critical issues

    SciTech Connect

    Lippmann, M.

    1993-12-01

    Definitive information on the chronic effects of exposure to ozone (O{sub 3}) in humans is not available. There is a strong concern that ozone could produce chronic lung damage in humans on the basis that exposures are ubiquitous at levels that produce transient symptoms, function deficits, and lung inflammation in humans and chronic lung damage in laboratory animals. Both prospective and national population surveys suggest an association between chronic O{sub 3} exposure and reduced lung function, and a pilot investigation of autopsied lungs of accident victims in Los Angeles reported an unexpectedly high incidence of disease in the centriacinar region, the lung region known to receive the highest dose of inhaled O{sub 3}. This paper discusses the advantages and limitations of further studies of structural changes in human lung tissue in relation to chronic O{sub 3} exposure. The major advantages of such studies are that (a) measurable effects may be related to realistic chronic exposures, (b) the effects may be described quantitatively and compared directly to those obtained in chronic animal inhalation exposures, and (c) evidence for chronic effects may be obtained much more rapidly than in prospective studies. The major limitations are the difficulties in obtaining sufficient reliable information on residential history, physical activity out-of-doors, and smoking and other confounding exposures to lung irritants from next of kin, and limited availability of adequate air quality data for determining ambient concentrations at places of residence and/or outdoor exercise. The paper also discusses approaches to minimizing these limitations in the design of specific studies. 15 refs.

  13. Decay-Accelerating Factor Mitigates Controlled Hemorrhage-Instigated Intestinal and Lung Tissue Damage and Hyperkalemia in Swine

    PubMed Central

    Dalle Lucca, Jurandir J.; Simovic, Milomir; Li, Yansong; Moratz, Chantal; Falabella, Michael; Tsokos, George C.

    2012-01-01

    Background Activation of complement system has been associated with tissue injury after hemorrhage and resuscitation in rats and swine. This study investigated whether administration of human recombinant decay-accelerating factor (DAF; a complement regulatory protein that inhibits classical and alternative pathways) reduces tissue damage in a porcine model of hemorrhagic shock. Methods Male Yorkshire swine assigned to four groups were subjected to controlled, isobaric hemorrhage over 15 minutes to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 minutes followed by a bolus intravenous injection of DAF or vehicle then animals were observed for 200 minutes. Blood chemistry and physiological parameters were recorded. Tissue samples from lung and small intestine were subjected to histopathological evaluation and detection of tissue deposition of complement proteins by immunohistochemistry and Western blot analyses. Results Administration of DAF significantly reduced intestinal and lung tissue damage in a dose-dependent manner (5, 25, and 50 µg/kg). In addition, DAF treatment improved hemorrhage-induced hyperkalemia. The protective effects of DAF appear to be related to its ability to reduce tissue complement activation and deposition on affected tissues. Conclusions DAF treatment decreased tissue complement activation and deposition in hemorrhaged animals and attenuated tissue damage at 200 minutes post treatment. The observed beneficial effects of DAF treatment on tissue injury after 20 minutes of severe hypotension presents an attractive model of small volume resuscitation, particularly in situations with a restrictive medical logistical footprint such as far-forward access to first responders in the battlefield or in remote rural or mountainous environments. PMID:21795874

  14. FORMATION OF SLOW-REACTING SUBSTANCE OF ANAPHYLAXIS IN HUMAN LUNG TISSUE AND CELLS BEFORE RELEASE

    PubMed Central

    Lewis, Robert A.; Wasserman, Stephen I.; Goetzl, Edward J.; Austen, K. Frank

    1974-01-01

    The capacity to extract slow-reacting substance of anaphylaxis (SRS-A) from human lung tissue or cells after immunologic activation, together with the measurement of SRS-A in both the extract and the surrounding fluid, permits study of total SRS-A generation. That the material extracted is SRS-A was established by both differential bioassay and purification. SRS-A accumulation was entirely intracellular after limited IgE-dependent direct or reversed anaphylactic activation. Intracellular accumulation also generally preceded release, with generation of SRS-A continuing well beyond a plateau in the cellular SRS-A level and the release of preformed mediators. The quantity of SRS-A generated after immunologic activation was modulated by the introduction of exogenous cyclic nucleotides, revealing a site of cyclic nucleotide action distinct from that on mediator release. The capacity to determine not only the release of preformed mediators but also the generation of a newly formed mediator, the sum of SRS-A in cells and supernate, adds an additional dimension to the analysis of the cellular events of immediate hypersensitivity. PMID:4378429

  15. Autofluorescence spectroscopy of normal and malignant tissues: both in-vivo and ex-vivo measurements in the upper aero-digestive tract and lung tissues

    NASA Astrophysics Data System (ADS)

    A'Amar, Ousama M.; Lignon, Dominique; Menard, O.; Begorre, Henri; Guillemin, Francois H.; Yvroud, Edouard

    1996-04-01

    A spectroscopic system with flexible three optical fiber sensor had been developed to study tissue fluorescence for a clinical use. Autofluorescence spectra at 413 nm and 10 mW excitation light power from different tissues in oral cavity had been measured in vivo in 25 subjects. The correlation coefficient in spectral shape between individual spectra and the mean emission spectrum of each site was about 0.9 and fluorescence intensity variation ranged between 20% and 45% according to the examined site. The variation in fluorescence intensity of the main emission wavelength at about 520 nm between spectra of the lower part of tongue, gingiva, lips, floor of cavity, cheek and palate was not statistically significant. But the spectrum of the upper part of tongue had been characterized by an additional peak around 635 nm. Otherwise, autofluorescence spectra at 410 nm and 0.5 mW excitation light power of 8 carcinoma of buccal and lung tissues were measured. The fluorescence ratio at 520 emission peak between normal tissue and carcinoma was evaluated at a maximum value of 13 for a lung cancer (ex vivo measurement) and a minimum of 3.3 for a cancer of the oro-pharynx (in vivo measurement). On the other hand, a fluorescence peak at 635 nm had characterized the carcinoma of the floor of cavity and the upper part of tongue.

  16. Ischemia and reperfusion of the lung tissues induced increase of lung permeability and lung edema is attenuated by dimethylthiourea (PP69).

    PubMed

    Chen, K H; Chao, D; Liu, C F; Chen, C F; Wang, D

    2010-04-01

    This study sought to determine whether oxygen radical scavengers of dimethylthiourea (DMTU), superoxide dismutase (SOD), or catalase (CAT) pretreatment attenuated ischemia-reperfusion (I/R)-induced lung injury. After isolation from a Sprague-Dawley rat, the lungs were perfused through the pulmonary artery cannula with rat whole blood diluted 1:1 with a physiological salt solution. An acute lung injury was induced by 10 minutes of hypoxia with 5% CO2-95% N2 followed by 65 minutes of ischemia and then 65 minutes of reperfusion. I/R significantly increased microvascular permeability as measured by the capillary filtration coefficient (Kfc), lung weight-to-body weight ratio (LW/BW), and protein concentration in bronchoalveolar lavage fluid (PCBAL). DMTU pretreatment significantly attenuated the acute lung injury. The capillary filtration coefficient (P<.01), LW/BW (P<.01) and PCBAL (P<.05) were significantly lower among the DMTU-treated rats than hosts pretreated with SOD or CAT. The possible mechanisms of the protective effect of DMTU in I/R-induced lung injury may relate to the permeability of the agent allowing it to scavenge intracellular hydroxyl radicals. However, whether superoxide dismutase or catalase antioxidants showed protective effects possibly due to their impermeability of the cell membrane not allowing scavenging of intracellular oxygen radicals. PMID:20430163

  17. Dynamic dual-energy chest radiography: a potential tool for lung tissue motion monitoring and kinetic study

    NASA Astrophysics Data System (ADS)

    Xu, Tong; Ducote, Justin L.; Wong, Jerry T.; Molloi, Sabee

    2011-02-01

    Dual-energy chest radiography has the potential to provide better diagnosis of lung disease by removing the bone signal from the image. Dynamic dual-energy radiography is now possible with the introduction of digital flat-panel detectors. The purpose of this study is to evaluate the feasibility of using dynamic dual-energy chest radiography for functional lung imaging and tumor motion assessment. The dual-energy system used in this study can acquire up to 15 frames of dual-energy images per second. A swine animal model was mechanically ventilated and imaged using the dual-energy system. Sequences of soft-tissue images were obtained using dual-energy subtraction. Time subtracted soft-tissue images were shown to be able to provide information on regional ventilation. Motion tracking of a lung anatomic feature (a branch of pulmonary artery) was performed based on an image cross-correlation algorithm. The tracking precision was found to be better than 1 mm. An adaptive correlation model was established between the above tracked motion and an external surrogate signal (temperature within the tracheal tube). This model is used to predict lung feature motion using the continuous surrogate signal and low frame rate dual-energy images (0.1-3.0 frames per second). The average RMS error of the prediction was (1.1 ± 0.3) mm. The dynamic dual energy was shown to be potentially useful for lung functional imaging such as regional ventilation and kinetic studies. It can also be used for lung tumor motion assessment and prediction during radiation therapy.

  18. Isolation, in vitro culture and identification of a new type of mesenchymal stem cell derived from fetal bovine lung tissues

    PubMed Central

    HU, PENGFEI; PU, YABIN; LI, XIAYUN; ZHU, ZHIQIANG; ZHAO, YUHUA; GUAN, WEIJUN; MA, YUEHUI

    2015-01-01

    Lung-derived mesenchymal stem cells (LMSCs) are considered to be important in lung tissue repair and regenerative processes. However, the biological characteristics and differentiation potential of LMSCs remain to be elucidated. In the present study, fetal lung-derived mesenchymal stem cells (FLMSCs) were isolated from fetal bovine lung tissues by collagenase digestion. The in vitro culture conditions were optimized and stabilized and the self-renewal ability and differentiation potential were evaluated. The results demonstrated that the FLMSCs were morphologically consistent with fibroblasts, were able to be cultured and passaged for at least 33 passages and the cell morphology and proliferative ability were stable during the first 10 passages. In addition, FLMSCs were found to express CD29, CD44, CD73 and CD166, however, they did not express hematopoietic cell specific markers, including CD34, CD45 and BOLA-DRα. The growth kinetics of FLMSCs consisted of a lag phase, a logarithmic phase and a plateau phase, and as the passages increased, the proliferative ability of cells gradually decreased. The majority of FLMSCs were in G0/G1 phase. Following osteogenic induction, FLMSCs were positive for the expression of osteopontin and collagen type I α2. Following neurogenic differentiation, the cells were morphologically consistent with neuronal cells and positive for microtubule-associated protein 2 and nestin expression. It was concluded that the isolated FLMSCs exhibited typical characteristics of mesenchymal stem cells and that the culture conditions were suitable for their proliferation and the maintenance of stemness. The present study illustrated the potential application of lung tissue as an adult stem cell source for regenerative therapies. PMID:26016556

  19. Response of rodents to inhaled diluted diesel exhaust: biochemical and cytological changes in bronchoalveolar lavage fluid and in lung tissue

    SciTech Connect

    Henderson, R.F.; Pickrell, J.A.; Jones, R.K.; Sun, J.D.; Benson, J.M.; Mauderly, J.L.; McClellan, R.O.

    1988-10-01

    The effect of long-term (24 months) inhalation of diesel exhaust on the bronchoalveolar region of the respiratory tract of rodents was assessed by serial (every 6 months) analysis of bronchoalveolar lavage fluid (BALF) and of lung tissue from F344/Crl rats and CD-1 mice (both sexes) exposed to diesel exhaust diluted to contain 0, 0.35, 3.5, or 7.0 mg soot/m3. The purpose of the study was twofold. One was to assess the potential health effects of inhaling diluted exhaust from light-duty diesel engines. The second was to determine the usefulness of BALF analysis in detecting the early stages in the development of nononcogenic lung disease and differentiating them from the normal repair processes. No biochemical or cytological changes in BALF or in lung tissue were noted in either species exposed to the lowest, and most environmentally relevant, concentration of diesel exhaust. In the two higher levels of exposure, a chronic inflammatory response was measured in both species by dose-dependent increases in inflammatory cells, cytoplasmic and lysosomal enzymes, and protein in BALF. Histologically, after 1 year of exposure, the rats had developed focal areas of fibrosis associated with the deposits of soot, while the mice, despite a higher lung burden of soot than the rats, had only a fine fibrillar thickening of an occasional alveolar septa in the high-level exposure group. Higher increases in BALF beta-glucuronidase activity and in hydroxyproline content accompanied the greater degree of fibrosis in the rat. BALF levels of glutathione (GSH) and glutathione reductase activity increased in a dose-dependent fashion and were higher in mice than in rats. Lung tissue GSH was depleted in a dose-dependent fashion in rats but was slightly increased in mice.

  20. Individualized Radical Radiotherapy of Non-Small-Cell Lung Cancer Based on Normal Tissue Dose Constraints: A Feasibility Study

    SciTech Connect

    Baardwijk, Angela van Bosmans, Geert; Boersma, Liesbeth; Wanders, Stofferinus; Dekker, Andre; Dingemans, Anne Marie C.; Bootsma, Gerben; Geraedts, Wiel; Pitz, Cordula; Simons, Jean; Lambin, Philippe; Ruysscher, Dirk de

    2008-08-01

    Purpose: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. Methods and Materials: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An {sup 18}F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. Results: Mean delivered dose was 63.0 {+-} 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. Conclusions: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.

  1. The effect of lead acetate on oxidative stress and antioxidant status in rat bronchoalveolar lavage fluid and lung tissue.

    PubMed

    Samarghandian, Saeed; Borji, Abasalt; Afshari, Reza; Delkhosh, Mohammad Bagher; gholami, Ali

    2013-07-01

    Despite the wide spread of lead environmental pollution, the effect of this heavy metal on respiratory disease was not shown yet. In respect to increased oxidative stress is an important mechanism in the pathogenesis of respiratory disease, the present study was designed to examine the association between lead toxicity and lung disease via measuring oxidative stress biomarkers in bronchoalveolar lavage fluid (BALF) and lung tissue of rat. For this aim, 32 rats were divided into the following groups of eight animals each: control, three lead tested (received lead acetate in the drinking water for a period of 14 d at concentrations of 250, 500 and 1000 ppm) groups. At the end of the 2 week period, malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) contents were measured to assess free radical activity in the BALF and lung tissue. Superoxide dismutase (SOD) was also determined. A significant dose-dependent increase in the BALF supernatant and lung homogenate levels of MDA and NO with decrease GSH level and SOD activity were observed in the lead-treated groups compared with the control group (p < 0.05). Thus, lead acetate may be contributed to respiratory disorders via increased oxidative stress. PMID:23419166

  2. The interaction of asbestos and iron in lung tissue revealed by synchrotron-based scanning X-ray microscopy

    PubMed Central

    Pascolo, Lorella; Gianoncelli, Alessandra; Schneider, Giulia; Salomé, Murielle; Schneider, Manuela; Calligaro, Carla; Kiskinova, Maya; Melato, Mauro; Rizzardi, Clara

    2013-01-01

    Asbestos is a potent carcinogen associated with malignant mesothelioma and lung cancer but its carcinogenic mechanisms are still poorly understood. Asbestos toxicity is ascribed to its particular physico-chemical characteristics, and one of them is the presence of and ability to adsorb iron, which may cause an alteration of iron homeostasis in the tissue. This observational study reports a combination of advanced synchrotron-based X-ray imaging and micro-spectroscopic methods that provide correlative morphological and chemical information for shedding light on iron mobilization features during asbestos permanence in lung tissue. The results show that the processes responsible for the unusual distribution of iron at different stages of interaction with the fibres also involve calcium, phosphorus and magnesium. It has been confirmed that the dominant iron form present in asbestos bodies is ferritin, while the concurrent presence of haematite suggests alteration of iron chemistry during asbestos body permanence. PMID:23350030

  3. Forcing lateral electron disequilibrium to spare lung tissue: a novel technique for stereotactic body radiation therapy of lung cancer

    NASA Astrophysics Data System (ADS)

    Disher, Brandon; Hajdok, George; Gaede, Stewart; Mulligan, Matthew; Battista, Jerry J.

    2013-10-01

    Stereotactic body radiation therapy (SBRT) has quickly become a preferred treatment option for early-stage lung cancer patients who are ineligible for surgery. This technique uses tightly conformed megavoltage (MV) x-ray beams to irradiate a tumour with ablative doses in only a few treatment fractions. Small high energy x-ray fields can cause lateral electron disequilibrium (LED) to occur within low density media, which can reduce tumour dose. These dose effects may be challenging to predict using analytic dose calculation algorithms, especially at higher beam energies. As a result, previous authors have suggested using low energy photons (<10 MV) and larger fields (>5 × 5 cm2) for lung cancer patients to avoid the negative dosimetric effects of LED. In this work, we propose a new form of SBRT, described as LED-optimized SBRT (LED-SBRT), which utilizes radiotherapy (RT) parameters designed to cause LED to advantage. It will be shown that LED-SBRT creates enhanced dose gradients at the tumour/lung interface, which can be used to manipulate tumour dose, and/or normal lung dose. To demonstrate the potential benefits of LED-SBRT, the DOSXYZnrc (National Research Council of Canada, Ottawa, ON) Monte Carlo (MC) software was used to calculate dose within a cylindrical phantom and a typical lung patient. 6 MV or 18 MV x-ray fields were focused onto a small tumour volume (diameter ˜1 cm). For the phantom, square fields of 1 × 1 cm2, 3 × 3 cm2, or 5 × 5 cm2 were applied. However, in the patient, 3 × 1 cm2, 3 × 2 cm2, 3 × 2.5 cm2, or 3 × 3 cm2 field sizes were used in simulations to assure target coverage in the superior-inferior direction. To mimic a 180° SBRT arc in the (symmetric) phantom, a single beam profile was calculated, rotated, and beams were summed at 1° segments to accumulate an arc dose distribution. For the patient, a 360° arc was modelled with 36 equally weighted (and spaced) fields focused on the tumour centre. A planning target volume (PTV) was

  4. Forcing lateral electron disequilibrium to spare lung tissue: a novel technique for stereotactic body radiation therapy of lung cancer.

    PubMed

    Disher, Brandon; Hajdok, George; Gaede, Stewart; Mulligan, Matthew; Battista, Jerry J

    2013-10-01

    Stereotactic body radiation therapy (SBRT) has quickly become a preferred treatment option for early-stage lung cancer patients who are ineligible for surgery. This technique uses tightly conformed megavoltage (MV) x-ray beams to irradiate a tumour with ablative doses in only a few treatment fractions. Small high energy x-ray fields can cause lateral electron disequilibrium (LED) to occur within low density media, which can reduce tumour dose. These dose effects may be challenging to predict using analytic dose calculation algorithms, especially at higher beam energies. As a result, previous authors have suggested using low energy photons (<10 MV) and larger fields (>5 × 5 cm(2)) for lung cancer patients to avoid the negative dosimetric effects of LED. In this work, we propose a new form of SBRT, described as LED-optimized SBRT (LED-SBRT), which utilizes radiotherapy (RT) parameters designed to cause LED to advantage. It will be shown that LED-SBRT creates enhanced dose gradients at the tumour/lung interface, which can be used to manipulate tumour dose, and/or normal lung dose. To demonstrate the potential benefits of LED-SBRT, the DOSXYZnrc (National Research Council of Canada, Ottawa, ON) Monte Carlo (MC) software was used to calculate dose within a cylindrical phantom and a typical lung patient. 6 MV or 18 MV x-ray fields were focused onto a small tumour volume (diameter ∼1 cm). For the phantom, square fields of 1 × 1 cm(2), 3 × 3 cm(2), or 5 × 5 cm(2) were applied. However, in the patient, 3 × 1 cm(2), 3 × 2 cm(2), 3 × 2.5 cm(2), or 3 × 3 cm(2) field sizes were used in simulations to assure target coverage in the superior-inferior direction. To mimic a 180° SBRT arc in the (symmetric) phantom, a single beam profile was calculated, rotated, and beams were summed at 1° segments to accumulate an arc dose distribution. For the patient, a 360° arc was modelled with 36 equally weighted (and spaced) fields focused on the tumour

  5. SU-E-T-573: Normal Tissue Dose Effect of Prescription Isodose Level Selection in Lung Stereotactic Body Radiation Therapy

    SciTech Connect

    Zhang, Q; Lei, Y; Zheng, D; Zhu, X; Wahl, A; Lin, C; Zhou, S; Zhen, W

    2015-06-15

    Purpose: To evaluate dose fall-off in normal tissue for lung stereotactic body radiation therapy (SBRT) cases planned with different prescription isodose levels (IDLs), by calculating the dose dropping speed (DDS) in normal tissue on plans computed with both Pencil Beam (PB) and Monte-Carlo (MC) algorithms. Methods: The DDS was calculated on 32 plans for 8 lung SBRT patients. For each patient, 4 dynamic conformal arc plans were individually optimized for prescription isodose levels (IDL) ranging from 60% to 90% of the maximum dose with 10% increments to conformally cover the PTV. Eighty non-overlapping rind structures each of 1mm thickness were created layer by layer from each PTV surface. The average dose in each rind was calculated and fitted with a double exponential function (DEF) of the distance from the PTV surface, which models the steep- and moderate-slope portions of the average dose curve in normal tissue. The parameter characterizing the steep portion of the average dose curve in the DEF quantifies the DDS in the immediate normal tissue receiving high dose. Provided that the prescription dose covers the whole PTV, a greater DDS indicates better normal tissue sparing. The DDS were compared among plans with different prescription IDLs, for plans computed with both PB and MC algorithms. Results: For all patients, the DDS was found to be the lowest for 90% prescription IDL and reached a highest plateau region for 60% or 70% prescription. The trend was the same for both PB and MC plans. Conclusion: Among the range of prescription IDLs accepted by lung SBRT RTOG protocols, prescriptions to 60% and 70% IDLs were found to provide best normal tissue sparing.

  6. Integrative Proteomics and Tissue Microarray Profiling Indicate the Association between Overexpressed Serum Proteins and Non-Small Cell Lung Cancer

    PubMed Central

    Hu, Haichuan; Wang, Rui; Sun, Yihua; Zeng, Rong; Chen, Haiquan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide. Clinically, the treatment of non-small cell lung cancer (NSCLC) can be improved by the early detection and risk screening among population. To meet this need, here we describe the application of extensive peptide level fractionation coupled with label free quantitative proteomics for the discovery of potential serum biomarkers for lung cancer, and the usage of Tissue microarray analysis (TMA) and Multiple reaction monitoring (MRM) assays for the following up validations in the verification phase. Using these state-of-art, currently available clinical proteomic approaches, in the discovery phase we confidently identified 647 serum proteins, and 101 proteins showed a statistically significant association with NSCLC in our 18 discovery samples. This serum proteomic dataset allowed us to discern the differential patterns and abnormal biological processes in the lung cancer blood. Of these proteins, Alpha-1B-glycoprotein (A1BG) and Leucine-rich alpha-2-glycoprotein (LRG1), two plasma glycoproteins with previously unknown function were selected as examples for which TMA and MRM verification were performed in a large sample set consisting about 100 patients. We revealed that A1BG and LRG1 were overexpressed in both the blood level and tumor sections, which can be referred to separate lung cancer patients from healthy cases. PMID:23284758

  7. SU-E-T-572: Normal Lung Tissue Sparing in Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

    SciTech Connect

    Hong, C; Ju, S; Ahn, Y

    2015-06-15

    Purpose: To compare normal lung-sparing capabilities of three advanced radiation therapy techniques for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Four-dimensional computed tomography (4DCT) was performed in 10 patients with stage IIIb LA-NSCLC. The internal target volume (ITV); planning target volume (PTV); and organs at risks (OARs) such as spinal cord, total normal lung, heart, and esophagus were delineated for each CT data set. Intensity-modulated radiation therapy (IMRT), Tomohelical-IMRT (TH-IMRT), and TomoDirect-IMRT (TD-IMRT) plans were generated (total prescribed dose, 66 Gy in 33 fractions to the PTV) for each patient. To reduce the normal lung dose, complete and directional block function was applied outside the normal lung far from the target for both TH-IMRT and TD-IMRT, while pseudo- OAR was set in the same region for IMRT. Dosimetric characteristics of the three plans were compared in terms of target coverage, the sparing capability for the OAR, and the normal tissue complication probability (NTCP). Beam delivery efficiency was also compared. Results: TH-IMRT and TD-IMRT provided better target coverage than IMRT plans. Lung volume receiving ≥–30 Gy, mean dose, and NTCP were significant with TH-IMRT than with IMRT (p=0.006), and volume receiving ≥20–30 Gy was lower in TD-IMRT than in IMRT (p<0.05). Compared with IMRT, TH-IMRT had better sparing effect on the spinal cord (Dmax, NTCP) and heart (V45) (p<0.05). NTCP for the spinal cord, V45 and V60 for the heart, and Dmax for the esophagus were significantly lower in TD-IMRT than in IMRT. The monitor units per fraction were clearly smaller for IMRT than for TH-IMRT and TD-IMRT (p=0.006). Conclusion: In LA-NSCLC, TH-IMRT gave superior PTV coverage and OAR sparing compared to IMRT. TH-IMRT provided better control of the lung volume receiving ≥5–30 Gy. The delivery time and monitor units were lower in TD-IMRT than in TH-IMRT.

  8. Combination effects of tissue heterogeneity and geometric targeting error in stereotactic body radiotherapy for lung cancer using CyberKnife.

    PubMed

    Kang, Ki Mun; Jeong, Bae Kwon; Choi, Hoon-Sik; Yoo, Seung Hoon; Hwang, Ui-Jung; Lim, Young Kyung; Jeong, Hojin

    2015-01-01

    We have investigated the combined effect of tissue heterogeneity and its variation associated with geometric error in stereotactic body radiotherapy (SBRT) for lung cancer. The treatment plans for eight lung cancer patients were calculated using effective path length (EPL) correction and Monte Carlo (MC) algorithms, with both having the same beam configuration for each patient. These two kinds of plans for individual patients were then subsequently recalculated with adding systematic and random geometric errors. In the ordinary treatment plans calculated with no geometric offset, the EPL calculations, compared with the MC calculations, largely overestimated the doses to PTV by ~ 21%, whereas the overestimation were markedly lower in GTV by ~ 12% due to relatively higher density of GTV than of PTV. When recalculating the plans for individual patients with assigning the systematic and random geometric errors, no significant changes in the relative dose distribution, except for overall shift, were observed in the EPL calculations, whereas largely altered in the MC calculations with a consistent increase in dose to GTV. Considering the better accuracy of MC than EPL algorithms, the present results demonstrated the strong coupling of tissue heterogeneity and geometric error, thereby emphasizing the essential need for simultaneous correction for tissue heterogeneity and geometric targeting error in SBRT of lung cancer. PMID:26699300

  9. Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue

    PubMed Central

    2011-01-01

    Introduction Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients. Methods We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student's t-test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test. Results Thirty-one ARDS patients (A: PaO2/FiO2 ≤200, 45 ± 14 years, 16 males) and 11 controls (C: 52 ± 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 ± 27.2%, C:76.7 ± 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 ± 35.2%, C:21.8 ± 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 ± 54.3 μm, C:86.4 ± 33.3 μm, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P ≤0.03). The extension of normal epithelium

  10. When is pneumonia not pneumonia: a clinicopathologic study of the utility of lung tissue biopsies in determining the suitability of cadaveric tissue for donation.

    PubMed

    Kubilay, Zeynep; Layon, A Joseph; Baer, Herman; Archibald, Lennox K

    2016-06-01

    Healthcare-associated pneumonia (HCAP) represents a major diagnostic challenge because of the relatively low sensitivity and specificity of clinical criteria, radiological findings, and microbiologic culture results. It is often difficult to distinguish between pneumonia, underlying pulmonary disease, or conditions with pulmonary complications; this is compounded by the often-subjective clinical diagnosis of pneumonia. We conducted this study to determine the utility of post-mortem lung biopsies for diagnosing pneumonia in tissue donors diagnosed with pneumonia prior to death. Subjects were deceased patients who had been hospitalized at death and diagnosed with pneumonia. Post-mortem lung biopsies were obtained from the anatomic portion of the cadaveric lung corresponding to chest radiograph abnormalities. Specimens were fixed, stained with hematoxylin and eosin, and read by a single board-certified pathologist. Histological criteria for acute pneumonia included intense neutrophilic infiltration, fibrinous exudates, cellular debris, necrosis, or bacteria in the interstitium and intra-alveolar spaces. Of 143 subjects with a diagnosis of pneumonia at time of death, 14 (9.8 %) had histological evidence consistent with acute pneumonia. The most common histological diagnoses were emphysema (53 %), interstitial fibrosis (40 %), chronic atelectasis (36 %), acute and chronic passive congestion consistent with underlying cardiomyopathy (25 %), fibro-bullous disease (12 %), and acute bronchitis (11 %). HCAP represents a major diagnostic challenge because of the relatively low sensitivity and specificity of clinical criteria, radiological findings, and microbiologic testing. We found that attending physician-diagnosed pneumonia did not correlate with post-mortem pathological diagnosis. We conclude that histological examination of cadaveric lung tissue biopsies enables ascertainment or rule out of underlying pneumonia and prevents erroneous donor deferrals. PMID