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Sample records for exfoliated pulmonary cells

  1. Nuclear anomalies in exfoliated buccal cells in Pakistani cotton weavers.

    PubMed

    Khan, Abdul Wali; Nersesyan, Armen; Knasmüller, Siegfried; Moshammer, Hanns; Kundi, Michael

    2015-09-01

    Cotton workers in small weaving household factories (power looms) in Pakistan are typically exposed to high levels of cotton dusts. Working in the textile manufacturing industry has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer. The study set out to determine potential cytotoxic and genotoxic effects of occupational exposure to cotton dusts in exfoliated buccal cells of exposed cotton workers. Nuclear anomalies reflecting cytotoxic and genotoxic effects were evaluated in a representative sample of 51 exposed male cotton weavers and in the same number of age-matched male non-exposed subjects applying the micronucleus cytome assay. Nuclear anomalies reflecting cytotoxicity (karyolysis, karyorrhexis, condensed chromatin and pyknosis) were significantly elevated in exposed cotton workers. The frequency of micronucleated cells increased significantly with increasing years of work in power looms (odds ratio = 1.043 per year; 95% confidence interval: 1.012-1.076, P = 0.007). Results were consistent with the typical inflammatory pattern and injury in epithelia due to unprotected occupational exposure to cotton dusts and other toxic, allergic and infectious substances in the working areas of the cotton industry. Occupational exposure in power looms induces cytotoxic effects and, upon chronic exposure, DNA damage. This may eventually result in typical obstructive patterns of pulmonary symptoms and in a clinical condition called byssinosis in exposed cotton workers. Long exposure may lead to chronic inflammation and cumulative damage of DNA in buccal stem cells that may indicate an increased risk of oropharyngeal cancer. PMID:25805022

  2. Immunofluorescent Detection of Herpesvirus Antigens in Exfoliated Cells from Human Cervical Carcinoma

    PubMed Central

    Royston, Ivor; Aurelian, Laure

    1970-01-01

    Exfoliated cells from patients with squamous carcinoma of the cervix contain antigens related to herpesvirus subtype 2, as revealed by direct or indirect immunofluorescent techniques. Normal squamous cells from the same subjects and from controls without the disease, and cells from a small number of tumors at sites other than the cervix, did not react with anti-herpesvirus subtype 2 serum. Antisera to adenovirus 18 or mycoplasma orale did not react with the exfoliated cells. Images PMID:4318779

  3. [Pulmonary Langerhans cell histiocytosis].

    PubMed

    Popper, H H

    2015-09-01

    Pulmonary Langerhans cell histiocytosis is regarded as a reactive proliferation of the dendritic Langerhans cell population stimulated by chronic tobacco-derived plant proteins due to incomplete combustion but can also occur in childhood as a tumor-like systemic disease. Currently, both these forms cannot be morphologically distinguished. In the lungs a nodular proliferation of Langerhans cells occurs in the bronchial mucosa and also peripherally in the alveolar septa with an accompanying infiltration by eosinophilic granulocytes and destruction of the bronchial wall. Langerhans cells can be selectively detected with antibodies against CD1a and langerin. In the reactive isolated pulmonary form, abstinence from tobacco smoking in most patients leads to regression of infiltration and improvement of symptoms. In high-resolution computed tomography (HRCT) the small star-like scars can still be detected even after complete cessation of tobacco smoking. PMID:26289803

  4. Pulmonary langerhans cell histiocytosis

    PubMed Central

    2012-01-01

    Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation. PMID:22429393

  5. The effect of the non-steroidal anti-inflammatory drug choline magnesium trisalicylate on gastric mucosal cell exfoliation.

    PubMed

    Mitchell, K G; Hearns, J; Crean, G P

    1984-01-01

    Gastric mucosal cell exfoliation was measured in 10 normal subjects taking choline magnesium trisalicylate (CMT), aspirin and placebo. Both drugs resulted in significantly elevated rates of exfoliation although the serum salicylate levels achieved with aspirin were lower than those achieved by CMT. Side-effects of tinnitus, nausea and increased faecal blood loss were more common while subjects were taking CMT. PMID:6691886

  6. Pulmonary Langerhans cell Histiocytosis.

    PubMed

    Harari, S; Comel, A

    2001-10-01

    Pulmonary Langerhans cell Histiocytosis is a rare granulomatous disease affecting both sexes, with greater incidence in the second and third decades of life; smoking appears to be the most important risk factor. Its etiology is unknown, although there are data indicating an uncontrolled immune response as possible cause, sustained by the Langerhans cells, antigen presenting cells for T lymphocytes, and their accumulation in the distal bronchioles; these cells express on their surface the CD1a and CD1c antigens, and the B7 molecule, essential for activating quiescent T lymphocytes. In its evolution the granuloma is characterized by the progressive reduction in the LC number, with the increase of fibrosis, surrounding and destroying the bronchiolar lumen; the remaining of the lumen, or the traction exerted by fibrous tissue on the adjacent alveolar spaces leads to the cyst development. Vascular involvement occurs frequently, and may explain the onset of pulmonary hypertension in advanced cases of the disease. The disease may be asymptomatic, or it may present with aspecific respiratory signs and symptoms, and has characteristic radiological findings, being included in the group of cysticaerial parenchymal alterations. The diagnosis could be suggested by the finding of a number of LC in BAL greater than 5%. Different therapies have been proposed, but it seems that the most important measure is smoking cessation. PMID:11587096

  7. Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth

    PubMed Central

    ZHANG, NAN; CHEN, BAOXING; WANG, WEI; CHEN, CHAO; KANG, JIE; DENG, SAMUEL QINNAN; ZHANG, BIN; LIU, SHUWEI; HAN, FABIN

    2016-01-01

    The aim of the present study was to isolate stem cells from human exfoliated deciduous teeth (SHEDs) and identify their phenotypes and multi-lineage differentiation potential. Three SHED cell strains were successfully isolated from three exfoliated deciduous teeth from different human subjects using the outgrowth method. Flow cytometric analysis indicated that SHEDs displayed high expression of the mesenchymal cell markers CD73 and CD90 but low expression of the hematopoietic stem cell marker CD34. PCR analysis illustrated that SHEDs expressed the mesenchymal stem cell markers CD44, CD73 and CD90, the osteoblast markers Alpl, Runx2, CBFA1 and collagen I, the cartilage cell markers Col10a1 and Acan, the adipose cell markers PPARγ2 and LPL, and the neuronal stem cell marker Nestin. In vitro induction experiments demonstrated the potential of the SHEDs for osteogenic, adipogenic and neurogenic differentiation. These SHED cells may be useful for further stem cell research and future therapeutic applications. PMID:27151462

  8. Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth.

    PubMed

    Zhang, Nan; Chen, Baoxing; Wang, Wei; Chen, Chao; Kang, Jie; Deng, Samuel Qinnan; Zhang, Bin; Liu, Shuwei; Han, Fabin

    2016-07-01

    The aim of the present study was to isolate stem cells from human exfoliated deciduous teeth (SHEDs) and identify their phenotypes and multi‑lineage differentiation potential. Three SHED cell strains were successfully isolated from three exfoliated deciduous teeth from different human subjects using the outgrowth method. Flow cytometric analysis indicated that SHEDs displayed high expression of the mesenchymal cell markers CD73 and CD90 but low expression of the hematopoietic stem cell marker CD34. PCR analysis illustrated that SHEDs expressed the mesenchymal stem cell markers CD44, CD73 and CD90, the osteoblast markers Alpl, Runx2, CBFA1 and collagen Ⅰ, the cartilage cell markers Col10a1 and Acan, the adipose cell markers PPARγ2 and LPL, and the neuronal stem cell marker Nestin. In vitro induction experiments demonstrated the potential of the SHEDs for osteogenic, adipogenic and neurogenic differentiation. These SHED cells may be useful for further stem cell research and future therapeutic applications. PMID:27151462

  9. Raman spectroscopy for cytopathology of exfoliated cervical cells.

    PubMed

    Ramos, I R; Meade, A D; Ibrahim, O; Byrne, H J; McMenamin, M; McKenna, M; Malkin, A; Lyng, F M

    2016-06-23

    Cervical cancer is the fourth most common cancer affecting women worldwide but mortality can be decreased by early detection of pre-malignant lesions. The Pap smear test is the most commonly used method in cervical cancer screening programmes. Although specificity is high for this test, it is widely acknowledged that sensitivity can be poor mainly due to the subjective nature of the test. There is a need for new objective tests for the early detection of pre-malignant cervical lesions. Over the past two decades, Raman spectroscopy has emerged as a promising new technology for cancer screening and diagnosis. The aim of this study was to evaluate the potential of Raman spectroscopy for cervical cancer screening using both Cervical Intraepithelial Neoplasia (CIN) and Squamous Intraepithelial Lesion (SIL) classification terminology. ThinPrep® Pap samples were recruited from a cervical screening population. Raman spectra were recorded from single cell nuclei and subjected to multivariate statistical analysis. Normal and abnormal ThinPrep® samples were discriminated based on the biochemical fingerprint of the cells using Principal Component Analysis (PCA). Principal Component Analysis - Linear Discriminant Analysis (PCA-LDA) was employed to build classification models based on either CIN or SIL terminology. This study has shown that Raman spectroscopy can be successfully applied to the study of routine cervical cytology samples from a cervical screening programme and that the use of CIN terminology resulted in improved sensitivity for high grade cases. PMID:27032537

  10. Pluripotency of Stem Cells from Human Exfoliated Deciduous Teeth for Tissue Engineering

    PubMed Central

    Rosa, Vinicius; Dubey, Nileshkumar; Islam, Intekhab; Min, Kyung-San; Nör, Jacques E.

    2016-01-01

    Stem cells from human exfoliated deciduous teeth (SHED) are highly proliferative pluripotent cells that can be retrieved from primary teeth. Although SHED are isolated from the dental pulp, their differentiation potential is not limited to odontoblasts only. In fact, SHED can differentiate into several cell types including neurons, osteoblasts, adipocytes, and endothelial cells. The high plasticity makes SHED an interesting stem cell model for research in several biomedical areas. This review will discuss key findings about the characterization and differentiation of SHED into odontoblasts, neurons, and hormone secreting cells (e.g., hepatocytes and islet-like cell aggregates). The outcomes of the studies presented here support the multipotency of SHED and their potential to be used for tissue engineering-based therapies. PMID:27313627

  11. Pluripotency of Stem Cells from Human Exfoliated Deciduous Teeth for Tissue Engineering.

    PubMed

    Rosa, Vinicius; Dubey, Nileshkumar; Islam, Intekhab; Min, Kyung-San; Nör, Jacques E

    2016-01-01

    Stem cells from human exfoliated deciduous teeth (SHED) are highly proliferative pluripotent cells that can be retrieved from primary teeth. Although SHED are isolated from the dental pulp, their differentiation potential is not limited to odontoblasts only. In fact, SHED can differentiate into several cell types including neurons, osteoblasts, adipocytes, and endothelial cells. The high plasticity makes SHED an interesting stem cell model for research in several biomedical areas. This review will discuss key findings about the characterization and differentiation of SHED into odontoblasts, neurons, and hormone secreting cells (e.g., hepatocytes and islet-like cell aggregates). The outcomes of the studies presented here support the multipotency of SHED and their potential to be used for tissue engineering-based therapies. PMID:27313627

  12. Cell exfoliation, separation, and concentration in the field of a standing ultrasonic wave

    NASA Astrophysics Data System (ADS)

    Pashovkin, T. N.; Sadikova, D. G.

    2009-10-01

    We present theoretical and experimental results on the study of forces acting on cells in suspensions in the field of a standing ultrasonic wave (by the example of rat and guinea-pig erythrocytes, yeast, and chlorella) and leading to cell and liquid phase exfoliation, cell separation into fractions, and cell concentration in variable-pressure nodes. The experimental results are presented as plots in the coordinates of the average density of the energy of the ultrasonic field and the linear velocity of the flow of the cell suspension. Straight lines in the plots separate the regions of cell concentration, separation, and washout. The slope of these straight lines is a characteristic of a certain cell type. Agreement of the experimental and theoretically predicted data is shown.

  13. Laminated exfoliated graphite composite-metal compositions for fuel cell flow field plate or bipolar plate applications

    DOEpatents

    Zhamu, Aruna; Shi, Jinjun; Guo, Jiusheng; Jang, Bor Z

    2014-05-20

    An electrically conductive laminate composition for fuel cell flow field plate or bipolar plate applications. The laminate composition comprises at least a thin metal sheet having two opposed exterior surfaces and a first exfoliated graphite composite sheet bonded to the first of the two exterior surfaces of the metal sheet wherein the exfoliated graphite composite sheet comprises: (a) expanded or exfoliated graphite and (b) a binder or matrix material to bond the expanded graphite for forming a cohered sheet, wherein the binder or matrix material is between 3% and 60% by weight based on the total weight of the first exfoliated graphite composite sheet. Preferably, the first exfoliated graphite composite sheet further comprises particles of non-expandable graphite or carbon in the amount of between 3% and 60% by weight based on the total weight of the non-expandable particles and the expanded graphite. Further preferably, the laminate comprises a second exfoliated graphite composite sheet bonded to the second surface of the metal sheet to form a three-layer laminate. Surface flow channels and other desired geometric features can be built onto the exterior surfaces of the laminate to form a flow field plate or bipolar plate. The resulting laminate has an exceptionally high thickness-direction conductivity and excellent resistance to gas permeation.

  14. Measurements of ascorbic acid and glutathione in exfoliated cervicovaginal epithelial cells of smokers and women with cervical dysplasias.

    PubMed

    Basu, J; Mikhail, M S; Goldberg, G L; Palan, P R; Romney, S L

    1990-01-01

    This report emphasizes the ability to quantify ascorbic acid (AA) and reduced glutathione (GSH) levels in exfoliated cervicovaginal epithelial cells obtained by a lavage technique. Sixty-two women with abnormal Papanicolaou smears underwent colposcopic examinations. Colposcopic lesions were biopsied and histopathologically graded. Marked variations in the number of cells and in the levels of AA and GSH were observed. In cigarette smokers, the number of exfoliated cells retrieved was significantly higher (p less than 0.05, by Student's t test). The simultaneous investigation of biochemical and virologic parameters in exfoliated cervicovaginal epithelial cells, in conjunction with the known cytopathologic and epidemiologic risk variables, provides a novel approach to elucidate factor(s) that may inhibit or promote cervical carcinogenesis in designed prospective studies. PMID:2227613

  15. N-Acetyltransferase 2 genotype, exfoliated urothelial cells and benzidine exposure.

    PubMed

    Ma, Qing-wen; Lin, Guo-fang; Chen, Ji-gang; Guo, Wei-Chao; Qin, Yi-qiu; Golka, Klaus; Shen, Jian-hua

    2012-01-01

    Most studies report an association of the slow N-acetyltransferase 2 (NAT2) status with elevated bladder cancer risk. In this study, NAT2 genotypes and the decades-long records of Papanicolaou's grading of exfoliated urothelial cells in a former benzidine-exposed cohort of the Shanghai dyestuff industry (29 bladder cancer patients; 307 non-cancer cohort members, some of them presenting different grades of pre-malignant alterations of exfoliated urothelial cells) were investigated. The cohort members had been enrolled in regular medical surveillance since mid-1980s. No overall increase of slow NAT2 genotypes in the former benzidine-exposed bladder cancer patients was found, compared with non-diseased members of the same cohort. A lower presentation of the homozygous wild genotype NAT2 4/4 was observed in bladder cancer patients, compared with non-diseased members with averaged Papanicolaou's grading (APG)3 II (OR=0.31, 95 percent CI 0.10-0.96, p=0.034) or with APG less than II (OR=0.36,95 percent CI 0.12-1.10, p=0.063). Nevertheless, neither a protective influence of rapid NAT2 genotypes on bladder cancer risk nor on pre-malignant cytological alterations could be confirmed by the present data. PMID:22202012

  16. Micronuclei Frequencies and Nuclear Abnormalities in Oral Exfoliated Cells of Nuclear Power Plant Workers

    PubMed Central

    Babannavar, Roopa; Lohra, Abhishek; Kodgi, Ashwin; Bapure, Sunil; Rao, Yogesh; J., Arun; Malghan, Manjunath

    2014-01-01

    Aim: Biomonitoring provides a useful tool to estimate the genetic risk from exposure to genotoxic agents. The aim of this study was to evaluate the frequencies of Micronuclei (MN) and other Nuclear abnormalities (NA) from exfoliated oral mucosal cells in Nuclear Power Station (NPS) workers. Materials and Methods: Micronucleus frequencies in oral exfoliated cells were done from individuals not known to be exposed to either environmental or occupational carcinogens (Group I). Similarly samples were obtained from full-time Nuclear Power Station (NPS) workers with absence of Leukemia and any malignancy (Group II) and workers diagnosed as leukemic patients and undergoing treatment (Group III). Results: There was statistically significant difference between Group I, Group II & Group III. MN and NA frequencies in Leukemic Patients were significantly higher than those in exposed workers &control groups (p < 0.05). Conclusion: MN and other NA reflect genetic changes, events associated with malignancies. Therefore, there is a need to educate those who work in NPS about the potential hazard of occupational exposure and the importance of using protective measures. PMID:25654022

  17. Thermally exfoliated graphene based counter electrode for low cost dye sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Kaniyoor, Adarsh; Ramaprabhu, Sundara

    2011-06-01

    Graphene obtained from thermal exfoliation of graphite oxide are highly wrinkled and have large surface area. Their wrinkled nature is expected to give them excellent catalytic activity. Herein, we demonstrate the use of thermally exfoliated graphene (TEG) as cost effective electrocatalyst for the tri-iodide reduction in dye sensitized solar cells (DSSCs). X-ray diffraction, Raman and Infra red spectroscopy and electron microscopy studies confirm the defective and wrinkled nature of TEG. BET surface area measurement show a large surface area of ˜ 470 m2/g. The counter electrode was fabricated by drop casting a slurry of TEG dispersed in a Nafion:Ethanol solution on fluorine doped tin oxide (FTO) substrates. The use of Nafion prevented film "peel off," thus ensuring a good substrate adhesion. Electrochemical impedance spectroscopy reveals that TEG had a catalytic performance comparable to that of Pt, suggesting its use as counter electrode material. As expected, the DSSC fabricated with Nafion solubilized TEG/FTO as counter electrode shows an efficiency of about 2.8%, comparable to Pt counter electrode based DSSC which has an efficiency of about 3.4%.

  18. Clinical application of micronucleus test in exfoliated buccal cells: A systematic review and metanalysis.

    PubMed

    Bolognesi, Claudia; Bonassi, Stefano; Knasmueller, Siegfried; Fenech, Michael; Bruzzone, Marco; Lando, Cecilia; Ceppi, Marcello

    2015-01-01

    The micronucleus assay in uncultured exfoliated buccal mucosa cells, involving minimally invasive sampling, was successfully applied to evaluate inhalation and local exposure to genotoxic agents, impact of nutrition and lifestyle factors. The potential use of the assay in clinics to monitor the development of local oral lesions and as an early biomarker for tumors and different chronic disorders was also investigated. A systematic review of the literature was carried out focusing on the clinical application of the assay. The literature search updated to January 2015 allowed to retrieve 42 eligible articles. Fifty three percent of investigations are related to oral, head and neck cancer, and premalignant oral diseases. Our analysis evidences a potential usefulness of the MN assay applied in buccal exfoliated cells in the prescreening and in the follow up of precancerous oral lesions. A significant excess of MN, in patients compared with matched controls was observed for subgroups of oral and neck cancer (meta-MR of 2.40, 95% CI: 2.02-2.85) and leukoplakia (meta-MR 1.88, 95% CI: 1.51-2.35). The meta-analysis of studies available on other tumors (meta-MR 2.00; 95% CI:1.66-2.41) indicates that the MN frequency in buccal cells could reflect the chromosomal instability of other organs. Increased MN frequency was also observed in small size studies on patients with chronic diseases, with Alzheimer's disease and with Down syndrome. The application of the cytome approach providing information of genotoxic, cytotoxic and cytostatic effects is suggestive of the possibility of an improvement in the predictive value of the assay and this deserves further investigations. PMID:26596545

  19. The effect of stem cell from human exfoliated deciduous teeth on T lymphocyte proliferation

    PubMed Central

    Alipour, Razieh; Adib, Minoo; Hashemi-Beni, Batool; Sadeghi, Farzaneh

    2014-01-01

    Background: Mesenchymal stem cells (MSC), a specific type of adult tissue stem cell; have the immunosuppressive effects that make them valuable targets for regenerative medicine and treatment of many human illnesses. Hence, MSC have been the subject of numerous studies. The classical source of MSC is adult bone marrow (BM). Due to many shortcomings of harvesting MSC from BM, finding the alternative sources for MSC is an urgent. Stem cells from human exfoliated deciduous teeth (SHED) are relative new MSC populations that fulfill these criteria but their potential immunosuppressive effect has not been studied enough yet. Thus, in this work the effect of SHED on the proliferation of in vitro activated T lymphocytes were explored. Materials and Methods: In this study, both mitogen and alloantigen activated T cells were cultured in the presence of different numbers of SHED. In some co-cultures, activated T cells were in direct contact to MSCs and in other co-cultures; they were separated from SHED by a permeable membrane. In all co-cultures, the proliferation of T cells was measured by ELISA Bromodeoxyuridine proliferation assay. Results: In general, our results showed that SHED significantly suppress the proliferation of activated T cells in a dose-dependent manner. Moreover, the suppression was slightly stronger when MSCs were in physical contact to activated T cells. Conclusion: This study showed that SHED likewise other MSC populations can suppress the activation of T lymphocytes, which can be used instead of BM derived MSCs in many investigational and clinical applications. PMID:25337532

  20. Chromosomal Damage and Apoptosis in Exfoliated Buccal Cells from Individuals with Oral Cancer

    PubMed Central

    Dórea, Lavínia Tércia Magalhães; Meireles, José Roberto Cardoso; Lessa, Júlia Paula Ramos; Oliveira, Márcio Campos; de Bragança Pereira, Carlos Alberto; Polpo de Campos, Adriano; Cerqueira, Eneida de Moraes Macílio

    2012-01-01

    This study aimed to investigate cytological abnormalities indicative of chromosome damage (micronuclei) and apoptosis (karyorrhexis, pyknosis, and condensed chromatin) in exfoliated cells from the buccal mucosa of patients with oral cancer and control subjects. The sample included twenty individuals with oral cancer and forty individuals with normal buccal mucosa. Material was collected from the cheek epithelium in areas with lesions and areas without abnormalities. A minimum of one thousand cells was analyzed. Micronuclei were found significantly more frequently in cells collected from lesions than in cells from normal areas, independent of the presence/absence of cancer (P < 0.0001). They were also significantly more frequent in smokers and in mouthwash users (P < 0.0001). Apoptosis occurred significantly less frequently in individuals with oral cancer (P < 0.0001). These results show that oral cancer is associated with higher frequency of chromosomal damage and suggest that apoptosis is compromised in the buccal cells of individuals with this kind of neoplasia. PMID:22315605

  1. Chromosomal damage and apoptosis analysis in exfoliated oral epithelial cells from mouthwash and alcohol users

    PubMed Central

    Rocha, Rodrigo dos Santos; Meireles, José Roberto Cardoso; de Moraes Marcílio Cerqueira, Eneida

    2014-01-01

    Chromosomal damage and apoptosis were analyzed in users of mouthwash and/or alcoholic beverages, using the micronucleus test on exfoliated oral mucosa cells. Samples from four groups of 20 individuals each were analyzed: three exposed groups (EG1, EG2 and EG3) and a control group (CG). EG1 comprised mouthwash users; EG2 comprised drinkers, and EG3 users of both mouthwashes and alcoholic beverages. Cell material was collected by gently scraping the insides of the cheeks. Then the cells were fixed in a methanol/acetic acid (3:1) solution and stained and counterstained, respectively, with Schiff reactive and fast green. Endpoints were computed on 2,000 cells in a blind test. Statistical analysis showed that chromosomal damage and apoptosis were significantly higher in individuals of groups EG1 and EG3 than in controls (p < 0.005 and p < 0.001, respectively). No significant difference in chromosomal damage and apoptosis was observed between the exposed groups. In EG2, only the occurrence of apoptosis was significantly higher than in the controls. These results suggest that mouthwashes alone or in association with alcoholic drinks induce genotoxic effects, manifested as chromosomal damage and apoptosis. They also suggest that alcoholic drinks are effective for stimulating the process of apoptosis. However, these data need to be confirmed in larger samples. PMID:25505845

  2. Chromosomal damage and apoptosis analysis in exfoliated oral epithelial cells from mouthwash and alcohol users.

    PubMed

    Rocha, Rodrigo Dos Santos; Meireles, José Roberto Cardoso; de Moraes Marcílio Cerqueira, Eneida

    2014-10-01

    Chromosomal damage and apoptosis were analyzed in users of mouthwash and/or alcoholic beverages, using the micronucleus test on exfoliated oral mucosa cells. Samples from four groups of 20 individuals each were analyzed: three exposed groups (EG1, EG2 and EG3) and a control group (CG). EG1 comprised mouthwash users; EG2 comprised drinkers, and EG3 users of both mouthwashes and alcoholic beverages. Cell material was collected by gently scraping the insides of the cheeks. Then the cells were fixed in a methanol/acetic acid (3:1) solution and stained and counterstained, respectively, with Schiff reactive and fast green. Endpoints were computed on 2,000 cells in a blind test. Statistical analysis showed that chromosomal damage and apoptosis were significantly higher in individuals of groups EG1 and EG3 than in controls (p < 0.005 and p < 0.001, respectively). No significant difference in chromosomal damage and apoptosis was observed between the exposed groups. In EG2, only the occurrence of apoptosis was significantly higher than in the controls. These results suggest that mouthwashes alone or in association with alcoholic drinks induce genotoxic effects, manifested as chromosomal damage and apoptosis. They also suggest that alcoholic drinks are effective for stimulating the process of apoptosis. However, these data need to be confirmed in larger samples. PMID:25505845

  3. Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis.

    PubMed

    Shimojima, Chiaki; Takeuchi, Hideyuki; Jin, Shijie; Parajuli, Bijay; Hattori, Hisashi; Suzumura, Akio; Hibi, Hideharu; Ueda, Minoru; Yamamoto, Akihito

    2016-05-15

    Multiple sclerosis (MS) is a major neuroinflammatory demyelinating disease of the CNS. Current MS treatments, including immunomodulators and immunosuppressants, do not result in complete remission. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells derived from dental pulp. Both SHED and SHED-conditioned medium (SHED-CM) exhibit immunomodulatory and regenerative activities and have the potential to treat various diseases. In this study, we investigated the efficacy of SHED-CM in treating experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE mice treated with a single injection of SHED-CM exhibited significantly improved disease scores, reduced demyelination and axonal injury, and reduced inflammatory cell infiltration and proinflammatory cytokine expression in the spinal cord, which was associated with a shift in the microglia/macrophage phenotype from M1 to M2. SHED-CM also inhibited the proliferation of myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, as well as their production of proinflammatory cytokines in vitro. Treatment of EAE mice with the secreted ectodomain of sialic acid-binding Ig-like lectin-9, a major component of SHED-CM, recapitulated the effects of SHED-CM treatment. Our data suggest that SHED-CM and secreted ectodomain of sialic acid-binding Ig-like lectin-9 may be novel therapeutic treatments for autoimmune diseases, such as MS. PMID:27053763

  4. Staphylococcus sciuri Exfoliative Toxin C (ExhC) is a Necrosis-Inducer for Mammalian Cells

    PubMed Central

    Li, Haihua; Wang, Yongqiang; Ding, Lin; Zheng, Shijun J.

    2011-01-01

    Staphylococcus sciuri (S. sciuri) is a rare pathogen in humans, but it can cause a wide array of human infections. Recently a S. sciuri isolate (HBXX06) was reported to cause fatal exudative epidermitis (EE) in piglets and thus considered as a potential zoonotic agent. To investigate the pathogenicity of this bacterium, we cloned exfoliative toxin C (ExhC), a major toxin of the S. sciuri isolate and performed functional analysis of the recombinant ExhC-his (rExhC) protein using in vitro cell cultures and newborn mice as models. We found that rExhC could induce necrosis in multiple cell lines and peritoneal macrophages as well as skin lesions in newborn mice, and that the rExhC-induced necrosis in cells or skin lesions in newborn mice could be completely abolished if amino acids 79-128 of rExhC were deleted or blocked with a monoclonal antibody (3E4), indicating aa 79-128 portion as an essential necrosis-inducing domain. This information contributes to further understandings of the mechanisms underlying S. sciuri infection. PMID:21829591

  5. Light trapping in ultrathin 25  μm exfoliated Si solar cells.

    PubMed

    Hilali, Mohamed M; Saha, Sayan; Onyegam, Emmanuel; Rao, Rajesh; Mathew, Leo; Banerjee, Sanjay K

    2014-09-20

    The optical absorption in 25-μm-thick, single-crystal Si foils fabricated using a novel exfoliation technique for solar cells is studied and improved in this work. Various light-trapping and optical absorption enhancement schemes implemented show that it is possible to substantially narrow the gap in optical absorption loss between the 25 μm Si foils and industry-standard 180-μm-thick Si wafer solar cells. An improvement of absorption by 58% in the near-infrared (740-1200 nm) range is observed for the 25 μm monocrystalline Si substrates with the use of antireflective coating and texturing. The back reflectance of the metal foil that provides mechanical support to the ultrathin Si semiconductor-on-metal foils is extracted to be ∼51.5%, based on the reflectance matching with the simulated escape reflectance in the sub-bandgap region. The back reflectance is enhanced to ∼58% by incorporating an intermediate silicon nitride layer on the back between the Si and the metal. The incorporation of Al as an improved metal reflector on top of the silicon nitride at the backside of the solar cell results in a 5.8 times enhancement in optical path length as a consequence of the improved effective back reflectance of ∼95%. A thin Si foil solar cell with an unoptimized amorphous Si/crystalline Si heterojunction with intrinsic-thin-layer design with implementation of such light-trapping schemes shows an efficiency of 13.28% with a short-circuit current density (JSC) of 35.97  mA/cm2, which approaches the JSC of industrial wafer-based Si solar cells. PMID:25322089

  6. Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury

    PubMed Central

    Hattori, Yuka; Kim, Hangsoo; Tsuboi, Naotake; Yamamoto, Akihito; Akiyama, Shinichi; Shi, Yiqin; Katsuno, Takayuki; Kosugi, Tomoki; Ueda, Minoru; Matsuo, Seiichi; Maruyama, Shoichi

    2015-01-01

    Background Acute kidney injury (AKI) is a critical condition associated with high mortality. However, the available treatments for AKI are limited. Stem cells from human exfoliated deciduous teeth (SHED) have recently gained attention as a novel source of stem cells. The purpose of this study was to clarify whether SHED have a therapeutic effect on AKI induced by ischemia-reperfusion injury. Methods The left renal artery and vein of the mice were clamped for 20 min to induce ischemia. SHED, bone marrow derived mesenchymal stem cells (BMMSC) or phosphate-buffered saline (control) were administered into the subrenal capsule. To confirm the potency of SHED in vitro, H2O2 stimulation assays and scratch assays were performed. Results The serum creatinine and blood urea nitrogen levels of the SHED group were significantly lower than those of the control group, while BMMSC showed no therapeutic effect. Infiltration of macrophages and neutrophils in the kidney was significantly attenuated in mice treated with SHED. Cytokine levels (MIP-2, IL-1β, and MCP-1) in mice kidneys were significantly reduced in the SHED group. In in vitro experiments, SHED significantly decreased MCP-1 secretion in tubular epithelial cells (TEC) stimulated with H2O2. In addition, SHED promoted wound healing in the scratch assays, which was blunted by anti-HGF antibodies. Discussion SHED attenuated the levels of inflammatory cytokines and improved kidney function in AKI induced by IRI. SHED secreted factors reduced MCP-1 and increased HGF expression, which promoted wound healing. These results suggest that SHED might provide a novel stem cell resource, which can be applied for the treatment of ischemic kidney injury. PMID:26509261

  7. Electrochemically exfoliated graphene anodes with enhanced biocurrent production in single-chamber air-breathing microbial fuel cells.

    PubMed

    Najafabadi, Amin Taheri; Ng, Norvin; Gyenge, Előd

    2016-07-15

    Microbial fuel cells (MFCs) present promising options for environmentally sustainable power generation especially in conjunction with waste water treatment. However, major challenges remain including low power density, difficult scale-up, and durability of the cell components. This study reports enhanced biocurrent production in a membrane-free MFC, using graphene microsheets (GNs) as anode and MnOx catalyzed air cathode. The GNs are produced by ionic liquid assisted simultaneous anodic and cathodic electrochemical exfoliation of iso-molded graphite electrodes. The GNs produced by anodic exfoliation increase the MFC peak power density by over 300% compared to plain carbon cloth (i.e., 2.85Wm(-2) vs 0.66Wm(-2), respectively), and by 90% compared to conventional carbon black (i.e., Vulcan XC-72) anode. These results exceed previously reported power densities for graphene-containing MFC anodes. The fuel cell polarization results are corroborated by electrochemical impedance spectroscopy indicating three times lower charge transfer resistance for the GN anode. Material characterizations suggest that the best performing GN samples were of relatively smaller size (~500nm), with higher levels of ionic liquid induced surface functionalization during the electrochemical exfoliation process. PMID:26926591

  8. Method of producing exfoliated graphite composite compositions for fuel cell flow field plates

    DOEpatents

    Zhamu, Aruna; Shi, Jinjun; Guo, Jiusheng; Jang, Bor Z

    2014-04-08

    A method of producing an electrically conductive composite composition, which is particularly useful for fuel cell bipolar plate applications. The method comprises: (a) providing a supply of expandable graphite powder; (b) providing a supply of a non-expandable powder component comprising a binder or matrix material; (c) blending the expandable graphite with the non-expandable powder component to form a powder mixture wherein the non-expandable powder component is in the amount of between 3% and 60% by weight based on the total weight of the powder mixture; (d) exposing the powder mixture to a temperature sufficient for exfoliating the expandable graphite to obtain a compressible mixture comprising expanded graphite worms and the non-expandable component; (e) compressing the compressible mixture at a pressure within the range of from about 5 psi to about 50,000 psi in predetermined directions into predetermined forms of cohered graphite composite compact; and (f) treating the so-formed cohered graphite composite to activate the binder or matrix material thereby promoting adhesion within the compact to produce the desired composite composition. Preferably, the non-expandable powder component further comprises an isotropy-promoting agent such as non-expandable graphite particles. Further preferably, step (e) comprises compressing the mixture in at least two directions. The method leads to composite plates with exceptionally high thickness-direction electrical conductivity.

  9. Effects of low-level laser therapy on stem cells from human exfoliated deciduous teeth

    PubMed Central

    FERNANDES, Ana Paula; JUNQUEIRA, Marina de Azevedo; MARQUES, Nádia Carolina Teixeira; MACHADO, Maria Aparecida Andrade Moreira; SANTOS, Carlos Ferreira; OLIVEIRA, Thais Marchini; SAKAI, Vivien Thiemy

    2016-01-01

    ABSTRACT Low-Level Laser Therapy stimulates the proliferation of a variety of types of cells. However, very little is known about its effect on stem cells from human exfoliated deciduous teeth (SHED). Objective This study aimed to evaluate the influence of different laser therapy energy densities on SHED viability and proliferation. Material and Methods SHED were irradiated according to the groups: I (1.2 J/cm2 - 0.5 mW – 10 s), II (2.5 J/cm2 – 10 mW – 10 s), III (3.7 J/cm2 – 15 mW – 10 s), IV (5.0 J/cm2 – 20 mW – 10 s), V (6.2 J/cm2 – 25 mW – 10 s), and VI (not irradiated – control group). Cell viability was assessed 6 and 24 h after irradiation measuring the mitochondrial activity and using the Crystal Violet assay. Cell proliferation was assessed after 24, 48, and 72 h of irradiation by SRB assay. Results MTT assay demonstrated differences from 6 to 24 hours after irradiation. After 24 h, groups I and IV showed higher absorbance values than those of control group. Crystal Violet assay showed statistically differences in the absorbance rate from 6 to 24 h after irradiation for groups III and VI. At 24 h after irradiation, Group III absorbance rate was greater than that of groups I, II, and IV. Group VI absorbance rate was greater than that of groups I and IV. SRB assay showed that the group I had higher rates than those of groups II, III, V, and VI, at 24 h after irradiation. After 48 h, group I exhibited the greatest cell proliferation rate followed by groups III, V, and VI. After 72 h, group III exhibited the lowest cell proliferation rate than those of groups II, IV, and V. Conclusions The Low-Level Laser Therapy energy densities used in this study did not cause loss of cell viability and stimulated SHED proliferation within the parameters described in this study. PMID:27556203

  10. Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

    PubMed

    Isobe, Y; Koyama, N; Nakao, K; Osawa, K; Ikeno, M; Yamanaka, S; Okubo, Y; Fujimura, K; Bessho, K

    2016-01-01

    Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III β-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen. PMID:26235629

  11. Pulmonary Complications of Sickle Cell Disease

    PubMed Central

    Miller, Andrew C.

    2012-01-01

    Sickle cell disease (SCD) is a common monogenetic disorder with high associated morbidity and mortality. The pulmonary complications of SCD are of particular importance, as acute chest syndrome and pulmonary hypertension have the highest associated mortality rates within this population. This article reviews the pathophysiology, diagnosis, and treatment of clinically significant pulmonary manifestations of SCD, including acute chest syndrome, asthma, and pulmonary hypertension in adult and pediatric patients. Clinicians should be vigilant in screening and treating such comorbidities to improve patient outcomes. PMID:22447965

  12. The cytological diagnosis of nasopharyngeal carcinoma from exfoliated cells collected by suction method. An eight-year experience.

    PubMed

    Hanji, D; Shujing, S; Shuwei, H; Gohao, L

    1983-08-01

    A specially designed metallic tube, which is connected to a suction-pump and passed through the oral cavity into the nasopharynx for collecting exfoliative cells by negative pressure suction, is recommended in the diagnosis of nasopharyngeal carcinoma (NPC). From the beginning of 1973 through October 1976, among 458 cases of NPC, 405 cases were cytologically positive (with a positive rate of 88.4 per cent), and 433 cases were biopsy positive (with a positive rate of 94.3 per cent). In 1977, from January to October, among 116 cases of NPC, 103 cases were cytologically positive (with a positive rate of 88.8 per cent), and 108 cases were biopsy positive (with a positive rate of 93.1 per cent). The cytopathological features of the exfoliative NPC cells were correlated with the histopathological types of NPC. The degree of lymphocytic infiltration among the cancer cells in smears was compared with that in biopsies. They coincided roughly with each other. It indicates that one might interpret the immunological lymphocytic reaction by the number and typing of lymphocytes in smears too. The authors conclude that this cytological method is fairly dependable, less traumatic to the mucosa, convenient, and easily managed. A large number of tumor cells can be collected. It can also reflect the histologic typing of cancer cells. It can be used as a routine procedure in the clinico-pathological diagnosis of NPC, as well as in a mass screening program. PMID:6350514

  13. Metal decoration of exfoliated graphite nanoplatelets (xGnP) for fuel cell application

    NASA Astrophysics Data System (ADS)

    Do, In-Hwan

    The synthesis and characterization of metal particles at nanometer length scale has been the object of much research in modern nanotechnology due to their great impact on new nanoscale scientific and technological applications. Nanoscale metal particles possess unique optical, thermal, electronic, magnetic properties and chemical reactivity since the size of the resulting materials is on the same order as the fundamental interaction distances that give rise to physical properties and thus shows the quantum size effect which is not observed in their bulky status. Therefore, an effective synthetic method is required to obtain uniform small metal powders with controlled size and a narrow size distribution and also to produce nanocomposites consisting of either metals or metal oxides supported on carbons or metals dispersed on metal oxides for a variety of applications in chemical industries, automobiles, energy and power generating devices, hydrogen economy as well as for sensors. On the other hand, although their excellent mechanical, thermal and electrical conductivity, excellent corrosion and oxidation resistance, and low impurity levels which are required as a breakthrough material to increase performance of next generation energy devices, exfoliated graphite nanoplatelet (xGnP) has not been studied as deeply as recent new nano structured carbon materials such as single wall carbon nanotubes (SWNT), multi-wall carbon nanotubes (MWNT), carbon nanohorn (CNH), graphite nanofiber (GNF), and fullerenes. In addition, xGnP is much cost-effective compared to other carbon nanostructures. Hence, it is interesting to evaluate the applicability of xGnP as a support material for fuel cell which is one of promising energy devices for the future. In this research, a new simple, efficient and economic way is presented for the synthesis of noble metal nanoparticles such as Pt, Ru, Pd, etc and their deposition on various carbon supports and metal oxides via microwave heating in the

  14. Pulmonary complications of sickle cell disease.

    PubMed

    Khoury, Ruby A; Musallam, Khaled M; Mroueh, Salman; Abboud, Miguel R

    2011-01-01

    The pulmonary complications of sickle cell disease are a major cause of morbidity and mortality in affected patients. The acute chest syndrome (ACS) is a leading cause of death in patients with sickle cell disease and has a multifactorial etiology. Hydroxyurea (HU), stem cell transplantation (SCT) and chronic transfusions are known to prevent the recurrence of ACS. Careful management of patients admitted for pain crises and surgery including use of incentive spirometry is critical in preventing this complication. Pulmonary hypertension is well known to be associated with sickle cell disease and patients with pulmonary hypertension have increased mortality. Asthma is also commonly seen in patients with sickle cell disease and is associated with a more complicated course. Chronic lung disease develops in a significant proportion of patients with sickle cell disease. PMID:21973051

  15. Human Pulmonary Endothelial Cells in Culture

    PubMed Central

    Johnson, Alice R.

    1980-01-01

    Endothelial cells were cultured from various different human vessels, including aortas, pulmonary, ovarian, and umbilical arteries, and pulmonary, ovarian, and umbilical veins. The cultured cells were identified as endothelial cells by the presence of Factor VIII antigen and antiotensin I converting enzyme (kininase II). They retained these markers for at least five passages in culture, and some cells had them for seven passages or more. Endothelial cells from the various vessels were compared with respect to their ability to metabolize angiotensins I and II and bradykinin. Cells from arteries had three to five times the angiotensin I converting enzyme activity as cells from veins. The activity of angiotensinase A (aspartyl aminopeptidase) had a similar distribution, and cells from arteries were consistently more active than cells from veins. Cultures of endothelial cells from pulmonary and umbilical vessels formed prostacyclin in response to mechanical stimulation. Media from cell monolayers that were subjected to a change of medium and gentle agitation inhibited aggregation of human platelets. This inhibitory activity was generated within 2-5 min, and it was not formed by cells that were treated with indomethacin or tranylcypromine. Addition of prostaglandin (PG)H2 to indomethacin-treated cells restored the ability to form the inhibitor, but cells treated with tranylcypromine were not responsive to PGH2. In experiments where [14C]arachidonic acid was added to the cells before stimulation, the major metabolite identified by thin-layer chromatography was 6-keto PGF1α. Thus, it appears that pulmonary endothelial cells, as well as umbilical cord cells, can form prostacyclin. In experiments comparing the ability of arterial and venous cells to form prostacyclin, arterial cells were more active than venous cells. These studies of cells from various human vessels suggest that the vascular origin of cultured endothelial cells determines how they metabolize vasoactive

  16. Mesenchymal Stem Cells Derived from Human Exfoliated Deciduous Teeth (SHEDs) Induce Immune Modulatory Profile in Monocyte-Derived Dendritic Cells

    PubMed Central

    Silva, Fernando de Sá; Ramos, Rodrigo Nalio; de Almeida, Danilo Candido; Bassi, Enio Jose; Gonzales, Roberto Pereira; Miyagi, Sueli Patricia Harumi; Maranduba, Claudinéia Pereira; Sant'Anna, Osvaldo Augusto Brazil Esteves; Marques, Márcia Martins; Barbuto, José Alexandre Marzagão; Câmara, Niels Olsen Saraiva; da Costa Maranduba, Carlos Magno

    2014-01-01

    Background Mesenchymal stem cells have prominent immune modulatory properties, which may have clinical applications; however their major source, bone marrow, is of limited availability. On the other hand, mesenchymal stem cells derived from human exfoliated deciduous teeth (SHEDs) are readily accessible, but their immune regulatory properties have not been completely investigated. This study was designed, therefore, to evaluate the SHEDs influence on DCs differentiation, maturation, ability to activate T cells and to expand CD4+Foxp3+ T cells. Methodology/Principal Findings The experiments were based in cellular co-culture during differentiation and maturation of monocyte derived-DCs (moDCs), with, or not, presence of SHEDs. After co-culture with SHEDs, (moDCs) presented lower expression of BDCA-1 and CD11c, in comparison to DC cultivated without SHEDs. CD40, CD80, CD83 and CD86 levels were also decreased in mature DCs (mDCs) after co-cultivation with SHEDs. To assess the ability of SHEDs-exposed moDCs to modulate T cell responses, the former were separated from SHEDs, and co-cultured with peripheral blood lymphocytes. After 5 days, the proliferation of CD4+ and CD8+ T cells was evaluated and found to be lower than that induced by moDCs cultivated without SHEDs. In addition, an increase in the proportion of CD4+Foxp3+IL-10+ T cells was observed among cells stimulated by mature moDCs that were previously cultivated with SHEDs. Soluble factors released during co-cultures also showed a reduction in the pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ), and an increase in the anti-inflammatory molecule IL-10. Conclusion/Significance This study shows that SHEDs induce an immune regulatory phenotype in moDCs cells, evidenced by changes in maturation and differentiation rates, inhibition of lymphocyte stimulation and ability to expand CD4+Foxp3+ T cells. Further characterization and validation of this phenomenon could support the use of SHEDs, directly or indirectly

  17. Comparing the immunoregulatory effects of stem cells from human exfoliated deciduous teeth and bone marrow-derived mesenchymal stem cells.

    PubMed

    Alipour, Razieh; Adib, Minoo; Masoumi Karimi, Masoumeh; Hashemi-Beni, Batool; Sereshki, Nasrin

    2013-12-01

    Stem cells from human exfoliated deciduous teeth (SHED) have been introduced recently and possess characteristics similar to mesenchymal stem cells (MSCs). Because of their convenient accessibility and safety of harvest, SHED can be a preferable source for the ever-increasing MSCs' applications  While they are new, their immunoproperties have not been adequately studied. In this study, we aimed to explore the effect of SHED on T lymphocytes and compare it to conventional MSCs (BMMSCs).At first the isolated T lymphocytes were activated specifically/nonspecifically in vitro and cocultured with SHED or BMMSCs under the same conditions, subsequently their proliferation and cytokine secretion (IL-2 and IFN-γ) were measured.In our experiment, BMMSCs and SHED inhibit the proliferation and cytokine production of both PHA and alloantigen stimulated T lymphocytes in a dose-dependent manner. In direct and indirect contact to T lymphocytes, the inhibition of BMMSCs (but not of SHED) was significantly different The cytokine production from activated T cells was affected differently by two types of MSCs. The inhibition decreased by the separation of lymphocytes and MSCs by a semipermeable membrane, but it was not abolished.This study showed that SHED suppress the activation of human T lymphocytes in vitro like other MSCs. Compared to BMMSCs, this suppression was alleviated. In the equal conditions, the pattern of immune-modulation of BMMSCs and SHED was different, suggesting that SHED do not exert the exact mechanisms of BMMSCs' immunosuppression., This finding should be verified by further studies focused on the detailed mechanisms  of the immunomodulation of SHED and also BMMSCs. PMID:23996709

  18. The Comparison of the Immunologic Properties of Stem Cells Isolated from Human Exfoliated Deciduous Teeth, Dental Pulp, and Dental Follicles

    PubMed Central

    Yildirim, Selin; Zibandeh, Noushin; Genc, Deniz; Ozcan, Elif Merve; Goker, Kamil; Akkoc, Tunc

    2016-01-01

    Aim. To compare the effects of various mesenchymal stem cells, those isolated from human exfoliated deciduous teeth (SHEDs), dental pulp stem cells (DPSCs), and dental follicle stem cells (DFSCs), on human peripheral blood mononuclear cells (PBMCs). Method. Mesenchymal stem cells were isolated from three sources in the orofacial region. Characterization and PCR analyses were performed. Lymphocytes were isolated from healthy peripheral venous blood. Lymphocytes were cocultured with stem cells in the presence and absence of IFN-γ and stimulated with anti-CD2, anti-CD3, and anti-CD28 for 3 days. Then, lymphocyte proliferation, the number of CD4+FoxP3+ T regulatory cells, and the levels of Fas/Fas ligand, IL-4, IL-10, and IFN-γ in the culture supernatant were measured. Results. The DFSCs exhibited an enhanced differentiation capacity and an increased number of CD4+FoxP3+ T lymphocytes and suppressed the proliferation and apoptosis of PBMCs compared with SHEDs and DPSCs. The addition of IFN-γ augmented the proliferation of DFSCs. Furthermore, the DFSCs suppressed IL-4 and IFN-γ cytokine levels and enhanced IL-10 levels compared with the other cell sources. Conclusion. These results suggest that IFN-γ stimulates DFSCs by inducing an immunomodulatory effect on the PBMCs of healthy donors while suppressing apoptosis and proliferation and increasing the number of CD4+FoxP3+ cells. PMID:26770205

  19. Comparative Study of Genotoxicity in Different Tobacco Related Habits using Micronucleus Assay in Exfoliated Buccal Epithelial Cells

    PubMed Central

    Guruprasad, Yadavalli; Jose, Maji; Saxena, Kartikay; K, Deepa; Prabhu, Vishnudas

    2014-01-01

    Background: Oral cancer is one of the most debilitating diseases afflicting mankind. Consumption of tobacco in various forms constitutes one of the most important etiological factors in initiation of oral cancer. When the focus of today’s research is to determine early genotoxic changes in human cells, micronucleus (MN) assay provides a simple, yet reliable indicator of genotoxic damage. Aims and Objectives: To identify and quantify micronuclei in the exfoliated cells of oral mucosa in individuals with different tobacco related habits and control group, to compare the genotoxicity of different tobacco related habits between each group and also with that of control group. Patients and Methods: In the present study buccal smears of 135 individuals with different tobacco related habits & buccal smears of 45 age and sex matched controls were obtained, stained using Giemsa stain and then observed under 100X magnification in order to identify and quantify micronuclei in the exfoliated cells of oral mucosa. Results: The mean Micronucleus (MN) count in individuals having smoking habit were 3.11 while the count was 0.50, 2.13, and 1.67 in normal control, smoking with beetle quid and smokeless tobacco habit respectively. MN count in smokers group was 2.6 times more compared to normal controls. MN count was more even in other groups when compared to normal control but to a lesser extent. Conclusion: From our study we concluded that tobacco in any form is genotoxic especially smokers are of higher risk and micronucleus assay can be used as a simple yet reliable marker for genotoxic evaluation. PMID:24995238

  20. Nuclear morphometric and morphological analysis of exfoliated buccal and tongue dorsum cells in type-1 diabetic patients

    PubMed Central

    Oz, Zehra Safi; Bektas, Sibel; Battal, Fatih; Atmaca, Hulusi; Ermis, Bahri

    2014-01-01

    Background: Diabetes mellitus type 1 that results from immunologically mediated damage to the β-cells in the pancreas. Diabetes mellitus is characterized by recurrent or persistent hyperglycemia. Hyperglycemia can be associated with salivary gland dysfunction and alterations in the oral epithelial cells. Aim: The aim of this study was to evaluate the qualitative and quantitative changes in buccal and tongue dorsum epithelial cells using an exfoliative cytology method in type 1 diabetic patients. Materials and Methods: We performed light microscopic analysis of the buccal and tongue dorsum smears in thirty type 1 diabetic patients and thirty healthy individuals. The oral smears were stained using Papanicolaou method for cytological examination and nuclear morphometric analysis. In each case, the mean nuclear area, perimeter, length, breadth, and roundness factor were evaluated in each smear using the image analysis software (Q Win, Leica™). Results: The nuclear area, length, breadth, and perimeters were significantly higher in the diabetic group from tongue dorsum smear than that of the control group (P < 0.05). In the cytological examination, karyorrhexis-karyolysis-karyopyknosis, binucleation, nuclear membrane irregularity, cytoplasmic polymorphism, perinuclear halo were observed in oral smears with type 1 diabetic patients. Binucleation (P = 0.002) and nuclear membrane irregularity (P = 0.024) were significantly more common in buccal smears of diabetic group. Furthermore, the sensitivity of buccal mucosa was significantly higher in the diabetic group (P = 0.006). Conclusion: The light microscopic and nuclear morphometric study indicates that type 1 diabetes can produce morphological and nuclear morphometric changes in the oral mucosa that are noticeable with exfoliative cytology. PMID:25538382

  1. [Pulmonary manifestations of Langerhans cell histiocytosis].

    PubMed

    Obert, J; Tazi, A

    2015-10-01

    Pulmonary Langerhans cell histiocytosis is a rare diffuse cystic interstitial pneumonia of unknown etiology that occurs selectively in young smokers of both genders. The multicenter studies conducted by the reference center have better defined the short and medium terms natural history of the disease and the clinical management of patients. A substantial proportion of patients experience a dramatic decline in their lung function soon after diagnosis. Importantly, smoking cessation is associated with a decreased risk of subsequent deterioration. Cladribine, a purine analogue, chemotherapy may dramatically improve lung function in patients with progressive pulmonary Langerhans cell histiocytosis, but this treatment should be used only in the setting of clinical research. Specific pulmonary hypertension therapies (anti-endothelin receptors, inhibitors of phosphodiesterases) may be used with caution in specialized centres for patients with severe pulmonary hypertension, and seem to be well tolerated. The recent identification of the V600E mutation of the BRAF oncogene in approximately half of the Langerhans cell histiocytosis lesions, including pulmonary granulomas, represents an important step forward in the understanding of the pathogenesis of Langerhans cell histiocytosis. Potentially it opens the way to targeted therapies. PMID:26003197

  2. Evaluation of DNA damage in exfoliated tear duct epithelial cells from individuals exposed to air pollution assessed by single cell gel electrophoresis assay.

    PubMed

    Rojas, E; Valverde, M; Lopez, M C; Naufal, I; Sanchez, I; Bizarro, P; Lopez, I; Fortoul, T I; Ostrosky-Wegman, P

    2000-06-22

    The search for relevant target cells for human monitoring purposes has increased during the last few years. Cells such as sperm, buccal or nasal and gastric epithelium are being used. In this study, we report the use of exfoliated tear duct epithelial cells as a potential material for human biomonitoring studies, since these cells are a target for environmental pollutants. We employed the alkaline single cell gel electrophoresis (SCGE) assay to evaluate for differences in the basal level of DNA damage between young adults from the south (exposed mainly to high levels of ozone) and from the north (exposed principally to hydrocarbons) regions of Mexico City. We found an increase in DNA migration in tear duct epithelial cells from individuals who live in the southern part of the city compared to those living in the northern part. Moreover, young people who live in the southwest part of the city with the highest values of ozone presented the highest values of DNA damage. These results show the feasibility of using exfoliated tear duct epithelial cells in human biomonitoring studies. PMID:10863153

  3. Recompressed exfoliated graphite articles

    DOEpatents

    Zhamu, Aruna; Shi, Jinjun; Guo, Jiusheng; Jang, Bor Z

    2013-08-06

    This invention provides an electrically conductive, less anisotropic, recompressed exfoliated graphite article comprising a mixture of (a) expanded or exfoliated graphite flakes; and (b) particles of non-expandable graphite or carbon, wherein the non-expandable graphite or carbon particles are in the amount of between about 3% and about 70% by weight based on the total weight of the particles and the expanded graphite flakes combined; wherein the mixture is compressed to form the article having an apparent bulk density of from about 0.1 g/cm.sup.3 to about 2.0 g/cm.sup.3. The article exhibits a thickness-direction conductivity typically greater than 50 S/cm, more typically greater than 100 S/cm, and most typically greater than 200 S/cm. The article, when used in a thin foil or sheet form, can be a useful component in a sheet molding compound plate used as a fuel cell separator or flow field plate. The article may also be used as a current collector for a battery, supercapacitor, or any other electrochemical cell.

  4. Stem cells from human exfoliated deciduous teeth differentiate toward neural cells in a medium dynamically cultured with Schwann cells in a series of polydimethylsiloxanes scaffolds

    NASA Astrophysics Data System (ADS)

    Su, Wen-Ta; Pan, Yu-Jing

    2016-08-01

    Objective. Schwann cells (SCs) are primary structural and functional cells in the peripheral nervous system. These cells play a crucial role in peripheral nerve regeneration by releasing neurotrophic factors. This study evaluated the neural differentiation potential effects of stem cells from human exfoliated deciduous teeth (SHEDs) in a rat Schwann cell (RSC) culture medium. Approach. SHEDs and RSCs were individually cultured on a polydimethylsiloxane (PDMS) scaffold, and the effects of the RSC medium on the SHEDs differentiation between static and dynamic cultures were compared. Main results. Results demonstrated that the SHED cells differentiated by the RSC cultured medium in the static culture formed neurospheres after 7 days at the earliest, and SHED cells formed neurospheres within 3 days in the dynamic culture. These results confirm that the RSC culture medium can induce neurospheres formation, the speed of formation and the number of neurospheres (19.16 folds high) in a dynamic culture was superior to the static culture for 3 days culture. The SHED-derived spheres were further incubated in the RSCs culture medium, these neurospheres continuously differentiated into neurons and neuroglial cells. Immunofluorescent staining and RT-PCR revealed nestin, β-III tubulin, GFAP, and γ-enolase of neural markers on the differentiated cells. Significance. These results indicated that the RSC culture medium can induce the neural differentiation of SHED cells, and can be used as a new therapeutic tool to repair nerve damage.

  5. Pulmonary manifestations of renal cell carcinoma.

    PubMed

    Agrawal, Abhinav; Sahni, Sonu; Iftikhar, Asma; Talwar, Arunabh

    2015-12-01

    Renal cell carcinoma (RCC) accounts for majority of all primary renal neoplasms. Classic manifestations of RCC include the triad of flank pain, hematuria and a palpable renal mass. Patients with RCC can develop various extra renal manifestations including involvements of the lungs, inferior vena cava, liver and the bones. The pulmonary manifestations of renal cell carcinoma include metastatic disease including endobronchial, pleural, parenchymal or lymph node metastasis, pleural effusion or hemothorax. Pulmonary embolism and tumor embolism is another common manifestation of renal cell carcinoma. RCC is a highly vascular tumor and can cause pulmonary arterio-venous fistulas leading to high output failure. Rarely, RCC can also present with paraneoplastic presentations including cough or bilateral diaphragm paralysis. Drugs used to treat RCC have been associated with drug related pneumonitis and form an important differential diagnosis in patients with RCC on therapy presenting with shortness of breath. In this review we discuss the various pulmonary manifestations of RCC. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention. PMID:26525375

  6. Estimation of Salivary Glucose and Glycogen Content in Exfoliated Buccal Mucosal Cells of Patients with Type II Diabetes Mellitus

    PubMed Central

    Gopinathan, Deepa Moothedathu; Sukumaran, Sunil

    2015-01-01

    Background Diabetes mellitus is a common metabolic disorder which shows an increasing incidence worldwide. Constant monitoring of blood glucose in diabetic patient is required which involves painful invasive techniques. Saliva is gaining acceptance as diagnostic tool for various systemic diseases which can be collected noninvasively and by individuals with limited training. Aim The aim of the present study was to analyse the possibility of using salivary glucose and glycogen content of buccal mucosal cells as a diagnostic marker in Type II Diabetes mellitus patients which can be considered as adjuvant diagnostic tool to the gold standards. Materials and Methods Sample consists of 30 study and 30 control groups. Saliva was collected by passive drool method.Intravenous blood samples were collected for glucose estimation. Exfoliated buccal mucosal cells were collected from apparently normal buccal mucosa, smeared on dry glass slide and stained with PAS. Blood and salivary glucose are estimated by Glucose Oxidase endpoint method. For Glycogen estimation, number of PAS positive cells in fifty unfolded cells was analysed. Results The results of the present study revealed a significant increase in the salivary glucose level and the number of PAS positive buccal mucosal cells in the diabetics than in the controls. The correlation between the fasting serum glucose and fasting salivary glucose and also that between fasting serum glucose and PAS positive cells was statistically significant. But the correlation between the staining intensity and fasting serum glucose was statistically insignificant. Conclusion With the results of the present study it is revealed that salivary glucose and PAS positive cells are increased in diabetics which can be considered as adjuvant diagnostic tool for Diabetes mellitus. PMID:26155572

  7. [Pulmonary complications in adult sickle cell disease].

    PubMed

    Maître, B; Mekontso-Dessap, A; Habibi, A; Bachir, D; Parent, F; Godeau, B; Galacteros, F

    2011-02-01

    Sickle cell disease is an autosomal genetic condition which represents the most frequent genetic disease in Île-de-France and Caribbean islands. The main clinical manifestations can be divided into infectious disease, hemolytic anemia and vaso-occlusive events. Pulmonary complications represent 20 to 30% of mortality due to sickle cell and can be divided into acute and chronic events. Acute chest syndrome (ACS) is an acute lung injury often preceded by a vaso-occlusive crisis and triggered by different factors including: hypoventilation, pulmonary infectious disease and vascular occlusions. These occlusions can be secondary to fat embolism, thrombosis or sickling. Treatment is mainly supportive combining oxygen supplementation adequate hydration analgesia and sedation. Exchange transfusion may be indicated in severe forms of ACS, characterized by a right ventricular dysfunction and acute respiratory failure. Pulmonary hypertension is the most serious chronic complication. Its frequency is estimated at 6% in adult patients and is more often described in patients with venous ulcers and higher levels of chronic hemolysis. Prognosis is poor with 12.5% of patients dying in the first two years following diagnosis irrespective of the actual pulmonary artery pressure level. There are currently limited data on the effects of any treatment modality. Other respiratory complications such as sleep disorders and nocturnal hypoxemia, infiltrative lung disease and exertional dyspnea are described and should be considered. PMID:21402228

  8. Associations between Arsenic Species in Exfoliated Urothelial Cells and Prevalence of Diabetes among Residents of Chihuahua, Mexico

    PubMed Central

    Currier, Jenna M.; Ishida, María C.; González-Horta, Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Gutiérrez-Torres, Daniela S.; Cerón, Roberto Hernández; Morales, Damián Viniegra; Terrazas, Francisco A. Baeza; Del Razo, Luz M.; García-Vargas, Gonzalo G.; Saunders, R. Jesse; Drobná, Zuzana; Fry, Rebecca C.; Matoušek, Tomáš; Buse, John B.; Mendez, Michelle A.; Loomis, Dana

    2014-01-01

    Background: A growing number of studies link chronic exposure to inorganic arsenic (iAs) with the risk of diabetes. Many of these studies assessed iAs exposure by measuring arsenic (As) species in urine. However, this approach has been criticized because of uncertainties associated with renal function and urine dilution in diabetic individuals. Objectives: Our goal was to examine associations between the prevalence of diabetes and concentrations of As species in exfoliated urothelial cells (EUC) as an alternative to the measures of As in urine. Methods: We measured concentrations of trivalent and pentavalent iAs methyl-As (MAs) and dimethyl-As (DMAs) species in EUC from 374 residents of Chihuahua, Mexico, who were exposed to iAs in drinking water. We used fasting plasma glucose, glucose tolerance tests, and self-reported diabetes diagnoses or medication to identify diabetic participants. Associations between As species in EUC and diabetes were estimated using logistic and linear regression, adjusting for age, sex, and body mass index. Results: Interquartile-range increases in trivalent, but not pentavalent, As species in EUC were positively and significantly associated with diabetes, with ORs of 1.57 (95% CI: 1.19, 2.07) for iAsIII, 1.63 (1.24, 2.15) for MAsIII, and 1.31 (0.96, 1.84) for DMAsIII. DMAs/MAs and DMAs/iAs ratios were negatively associated with diabetes (OR = 0.62; 95% CI: 0.47, 0.83 and OR = 0.72; 95% CI: 0.55, 0.96, respectively). Conclusions: Our data suggest that uncertainties associated with measures of As species in urine may be avoided by using As species in EUC as markers of iAs exposure and metabolism. Our results provide additional support to previous findings suggesting that trivalent As species may be responsible for associations between diabetes and chronic iAs exposure. Citation: Currier JM, Ishida MC, González-Horta C, Sánchez-Ramírez B, Ballinas-Casarrubias L, Gutiérrez-Torres DS, Hernández Cerón R, Viniegra Morales D, Baeza

  9. Pulmonary artery segmentation and quantification in sickle cell associated pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Linguraru, Marius George; Mukherjee, Nisha; Van Uitert, Robert L.; Summers, Ronald M.; Gladwin, Mark T.; Machado, Roberto F.; Wood, Bradford J.

    2008-03-01

    Pulmonary arterial hypertension is a known complication associated with sickle-cell disease; roughly 75% of sickle cell disease-afflicted patients have pulmonary arterial hypertension at the time of death. This prospective study investigates the potential of image analysis to act as a surrogate for presence and extent of disease, and whether the size change of the pulmonary arteries of sickle cell patients could be linked to sickle-cell associated pulmonary hypertension. Pulmonary CT-Angiography scans from sickle-cell patients were obtained and retrospectively analyzed. Randomly selected pulmonary CT-Angiography studies from patients without sickle-cell anemia were used as negative controls. First, images were smoothed using anisotropic diffusion. Then, a combination of fast marching and geodesic active contours level sets were employed to segment the pulmonary artery. An algorithm based on fast marching methods was used to compute the centerline of the segmented arteries. From the centerline, the diameters at the pulmonary trunk and first branch of the pulmonary arteries were measured automatically. Arterial diameters were normalized to the width of the thoracic cavity, patient weight and body surface. Results show that the pulmonary trunk and first right and left pulmonary arterial branches at the pulmonary trunk junction are significantly larger in diameter with increased blood flow in sickle-cell anemia patients as compared to controls (p values of 0.0278 for trunk and 0.0007 for branches). CT with image processing shows great potential as a surrogate indicator of pulmonary hemodynamics or response to therapy, which could be an important tool for drug discovery and noninvasive clinical surveillance.

  10. Isolation and culture of pulmonary endothelial cells.

    PubMed

    Ryan, U S

    1984-06-01

    Methods for isolation, identification and culture of pulmonary endothelial cells are now routine. In the past, methods of isolation have used proteolytic enzymes to detach cells; thereafter, traditional methods for cell passaging have used trypsin/EDTA mixtures. Cells isolated and passaged using proteolytic enzymes have been useful in establishing the field and in verifying certain endothelial properties. However, there is a growing awareness of the role of endothelial cells in processing vasoactive substances, in responding to hormones and other agonists and in cell-cell interactions with other cell types of the vascular wall, with blood cells and with cellular products. Consequently, a new requirement has arisen for cells in vitro that maintain the differentiated properties of their counterparts in vivo. The deleterious effects of trypsin and other proteolytic enzymes commonly used in cell culture on surface structures of endothelial cells such as enzymes, receptors and junctional proteins, as well as on extracellular layers such as the glycocalyx or "endothelial fuzz," have led to the development of methods that avoid use of proteolytic enzymes at both the isolation step and during subsequent subculture. This chapter describes traditional methods for isolating pulmonary endothelial cells but emphasizes newer approaches using mechanical harvest and scale-up using microcarriers. The new methods allow maintenance of long-term, large-scale cultures of cells that retain the full complement of surface properties and that maintain the cobblestone monolayer morphology and differentiated functional properties. Methods for identification of isolated cells are therefore also considered as methods for validation of cultures during their in vitro lifespan. PMID:6090112

  11. Chronic Pulmonary Complications of Sickle Cell Disease.

    PubMed

    Mehari, Alem; Klings, Elizabeth S

    2016-05-01

    Sickle cell disease (SCD), the most common genetic hemolytic anemia worldwide, affects 250,000 births annually. In the United States, SCD affects approximately 100,000 individuals, most of African descent. Hemoglobin S (HbS) results from a glutamate-to-valine mutation of the sixth codon of the β-hemoglobin allele; the homozygous genotype (HbSS) is associated with the most prevalent and severe form of the disease. Other SCD genotypes include HbSC, composed of one HbS allele and one HbC (glutamate-to-lysine mutation) allele; and HbS-β-thalassemia(0) or HbS-β-thalassemia(+), composed of one HbS allele and one β-thalassemia allele with absent or reduced β-chain production, respectively. Despite advances in care, median survival remains in the fifth decade, due in large part to chronic complications of the disease. Chronic pulmonary complications in SCD are major contributors to this early mortality. Although our understanding of these conditions has improved much over the past 10 to 15 years, there remains no specific treatment for pulmonary complications of SCD. It is unclear whether conventional treatment regimens directed at non-SCD populations have equivalent efficacy in patients with SCD. This represents a critical research need. In this review, the authors review the state-of-the-art understanding of the following pulmonary complications of SCD: (1) pulmonary hypertension; (2) venous thromboembolic disease; (3) sleep-disordered breathing; (4) asthma and recurrent wheezing; and (5) pulmonary function abnormalities. This review highlights the advances as well as the knowledge gaps in this field to update clinicians and other health care providers and to garner research interest from the medical community. PMID:26836905

  12. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease.

    PubMed

    Gordeuk, Victor R; Castro, Oswaldo L; Machado, Roberto F

    2016-02-18

    Pulmonary hypertension affects ∼10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments

  13. Phenotypic and Proteomic Characteristics of Human Dental Pulp Derived Mesenchymal Stem Cells from a Natal, an Exfoliated Deciduous, and an Impacted Third Molar Tooth

    PubMed Central

    Akpinar, Gurler; Aksoy, Ayca; Duruksu, Gokhan; Gacar, Gulcin; Karaoz, Erdal

    2014-01-01

    The level of heterogeneity among the isolated stem cells makes them less valuable for clinical use. The purpose of this study was to understand the level of heterogeneity among human dental pulp derived mesenchymal stem cells by using basic cell biology and proteomic approaches. The cells were isolated from a natal (NDPSCs), an exfoliated deciduous (stem cells from human exfoliated deciduous (SHED)), and an impacted third molar (DPSCs) tooth of three different donors. All three stem cells displayed similar features related to morphology, proliferation rates, expression of various cell surface markers, and differentiation potentials into adipocytes, osteocytes, and chondrocytes. Furthermore, using 2DE approach coupled with MALDI-TOF/TOF, we have generated a common 2DE profile for all three stem cells. We found that 62.3 ± 7% of the protein spots were conserved among the three mesenchymal stem cell lines. Sixty-one of these conserved spots were identified by MALDI-TOF/TOF analysis. Classification of the identified proteins based on biological function revealed that structurally important proteins and proteins that are involved in protein folding machinery are predominantly expressed by all three stem cell lines. Some of these proteins may hold importance in understanding specific properties of human dental pulp derived mesenchymal stem cells. PMID:25379041

  14. Genotoxicity profiles in exfoliated human mammary cells recovered from lactating mothers in Istanbul; relationship with demographic and dietary factors.

    PubMed

    Yilmaz, Bayram; Sandal, Suleyman; Ayvaci, Habibe; Tug, Niyazi; Vitrinel, Ayca

    2012-12-12

    We have investigated the presence of DNA damage in human mammary epithelial cells collected from healthy lactating mothers (age, 20-35 years) who were resident in the Istanbul area. Breast milk (10ml) was collected from 30 women between one and two weeks post-partum. Demographic information (parity, breast cancer, occupation, duration of residency in Istanbul, consumption of fish, beef and poultry) was also obtained. Milk samples were diluted 1:1 with RPMI 1640 medium and centrifuged to collect cells. The cells were re-suspended and cell viability was determined by use of 0.4% trypan blue. DNA damage was assessed by use of the comet assay (alkaline single-cell gel electrophoresis). Fifty cells per slide and two slides per sample were scored to evaluate DNA damage. The cells were visually classified into four categories on the basis of extent of migration: undamaged (UD), lightly damaged (LD), moderately damaged (MD) and highly damaged (HD). Total comet scores (TCS) were calculated as: 1× UD+2× LD+3× MD+4× HD. Exfoliated mammary cells of the donors showed high (TCS≥150a.u.), moderate and low DNA damage in 10 (33.3%), 8 (26.7%) and 12 (40%) mothers, respectively. There was no significant correlation between TCS for DNA damage and the duration of previous breastfeeding, parity or age. None of the mothers was vegetarian, smoker or on any medication. Meat and chicken consumption did not significantly correlate with the TCS values. Fish consumption was significantly correlated with TCS results (Spearman's rho=0.39, p<0.05). No significant correlation was found between the DNA-damage scores and the period of residency in Istanbul, but fish consumption increased as the duration of stay was longer (Spearman's rho=0.53, p<0.01). These findings suggest that the primary causes of differences in genotoxicity detected in lactating mothers in Istanbul may be of dietary origin. Our experience also confirms that sampling breast milk from lactating mothers provides a valuable

  15. Chemosensory Functions for Pulmonary Neuroendocrine Cells

    PubMed Central

    Gu, Xiaoling; Karp, Philip H.; Brody, Steven L.; Pierce, Richard A.; Welsh, Michael J.; Holtzman, Michael J.

    2014-01-01

    The mammalian airways are sensitive to inhaled stimuli, and airway diseases are characterized by hypersensitivity to volatile stimuli, such as perfumes, industrial solvents, and others. However, the identity and function of the cells in the airway that can sense volatile chemicals remain uncertain, particularly in humans. Here, we show that solitary pulmonary neuroendocrine cells (PNECs), which are morphologically distinct and physiologically undefined, might serve as chemosensory cells in human airways. This conclusion is based on our finding that some human PNECs expressed members of the olfactory receptor (OR) family in vivo and in primary cell culture, and are anatomically positioned in the airway epithelium to respond to inhaled volatile chemicals. Furthermore, apical exposure of primary-culture human airway epithelial cells to volatile chemicals decreased levels of serotonin in PNECs, and the led to the release of the neuropeptide calcitonin gene-related peptide (CGRP) to the basal medium. These data suggest that volatile stimulation of PNECs can lead to the secretion of factors that are capable of stimulating the corresponding receptors in the lung epithelium. We also found that the distribution of serotonin and neuropeptide receptors may change in chronic obstructive pulmonary disease, suggesting that increased PNEC-dependent chemoresponsiveness might contribute to the altered sensitivity to volatile stimuli in this disease. Together, these data indicate that human airway epithelia harbor specialized cells that respond to volatile chemical stimuli, and may help to explain clinical observations of odorant-induced airway reactions. PMID:24134460

  16. Thermally exfoliated graphite oxide

    NASA Technical Reports Server (NTRS)

    Prud'Homme, Robert K. (Inventor); Aksay, Ilhan A. (Inventor); Abdala, Ahmed (Inventor)

    2011-01-01

    A modified graphite oxide material contains a thermally exfoliated graphite oxide with a surface area of from about 300 sq m/g to 2600 sq m/g, wherein the thermally exfoliated graphite oxide displays no signature of the original graphite and/or graphite oxide, as determined by X-ray diffraction.

  17. Pulmonary function testing and pulmonary Langerhans cell histiocytosis.

    PubMed

    Bernstrand, Cecilia; Cederlund, Kerstin; Henter, Jan-Inge

    2007-09-01

    In a long-term single-center follow-up (median 16-years), we studied high-resolution computed tomography (HRCT) and pulmonary function testing (PFT) in pulmonary LCH. Diffusing capacity corrected for alveolar volume (K(CO)) and total lung capacity (TLC) were significantly decreased (P=0.016 and P=0.030, respectively) in patients with extensive HRCT abnormalities. Patients with late stage disease on HRCT had increased forced expiratory volume (FEV1.0)(P=0.037) and vital capacity (VC)(P=0.036). Disease monitoring is important in pulmonary LCH, and since PFT with diffusing capacity provides a measurement of the current lung function, it may be a valuable tool in monitoring pulmonary LCH, and a good complement to imaging. PMID:16317743

  18. [Pulmonary Langerhans cell histiocytosis in adults].

    PubMed

    Feuillet, Séverine; Giroux-Leprieur, Bénédicte; Tazi, Abdellatif

    2010-01-01

    Pulmonary Langerhans-cell histiocytosis in adults is a rare condition of unknown etiology characterized by the accumulation of Langerhans cells organized in granulomas involving the distal bronchioles and destroying their walls. It occurs in young subjects who smoke, with frequency peaking between 20 and 40 years. High-resolution thoracic CT is essential for diagnosis; in typical forms it shows a combination of nodules, cavitary nodules, thick-walled cysts, and thin-walled cysts. Diagnostic certainty requires a surgical lung biopsy, by videothoracoscopy, but only if a specialist considers it indicated. It is difficult to predict the disease course for any given patient. A prospective multicenter cohort study currently underway should provide more information about the natural history of this disease. Management is empirical, for efficacy has not been proved for any treatment. Stopping smoking is especially important to prevent the added development of chronic obstructive pulmonary disease (COPD), cardiovascular complications, or the onset of bronchopulmonary cancer, the frequency of which appears elevated in these patients. Oral corticosteroids are used to treat disease progression, especially in the symptomatic mainly nodular forms, but their efficacy for respiratory function has not been shown. Vinblastine, the reference treatment for multisystem forms of Langerhans-cell histiocytosis, is not indicated for pulmonary involvement in adults. Better knowledge of the pathogenic mechanisms involved in this condition should eventually make it possible to develop innovative treatment strategies. The creation of the national reference center for Langerhans-cell histiocytosis has given new momentum to clinical and pathophysiologic research on this orphan disease. PMID:19959324

  19. Computer-assisted diagnostic tool to quantify the pulmonary veins in sickle cell associated pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Jajamovich, Guido H.; Pamulapati, Vivek; Alam, Shoaib; Mehari, Alem; Kato, Gregory J.; Wood, Bradford J.; Linguraru, Marius George

    2012-03-01

    Pulmonary hypertension is a common cause of death among patients with sickle cell disease. This study investigates the use of pulmonary vein analysis to assist the diagnosis of pulmonary hypertension non-invasively with CT-Angiography images. The characterization of the pulmonary veins from CT presents two main challenges. Firstly, the number of pulmonary veins is unknown a priori and secondly, the contrast material is degraded when reaching the pulmonary veins, making the edges of these vessels to appear faint. Each image is first denoised and a fast marching approach is used to segment the left atrium and pulmonary veins. Afterward, a geodesic active contour is employed to isolate the left atrium. A thinning technique is then used to extract the skeleton of the atrium and the veins. The locations of the pulmonary veins ostia are determined by the intersection of the skeleton and the contour of the atrium. The diameters of the pulmonary veins are measured in each vein at fixed distances from the corresponding ostium, and for each distance, the sum of the diameters of all the veins is computed. These indicators are shown to be significantly larger in sickle-cell patients with pulmonary hypertension as compared to controls (p-values < 0.01).

  20. CD133+ cells in pulmonary arterial hypertension.

    PubMed

    Foris, Vasile; Kovacs, Gabor; Marsh, Leigh M; Bálint, Zoltán; Tötsch, Martin; Avian, Alexander; Douschan, Philipp; Ghanim, Bahil; Klepetko, Walter; Olschewski, Andrea; Olschewski, Horst

    2016-08-01

    Circulating mononuclear cells may play an important role for the vascular remodelling in pulmonary arterial hypertension (PAH), but studies addressing multiple progenitor populations are rare and inconsistent.We used a comprehensive fluorescence-activated cell sorting analysis of circulating mononuclear cells in 20 PAH patients and 20 age- and sex-matched controls, and additionally analysed CD133(+) cells in the lung tissue of five PAH transplant recipients and five healthy controls (donor lungs).PAH patients were characterised by increased numbers of circulating CD133(+) cells and lymphopenia as compared with control. In PAH, CD133(+) subpopulations positive for CD117 or CD45 were significantly increased, whereas CD133(+)CD309(+), CD133(+)CXCR2(+) and CD133(+)CD31(+) cells were decreased. In CD133(+) cells, SOX2, Nanog, Ki67 and CXCR4 were not detected, but Oct3/4 mRNA was present in both PAH and controls. In the lung tissue, CD133(+) cells included three main populations: type 2 pneumocytes, monocytes and undifferentiated cells without significant differences between PAH and controls.In conclusion, circulating CD133(+) progenitor cells are elevated in PAH and consist of phenotypically different subpopulations that may be up- or downregulated. This may explain the inconsistent results in the literature. CD133(+) type 2 pneumocytes in the lung tissue are not associated with circulating CD133(+) mononuclear cells. PMID:27103380

  1. Pulmonary toxicity of cytostatic drugs: cell kinetics.

    PubMed

    Witschi, H; Godfrey, G; Frome, E; Lindenschmidt, R C

    1987-02-01

    Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid. PMID:3556836

  2. Pulmonary toxicity of cytostatic drugs: cell kinetics

    SciTech Connect

    Witschi, H.; Godfrey, G.; Frome, E.; Lindenschmidt, R.C.

    1987-02-01

    Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of /sup 3/H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid.

  3. Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons.

    PubMed

    Majumdar, Debanjana; Kanafi, Mohammad; Bhonde, Ramesh; Gupta, Pawan; Datta, Indrani

    2016-09-01

    Based on early occurrence in chronological age, stem-cells from human exfoliated deciduous teeth (SHED) has been reported to possess better differentiation-potential toward certain cell-lineage in comparison to stem-cells from adult teeth (DPSCs). Whether this same property between them extends for the yield of functional central nervous system neurons is still not evaluated. Hence, we aim to assess the neuronal plasticity of SHED in comparison to DPSCs toward dopaminergic-neurons and further, if the difference is reflected in a differential expression of sonic-hedgehog (SHH)-receptors and basal-expressions of tyrosine-hydroxylase [TH; through cAMP levels]. Human SHED and DPSCs were exposed to midbrain-cues [SHH, fibroblast growth-factor8, and basic fibroblast growth-factor], and their molecular, immunophenotypical, and functional characterization was performed at different time-points of induction. Though SHED and DPSCs spontaneously expressed early-neuronal and neural-crest marker in their naïve state, only SHED expressed a high basal-expression of TH. The upregulation of dopaminergic transcription-factors Nurr1, Engrailed1, and Pitx3 was more pronounced in DPSCs. The yield of TH-expressing cells decreased from 49.8% to 32.16% in SHED while it increased from 8.09% to 77.47% in DPSCs. Dopamine release and intracellular-Ca(2+) influx upon stimulation (KCl and ATP) was higher in induced DPSCs. Significantly lower-expression of SHH-receptors was noted in naïve SHED than DPSCs, which may explain the differential neuronal plasticity. In addition, unlike DPSCs, SHED showed a down-regulation of cyclic adenosine-monophosphate (cAMP) upon exposure to SHH; possibly another contributor to the lesser differentiation-potential. Our data clearly demonstrates for the first time that DPSCs possess superior neuronal plasticity toward dopaminergic-neurons than SHED; influenced by higher SHH-receptor and lower basal TH expression. J. Cell. Physiol. 231: 2048-2063, 2016. © 2016

  4. Respiratory epithelial cells orchestrate pulmonary innate immunity.

    PubMed

    Whitsett, Jeffrey A; Alenghat, Theresa

    2015-01-01

    The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury. PMID:25521682

  5. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome.

    PubMed

    Rossi, Giulio; Cavazza, Alberto; Spagnolo, Paolo; Sverzellati, Nicola; Longo, Lucia; Jukna, Agita; Montanari, Gloria; Carbonelli, Cristiano; Vincenzi, Giada; Bogina, Giuseppe; Franco, Renato; Tiseo, Marcello; Cottin, Vincent; Colby, Thomas V

    2016-06-01

    The term diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) may be used to describe a clinico-pathological syndrome, as well as an incidental finding on histological examination, although there are obvious differences between these two scenarios. According to the World Health Organization, the definition of DIPNECH is purely histological. However, DIPNECH encompasses symptomatic patients with airway disease, as well as asymptomatic patients with neuroendocrine cell hyperplasia associated with multiple tumourlets/carcinoid tumours. DIPNECH is also considered a pre-neoplastic lesion in the spectrum of pulmonary neuroendocrine tumours, because it is commonly found in patients with peripheral carcinoid tumours.In this review, we summarise clinical, physiological, radiological and histological features of DIPNECH and critically discuss recently proposed diagnostic criteria. In addition, we propose that the term "DIPNECH syndrome" be used to indicate a sufficiently distinct patient subgroup characterised by respiratory symptoms, airflow obstruction, mosaic attenuation with air trapping on chest imaging and constrictive obliterative bronchiolitis, often with nodular proliferation of neuroendocrine cells with/without tumourlets/carcinoid tumours on histology. Surgical lung biopsy is the diagnostic gold standard. However, in the appropriate clinical and radiological setting, transbronchial lung biopsy may also allow a confident diagnosis of DIPNECH syndrome. PMID:27076588

  6. Comparative analysis of proliferation and differentiation potentials of stem cells from inflamed pulp of deciduous teeth and stem cells from exfoliated deciduous teeth.

    PubMed

    Yu, Shi; Diao, Shu; Wang, Jinsong; Ding, Gang; Yang, Dongmei; Fan, Zhipeng

    2014-01-01

    Stem cells isolated from exfoliated deciduous teeth (SHEDs) are highly capable of proliferation and differentiation, and they represent good cell sources for mesenchymal stem cell- (MSC-) mediated dental tissue regeneration, but the supply of SHEDs is limited. A previous study found that stem cells could be isolated from inflamed tissues, but it is unknown whether primary dental pulp diagnosed with irreversible pulpitis might contain stem cells with appropriate tissue regeneration capacity. In this study, we aimed to isolate stem cells from both inflamed pulps of deciduous teeth (SCIDs) and SHEDs from Chinese children and to compare their proliferation and differentiation potentials. Our results showed that SCIDs were positive for cell surface markers, including CD105, CD90, and CD146, and they had high proliferation ability and osteogenic, adipogenic, and chondrogenic differentiation potentials. There was no significant difference in proliferation and differentiation potentials between SCIDs and SHEDs. The mRNA of inflammatory factors, including IL-1β, IL-6, and TNF-α, was expressed at similar levels in SCIDs and SHEDs, but SCIDs secreted more TNF-α protein. In conclusion, our in vitro results showed that SCIDs have proliferation and differentiation potentials similar to those of SHEDs. Thus, SCIDs represent a new potentially applicable source for MSC mediated tissue regeneration. PMID:25045714

  7. Comparative Analysis of Proliferation and Differentiation Potentials of Stem Cells from Inflamed Pulp of Deciduous Teeth and Stem Cells from Exfoliated Deciduous Teeth

    PubMed Central

    Yu, Shi; Diao, Shu; Wang, Jinsong; Ding, Gang; Yang, Dongmei; Fan, Zhipeng

    2014-01-01

    Stem cells isolated from exfoliated deciduous teeth (SHEDs) are highly capable of proliferation and differentiation, and they represent good cell sources for mesenchymal stem cell- (MSC-) mediated dental tissue regeneration, but the supply of SHEDs is limited. A previous study found that stem cells could be isolated from inflamed tissues, but it is unknown whether primary dental pulp diagnosed with irreversible pulpitis might contain stem cells with appropriate tissue regeneration capacity. In this study, we aimed to isolate stem cells from both inflamed pulps of deciduous teeth (SCIDs) and SHEDs from Chinese children and to compare their proliferation and differentiation potentials. Our results showed that SCIDs were positive for cell surface markers, including CD105, CD90, and CD146, and they had high proliferation ability and osteogenic, adipogenic, and chondrogenic differentiation potentials. There was no significant difference in proliferation and differentiation potentials between SCIDs and SHEDs. The mRNA of inflammatory factors, including IL-1β, IL-6, and TNF-α, was expressed at similar levels in SCIDs and SHEDs, but SCIDs secreted more TNF-α protein. In conclusion, our in vitro results showed that SCIDs have proliferation and differentiation potentials similar to those of SHEDs. Thus, SCIDs represent a new potentially applicable source for MSC mediated tissue regeneration. PMID:25045714

  8. Morphologic and cytomorphometric analysis of exfoliated buccal mucosal cells in diabetes patients

    PubMed Central

    Prasad, H; Ramesh, V; Balamurali, PD

    2010-01-01

    Background: It is now known that the disease process of diabetes has effects on various tissues of the body. The following study was done to analyze the effects of diabetes on oral tissues. Aims: To study the morphology and cytomorphometry of the cells obtained in cytologic smears from the buccal mucosa of diabetic patients. Materials and Methods: Smears were obtained from clinically normal buccal mucosa of 50 randomly selected diabetic patients attending the diabetic clinic and the out-patient department and of five healthy subjects as control. Smears were stained using Papanicolaou method, and using a micrometer mean values of nuclear diameter (ND), cell diameter (CD), cytoplasmic diameter (CyD) and nucleus: cytoplasm ratio (N: C ratio) were obtained for each patient. Diabetic patients were divided into four groups based on the glycosylated hemoglobin (GHb) values for comparison. Statistical analysis used: Student’s T-test and Fisher’s F-test. Results: Statistically significant increase in ND (P=0.0367) was found in diabetic patients compared to controls. Degree of glycemic control significantly affected ND (P=0.0042) and N: C ratio (P=0.0055). In general, as the severity of diabetes increases, ND and N: C ratio rise gradually. Conclusions: Diabetes produces definite morphologic and cytomorphometric changes in the buccal mucosa of patients. However, further research in this direction is indicated, to analyze the significance of these findings as a tool for diabetes detection, as well as to obtain deeper insights into its effects on various tissues. PMID:21157560

  9. PULMONARY CELL POPULATIONS IN HAMSTERS MAINTAINED UNDER EGYPTIAN LABORATORY CONDITIONS

    EPA Science Inventory

    The study was conducted to obtain baseline values for pulmonary cells in golden hamsters (Mesocricetus auratus) bred and maintained under the laboratory conditions of Al-Azhar University in Egypt. An improvised technique is presented for measuring pulmonary cells obtained by lung...

  10. Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes.

    PubMed

    Sathyanarayana, Ubaradka G; Maruyama, Riichiroh; Padar, Asha; Suzuki, Makoto; Bondaruk, Jolanta; Sagalowsky, Arthur; Minna, John D; Frenkel, Eugene P; Grossman, H Barton; Czerniak, Bogdan; Gazdar, Adi F

    2004-02-15

    Laminin-5 (LN5) anchors epithelial cells to the underlying basement membrane, and it is encoded by three distinct genes: LAMA3, LAMB3, and LAMC2. To metastasize and grow, cancer cells must invade and destroy the basement membrane. Our previous work has shown that epigenetic inactivation is a major mechanism of silencing LN5 genes in lung cancers. We extended our methylation studies to resected bladder tumors (n = 128) and exfoliated cell samples (bladder washes and voided urine; n = 71) and correlated the data with clinicopathologic findings. Nonmalignant urothelium had uniform expression of LN5 genes and lacked methylation. The methylation frequencies for LN5 genes in tumors were 21-45%, and there was excellent concordance between methylation in tumors and corresponding exfoliated cells. Methylation of LAMA3 and LAMB3 and the methylation index were correlated significantly with several parameters of poor prognosis (tumor grade, growth pattern, muscle invasion, tumor stage, and ploidy pattern), whereas methylation of LAMC2 and methylation index were associated with shortened patient survival. Of particular interest, methylation frequencies of LAMA3 helped to distinguish invasive (72%) from noninvasive (12%) tumors. These results suggest that methylation of LN5 genes has potential clinical applications in bladder cancers. PMID:14973053

  11. Lymphatic endothelial differentiation in pulmonary lymphangioleiomyomatosis cells.

    PubMed

    Davis, Jennifer M; Hyjek, Elizabeth; Husain, Aliya N; Shen, Le; Jones, Jennifer; Schuger, Lucia A

    2013-08-01

    Pulmonary lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm affecting almost exclusively women of childbearing age. LAM belongs to the family of perivascular epithelioid cell tumors, characterized by spindle and epithelioid cells with smooth muscle and melanocytic differentiation. LAM cells infiltrate the lungs, producing multiple, bilateral lesions rich in lymphatic channels and forming cysts, leading to respiratory insufficiency. Here we used antibodies against four lymphatic endothelial markers-podoplanin (detected by D2-40), prospero homeobox 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR-3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)-to determine whether LAM cells show lymphatic differentiation. Twelve of 12 diagnostic biopsy specimens (early-stage LAM) and 19 of 19 explants (late-stage LAM) showed immunopositivity for D2-40 in most neoplastic cells. PROX1, VEGFR-3, and LYVE1 immunoreactivity varied from scarce in the early stage to abundant in the late stage. Lymphatic endothelial, smooth muscle, and melanocytic markers were partially co-localized. These findings indicate that lymphatic endothelial differentiation is a feature of LAM and provide evidence of a previously unidentified third lineage of differentiation in this neoplasm. This study has implications for the histological diagnosis of LAM, the origin of the neoplastic cells, and potential future treatment with drugs targeting lymphangiogenesis. PMID:23609227

  12. Confocal microscopy and exfoliative cytology

    PubMed Central

    Reddy, Shyam Prasad; Ramani, Pratibha; Nainani, Purshotam

    2013-01-01

    Context: Early detection of potentially malignant lesions and invasive squamous-cell carcinoma in the oral cavity could be greatly improved through techniques that permit visualization of subtle cellular changes indicative of the neoplastic transformation process. One such technique is confocal microscopy. Combining rapidity with reliability, an innovative idea has been put forward using confocal microscope in exfoliative cytology. Aims: The main objective of this study was to assess confocal microscopy for cytological diagnosis and the results were compared with that of the standard PAP stain. Settings and Design: Confocal microscope, acridine orange (AO) stain, PAP (Papanicolaou) stain. The study was designed to assess confocal microscopy for cytological diagnosis. In the process, smears of patients with (clinically diagnosed and/or suspected) oral squamous cell carcinoma as well as those of controls (normal people) were stained with acridine orange and observed under confocal microscope. The results were compared with those of the standard PAP method. Materials and Methods: Samples of buccal mucosa smears from normal patients and squamous cell carcinoma patients were made, fixed in 100% alcohol, followed by AO staining. The corresponding set of smears was stained with PAP stain using rapid PAP stain kit. The results obtained were compared with those obtained with AO confocal microscopy. Results: The study had shown nuclear changes (malignant cells) in the smears of squamous cell carcinoma patients as increased intensity of fluorescence of the nucleus, when observed under confocal microscope. Acridine orange confocal microscopy showed good amount of sensitivity and specificity (93%) in identifying malignant cells in exfoliative cytological smears. Conclusion: Confocal microscopy was found to have good sensitivity in the identification of cancer (malignant) cells in exfoliative cytology, at par with the PAP method. The rapidity of processing and screening a

  13. Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

    PubMed Central

    Ochoa, Cristhiaan D.; Baker, Haven; Hasak, Stephen; Matyal, Robina; Salam, Aleya; Hales, Charles A.; Hancock, William; Quinn, Deborah A.

    2008-01-01

    Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC-conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1–blocking antibodies reversed conditioned media–induced inhibition of PASMC growth. Cyclic stretched PAECs secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling. PMID:18314539

  14. Genotoxic and histopathological biomarkers for assessing the effects of magnetic exfoliated vermiculite and exfoliated vermiculite in Danio rerio.

    PubMed

    Cáceres-Vélez, Paolin Rocio; Fascineli, Maria Luiza; Grisolia, Cesar Koppe; de Oliveira Lima, Emília Celma; Sousa, Marcelo Henrique; de Morais, Paulo César; Bentes de Azevedo, Ricardo

    2016-05-01

    Magnetic exfoliated vermiculite is a synthetic nanocomposite that quickly and efficiently absorbs organic compounds such as oil from water bodies. It was developed primarily to mitigate pollution, but the possible adverse impacts of its application have not yet been evaluated. In this context, the acute toxicity of magnetic exfoliated vermiculite and exfoliated vermiculite was herein assessed by genotoxic and histopathological biomarkers in zebrafish (Danio rerio). DNA fragmentation was statistically significant for all groups exposed to the magnetic exfoliated vermiculite and for fish exposed to the highest concentration (200mg/L) of exfoliated vermiculite, whereas the micronucleus frequency, nuclear abnormalities and histopathological alterations were not statistically significant for the fish exposed to these materials. In the intestinal lumen, epithelial cells and goblet cells, we found the presence of magnetic exfoliated vermiculite and exfoliated vermiculite, but no alterations or presence of the materials-test in the gills or liver were observed. Our findings suggest that the use of magnetic exfoliated vermiculite and exfoliated vermiculite during standard ecotoxicological assays caused DNA damage in D. rerio, whose alterations may be likely to be repaired, indicating that the magnetic nanoparticles have the ability to promote genotoxic damage, such as DNA fragmentation, but not mutagenic effects. PMID:26878635

  15. Use of the fluorescent micronucleus assay to detect the genotoxic effects of radiation and arsenic exposure in exfoliated human epithelial cells

    SciTech Connect

    Moore, L.E.; Warner, M.L.; Smith, A.H.

    1996-12-31

    The exfoliated cell micronucleus (MN) assay using fluorescent in situ hybridization (FISH) with a centromeric probe is a rapid method for determining the mechanism of MN formation in epithelial tissues exposed to carcinogenic agents. Here, we describe the use of this assay to detect the presence or absence of centromeric DNA in MN induced in vivo by radiation therapy and chronic arsenic (As) ingestion. We examined the buccal cells of an individual receiving 6,500 rads of photon radiation to the head and neck. Exfoliated cells were collected before, during, and after treatment. After radiation exposure a 16.6-fold increase in buccal cell MN frequency was seen. All induced MN were centromere negative (MN-) resulting from chromosome breakage. This finding is consistent with the clastogenic action of radiation and confirmed the reliability of the method. Three weeks post-therapy, MN frequencies returned to baseline. The assay was used on 18 people chronically exposed to high levels of inorganic arsenic (In-As) in drinking water (average level, 1,312 {mu}g As/L) and 18 matched controls (average level, 16 {mu}g As/L). The combined increase in MN frequency was 1.8-fold (P = 0.001, Fisher`s exact test). Frequencies of micronuclei containing acentric fragments (MN-) and those containing whole chromosomes (MN+) both increased, suggesting that arsenic may have both clastogenic and weak aneuploidogenic properties in vivo. After stratification on sex, the effect was stronger in male than in female bladder cells. In males the MN-frequency increased 2.06-fold (P =0.07) while the frequency of MN+ increased 1.86-fold (P = 0.08). In addition, the frequencies of MN and MN+ were positively associated with urinary arsenic and its metabolites. The association was stronger for micronuclei containing acentric fragments. By using FISH with centromeric probes, the mechanism of chemically induced genotoxicity can not be determined in epithelial tissues. 35 refs., 4 tabs.

  16. Pulmonary hypertension due to isolated metastatic squamous cell carcinoma thromboemboli.

    PubMed

    Wilson, Michael K; Granger, Emily K; Preda, Veronica A

    2006-04-01

    Pulmonary hypertension as the initial presentation of occult malignancy is extremely rare. The differential diagnosis of pulmonary hypertension due to arterial tumour embolism is often overlooked and deserves contemplation. Our case report details the presentation of cardiorespiratory decompensation from an assumed classic saddle pulmonary embolus in a previously fit, well 80-year-old gentleman. The patient underwent successful pulmonary thromboendarterectomy, however, intraoperatively the specimen was noted to be atypical. This resulted in the surprising definitive diagnosis of thromboembolic pulmonary hypertension secondary to laminated thrombi of metastatic squamous cell tumour emboli. The site of tumour origin was however not histologically apparent and was unable to be elucidated on extensive further investigation. Post-operatively the patient had considerable subjective and functional improvement returning to activities of daily living. He however passed away some 9 months later. PMID:16412689

  17. Major Pulmonary Complications After Hematopoietic Stem Cell Transplant.

    PubMed

    Diab, Maria; ZazaDitYafawi, Jihane; Soubani, Ayman O

    2016-06-01

    Both autologous and allogeneic hematopoietic stem cell transplants are important therapeutic options for several benign and malignant disorders. Pulmonary complications, although they have become less frequent, remain a significant cause of morbidity and mortality after hematopoietic stem cell transplant. These complications range from bacterial, fungal, and viral pulmonary infections to noninfectious conditions such as diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. Bronchiolitis obliterans syndrome is the primary chronic pulmonary complication, and treatment of this condition remains challenging. This report highlights the advances in the diagnosis and management of the major pulmonary complications after hematopoietic stem cell transplant. It also underscores the need for prospective and multicenter research to have a better understanding of the mechanisms behind these complications and to obtain more effective diagnostic tool and therapeutic options. PMID:27040986

  18. Effect of chitosan conduit under a dynamic culture on the proliferation and neural differentiation of human exfoliated deciduous teeth stem cells.

    PubMed

    Su, Wen-Ta; Shih, Yi-An; Ko, Chih-Sheng

    2016-06-01

    Ex vivo engineering of artificial nerve conduit is a suitable alternative clinical treatment for nerve injuries. Stem cells from human exfoliated deciduous teeth (SHEDs) have been considered as alternative sources of adult stem cells because of their potential to differentiate into multiple cell lineages. These cells, when cultured in six-well plates, exhibited a spindle fibroblastic morphology, whereas those under a dynamic culture aggregated into neurosphere-like clusters in the chitosan conduit. In this study, we confirmed that SHEDs efficiently express the neural stem cell marker nestin, the early neural cell marker β-III-tubulin, the late neural marker neuron-specific enolase and the glial cell markers glial fibrillary acidic protein (GFAP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). The three-dimensional chitosan conduit and dynamic culture system generated fluid shear stress and enhanced nutrient transfer, promoting the differentiation of SHEDs to neural cells. In particular, the gene expressions of GFAP and CNPase increased by 28- and 53-fold, respectively. This study provides evidence for the dynamic culture of SHEDs during ex vivo neural differentiation and demonstrates its potential for cell therapy in neurological diseases. Copyright © 2013 John Wiley & Sons, Ltd. PMID:24130037

  19. [Staphylococcal epidermal exfoliation (Ritter's disease)].

    PubMed

    Ruiz Maldonado, R; Tamayo, L; Vazquez, V; Dominguez, J

    1976-01-01

    According to the authors the best designation of Ritter's disease would be "staphilococcic epidermal exfoliation" SEE. The physiopathological and agnoslogical basis for this denomination could be the following: 1st The "S. aureus" is the ehtiological agent of the SSE in man. The Koch postulates necessary to confirm this hypothesis have been accomplished. 2nd "Staphylococcus aureus" produces a thermostable toxin that is active indepently of the staphilococcus and gives rise to the separation of the cells of the stratum granulosus of the epidermis and eventually exfoliation in suckling babies and in the newborn mouse. 3rd The "Staphylococcus aureus" may be present on the skin or in other localisations such as the bowel or pharinx. 4th The viable "S. aureus" when administered subcutaneously to the adult mice gives rise to lesions clinically and histologically similar to the impetigo observed in children. 5th The "S. aureus" killed by means of autoclave (that is, the staphylococcic toxine by itself does not give rise to any lesion when administered to the healthy adult mouse). Neijther has the SEE been observed in healthy adult man. The authors reach the conclusion that the SSE and the toxic epidermal necrolysis are basically different according to the histopathology therapeutic response and prognosis and they must be considered as independant entities. PMID:138775

  20. Pulmonary Langerhans Cell Histiocytosis-associated Pulmonary Hypertension Showing a Drastic Improvement Following Smoking Cessation.

    PubMed

    Kinoshita, Yoshiaki; Watanabe, Kentaro; Sakamoto, Atsuhiko; Hidaka, Kouko

    2016-01-01

    Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking-related, interstitial lung disease, and pulmonary hypertension (PH) is associated with mortality. We herein report a case of PLCH complicated by severe PH and respiratory impairment. After developing PH, the patient displayed a cystic pattern on chest high-resolution computed tomography (HRCT). This, in turn, corresponded with the scarring stage of PLCH. However, the patient's PH and respiratory impairment improve dramatically following smoking cessation. PLCH patients with a cystic pattern on chest HRCT may still be able to improve their PH and respiratory impairment when they are able to quit smoking. PMID:26935369

  1. Protective role of Th17 cells in pulmonary infection.

    PubMed

    Rathore, Jitendra Singh; Wang, Yan

    2016-03-18

    Th17 cells are characterized as preferential producer of interleukins including IL-17A, IL-17F, IL-21 and IL-22. Corresponding receptors of these cytokines are expressed on number of cell types found in the mucosa, including epithelial cells and fibroblasts which constitute the prime targets of the Th17-associated cytokines. Binding of IL-17 family members to their corresponding receptors lead to modulation of antimicrobial functions of target cells including alveolar epithelial cells. Stimulated alveolar epithelial cells produce antimicrobial peptides and are involved in granulepoesis, neutrophil recruitment and tissue repair. Mucosal immunity mediated by Th17 cells is protective against numerous pulmonary pathogens including extracellular bacterial and fungal pathogens. This review focuses on the protective role of Th17 cells during pulmonary infection, highlighting subset differentiation, effector cytokines production, followed by study of the binding of these cytokines to their corresponding receptors, the subsequent signaling pathway they engender and their effector role in host defense. PMID:26878294

  2. Control of Francisella tularensis Intracellular Growth by Pulmonary Epithelial Cells

    PubMed Central

    Maggio, Savannah; Takeda, Kazuyo; Stark, Felicity; Meierovics, Anda I.; Yabe, Idalia; Cowley, Siobhan C.

    2015-01-01

    The virulence of F. tularensis is often associated with its ability to grow in macrophages, although recent studies show that Francisella proliferates in multiple host cell types, including pulmonary epithelial cells. Thus far little is known about the requirements for killing of F. tularensis in the non-macrophage host cell types that support replication of this organism. Here we sought to address this question through the use of a murine lung epithelial cell line (TC-1 cells). Our data show that combinations of the cytokines IFN-γ, TNF, and IL-17A activated murine pulmonary epithelial cells to inhibit the intracellular growth of the F. tularensis Live Vaccine Strain (LVS) and the highly virulent F. tularensis Schu S4 strain. Although paired combinations of IFN-γ, TNF, and IL-17A all significantly controlled LVS growth, simultaneous treatment with all three cytokines had the greatest effect on LVS growth inhibition. In contrast, Schu S4 was more resistant to cytokine-induced growth effects, exhibiting significant growth inhibition only in response to all three cytokines. Since one of the main antimicrobial mechanisms of activated macrophages is the release of reactive nitrogen intermediates (RNI) via the activity of iNOS, we investigated the role of RNI and iNOS in Francisella growth control by pulmonary epithelial cells. NOS2 gene expression was significantly up-regulated in infected, cytokine-treated pulmonary epithelial cells in a manner that correlated with LVS and Schu S4 growth control. Treatment of LVS-infected cells with an iNOS inhibitor significantly reversed LVS killing in cytokine-treated cultures. Further, we found that mouse pulmonary epithelial cells produced iNOS during in vivo respiratory LVS infection. Overall, these data demonstrate that lung epithelial cells produce iNOS both in vitro and in vivo, and can inhibit Francisella intracellular growth via reactive nitrogen intermediates. PMID:26379269

  3. Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure.

    PubMed

    Schreier, David A; Forouzan, Omid; Hacker, Timothy A; Sheehan, John; Chesler, Naomi

    2016-02-01

    Patients with sickle cell anemia (SCD) and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are stiffer, more dense, more frequently undergo hemolysis, and have a sixfold shorter lifespan compared to normal RBCs. Here, we sought to investigate the impact of increased RBC stiffness, independent of other SCD-related biological and mechanical RBC abnormalities, on the hemodynamic changes that ultimately cause PH and increase mortality in SCD. To do so, pulmonary vascular impedance (PVZ) measures were recorded in control C57BL6 mice before and after ∼50 μl of blood (Hct = 45%) was extracted and replaced with an equal volume of blood containing either untreated RBCs or RBCs chemically stiffened with glutaraldehyde (Hct = 45%). Chemically stiffened RBCs increased mean pulmonary artery pressure (mPAP) (13.5 ± 0.6 mmHg at baseline to 23.2 ± 0.7 mmHg after the third injection), pulmonary vascular resistance (PVR) (1.23 ± 0.11 mmHg*min/ml at baseline to 2.24 ± 0.14 mmHg*min/ml after the third injection), and wave reflections (0.31 ± 0.02 at baseline to 0.43 ± 0.03 after the third injection). Chemically stiffened RBCs also decreased cardiac output, but did not change hematocrit, blood viscosity, pulmonary arterial compliance, or heart rate. The main finding of this study is that increased RBC stiffness alone affects pulmonary pulsatile hemodynamics, which suggests that RBC stiffness plays an important role in the development of PH in patients with SCD. PMID:26638883

  4. Cytogenetic Abnormality in Exfoliated Cells of Buccal Mucosa in Head and Neck Cancer Patients in the Tunisian Population: Impact of Different Exposure Sources

    PubMed Central

    Khlifi, Rim; Trabelsi-Ksibi, Fatma; Chakroun, Amine; Rebai, Ahmed; Hamza-Chaffai, Amel

    2013-01-01

    Chromosome/DNA instability could be one of the primary causes of malignant cell transformation. The objective of the present study was to evaluate the spontaneous genetic damages in exfoliated cells of buccal mucosa of head and neck cancer (HNC) by counting micronucleus (MN) and binucleated (BN) cells frequencies. MN and BN frequencies were significantly increased in HNC patients compared with controls (5.53 ± 3.09/1000 cells, 5.63 ± 2.99/1000 cells versus 2.36 ± 2.11/1000 cells, 3.09 ± 1.82/1000 cells, P < 0.001). Regarding the gender and the age, the frequencies of the MN and BN were significantly higher than those of controls (P < 0.01). The evaluation of the MN and BN frequencies revealed a significant increase (P < 0.001) in the cases in relation to the control group after controlling the risk factors (tobacco smoking and chewing and occupational exposure) of HNC. Moreover, MN and BN frequencies were significantly increased in smokers and chewers compared with nonsmokers and nonchewers among patients (P < 0.05). MN frequency was significantly (P = 0.014) different between patients occupationally exposed (6.99 ± 3.40/1000 cells) and nonexposed (4.70 ± 2.48/1000 cells) among HNC group. The logistic regression model illustrated that HNC was significantly associated with frequencies of MN (OR = 8.63, P < 0.0001) and BN (OR = 5.62, P = 0.001). Our results suggest that increased chromosome/DNA instabilities may be associated with HNC. PMID:23957010

  5. Monitoring genotoxicity among gasoline station attendants and traffic enforcers in the City of Manila using the micronucleus assay with exfoliated epithelial cells.

    PubMed

    Hallare, A V; Gervasio, M K R; Gervasio, P L G; Acacio-Claro, P J B

    2009-09-01

    Some types of occupations involve high levels of exposure to potentially genotoxic gaseous and particulate substances from internal combustion engines used in motor vehicles. These occupational exposures may contribute to the development of many illnesses, usually through chromosomal change mechanisms that include strand breakage, deletions, sister chromatid exchange and non-disjunction. To determine the effect of occupational exposure in gasoline station attendants and traffic enforcers, the micronucleus test was used. Exfoliated oral mucosa cells from 18 gasoline station attendants, 18 traffic enforcers and 18 control subjects in the City of Manila were examined for micronucleated cell (MNC) frequency. Analysis of buccal cells showed that MNC frequencies in exposed individuals were significantly greater than in control subjects (p < or = 0.05). However, between gasoline station attendants and traffic enforcers, MNC frequencies of the two exposed groups exhibited no significant difference. No relation was also found between MNC frequency and any of the factors such as age, smoking habits, alcohol habits and working period. This was further confirmed in the multiple regression analysis which showed that only occupational exposure was a good predictor of MNC frequency. The results of this study suggest that gasoline station attendants and traffic enforcers, compared to the control individuals, are at a greater risk of chromosomal damage. For the assessment of chromosomal damage, the study, development, and standardization of tests are recommended for public institutions concerned with matters regarding environmental quality and community health. PMID:18712612

  6. Club cell protein 16 as a biomarker in pulmonary contusion

    PubMed Central

    Wu, Feng; Ding, Boying; Yang, Xiaolong; Ma, Dongchun; Zhang, Chaodong; Hua, Congshu

    2016-01-01

    The aim of the present study was to investigate the variation and clinical significance of the 16-kDa club cell protein (CC16) in patients with pulmonary contusion. A total of 42 patients with pulmonary contusion were divided into experimental groups I (n=24, moderate pulmonary contusion) and II (n=18, severe pulmonary contusion). An enzyme-linked immunosorbent assay was used to detect the serum levels of CC16 in the two groups of patients within 24 h after the incident and at days 1, 3, 7 and 14 after treatment. The results were compared with another 16 healthy subjects included as the controls. The serum CC16 level at each time point was higher in the two experimental groups compared to the controls (P<0.01). The difference was significant when regarding the levels of CC16 measured within 24 h after contusion and at days 1, 3, 7 and 14 after treatment (P<0.01); however, the levels appeared to decline. In addition, the levels at each time point in experimental group II were significantly higher compared to group I (P<0.01). In conclusion, serum CC16 levels are markedly elevated at the early stage of pulmonary contusion and appear to decrease following treatment. An increase of the CC16 levels is associated with the degree of injury, for which measurement of the levels may serve as a biomarker for evaluation of the serious condition of this pulmonary contusion. PMID:27446552

  7. Comprehensive Cytomorphologic Analysis of Pulmonary Adenoid Cystic Carcinoma: Comparison to Small Cell Carcinoma and Non-pulmonary Adenoid Cystic Carcinoma

    PubMed Central

    Kim, Seokhwi; Chu, Jinah; Kim, Hojoong; Han, Joungho

    2015-01-01

    Background: Cytologic diagnosis of pulmonary adenoid cystic carcinoma (AdCC) is frequently challenging and differential diagnosis with small cell carcinoma is often difficult. Methods: Eleven cytologically diagnosed cases of pulmonary AdCC were collected and reviewed according to fifteen cytomorphologic characteristics: small cell size, cellular uniformity, coarse chromatin, hyperchromasia, distinct nucleolus, frequent nuclear molding, granular cytoplasm, organoid cluster, sheet formation, irregular border of cluster, hyaline globule, hyaline basement membrane material, individual cell necrosis or apoptotic body, and necrotic background. Twenty cases of small cell carcinoma and fifteen cases of non-pulmonary AdCC were also reviewed for the comparison. Results: Statistically significant differences were identified between pulmonary AdCC and small cell carcinoma in fourteen of the fifteen cytomorphologic criteria (differences in sheet formation were not statistically significant). Cellular uniformity, distinct nucleolus, granular cytoplasm, distinct cell border, organoid cluster, hyaline globule, and hyaline basement membrane material were characteristic features of AdCC. Frequent nuclear molding, individual cell necrosis, and necrotic background were almost exclusively identified in small cell carcinoma. Although coarse chromatin and irregular cluster border were observed in both, they favored the diagnosis of small cell carcinoma. Hyaline globules were more frequently seen in non-pulmonary AdCC cases. Conclusions: Using the fifteen cytomorphologic criteria described by this study, pulmonary AdCC could be successfully distinguished from small cell carcinoma. Such a comprehensive approach to an individual case is recommended for the cytologic diagnosis of pulmonary AdCC. PMID:26477588

  8. Raman spectroscopy and oral exfoliative cytology

    NASA Astrophysics Data System (ADS)

    Sahu, Aditi; Shah, Nupur; Mahimkar, Manoj; Garud, Mandavi; Pagare, Sandeep; Nair, Sudhir; Krishna, C. Murali

    2014-03-01

    Early detection of oral cancers can substantially improve disease-free survival rates. Ex vivo and in vivo Raman spectroscopic (RS) studies on oral cancer have demonstrated the applicability of RS in identifying not only malignant and premalignant conditions but also cancer-field-effects: the earliest events in oral carcinogenesis. RS has also been explored for cervical exfoliated cells analysis. Exfoliated cells are associated with several advantages like non-invasive sampling, higher patient compliance, transportation and analysis at a central facility: obviating need for on-site instrumentation. Thus, oral exfoliative cytology coupled with RS may serve as a useful adjunct for oral cancer screening. In this study, exfoliated cells from healthy controls with and without tobacco habits, premalignant lesions (leukoplakia and tobacco-pouch-keratosis) and their contralateral mucosa were collected using a Cytobrush. Cells were harvested by vortexing and centrifugation at 6000 rpm. The cellular yield was ascertained using Neubauer's chamber. Cell pellets were placed on a CaF2 window and Raman spectra were acquired using a Raman microprobe (40X objective) coupled HE-785 Raman spectrometer. Approximately 7 spectra were recorded from each pellet, following which pellet was smeared onto a glass slide, fixed in 95% ethanol and subjected to Pap staining for cytological diagnosis (gold standard). Preliminary PC-LDA followed by leave-one-out cross validation indicate delineation of cells from healthy and all pathological conditions. A tendency of classification was also seen between cells from contralateral, healthy tobacco and site of premalignant lesions. These results will be validated by cytological findings, which will serve as the basis for building standard models of each condition.

  9. Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension to vasodilator therapy.

    PubMed

    May, Adam; Kane, Garvan; Yi, Eunhee; Frantz, Robert; Vassallo, Robert

    2015-01-01

    Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH. PMID:26029568

  10. Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension to vasodilator therapy

    PubMed Central

    May, Adam; Kane, Garvan; Yi, Eunhee; Frantz, Robert; Vassallo, Robert

    2014-01-01

    Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH. PMID:26029568

  11. Vasculopathy and pulmonary hypertension in sickle cell disease.

    PubMed

    Potoka, Karin P; Gladwin, Mark T

    2015-02-15

    Sickle cell disease (SCD) is an autosomal recessive disorder in the gene encoding the β-chain of hemoglobin. Deoxygenation causes the mutant hemoglobin S to polymerize, resulting in rigid, adherent red blood cells that are entrapped in the microcirculation and hemolyze. Cardinal features include severe painful crises and episodic acute lung injury, called acute chest syndrome. This population, with age, develops chronic organ injury, such as chronic kidney disease and pulmonary hypertension. A major risk factor for developing chronic organ injury is hemolytic anemia, which releases red blood cell contents into the circulation. Cell free plasma hemoglobin, heme, and arginase 1 disrupt endothelial function, drive oxidative and inflammatory stress, and have recently been referred to as erythrocyte damage-associated molecular pattern molecules (eDAMPs). Studies suggest that in addition to effects of cell free plasma hemoglobin on scavenging nitric oxide (NO) and generating reactive oxygen species (ROS), heme released from plasma hemoglobin can bind to the toll-like receptor 4 to activate the innate immune system. Persistent intravascular hemolysis over decades leads to chronic vasculopathy, with ∼10% of patients developing pulmonary hypertension. Progressive obstruction of small pulmonary arterioles, increase in pulmonary vascular resistance, decreased cardiac output, and eventual right heart failure causes death in many patients with this complication. This review provides an overview of the pathobiology of hemolysis-mediated endothelial dysfunction and eDAMPs and a summary of our present understanding of diagnosis and management of pulmonary hypertension in sickle cell disease, including a review of recent American Thoracic Society (ATS) consensus guidelines for risk stratification and management. PMID:25398989

  12. Vasculopathy and pulmonary hypertension in sickle cell disease

    PubMed Central

    Potoka, Karin P.

    2014-01-01

    Sickle cell disease (SCD) is an autosomal recessive disorder in the gene encoding the β-chain of hemoglobin. Deoxygenation causes the mutant hemoglobin S to polymerize, resulting in rigid, adherent red blood cells that are entrapped in the microcirculation and hemolyze. Cardinal features include severe painful crises and episodic acute lung injury, called acute chest syndrome. This population, with age, develops chronic organ injury, such as chronic kidney disease and pulmonary hypertension. A major risk factor for developing chronic organ injury is hemolytic anemia, which releases red blood cell contents into the circulation. Cell free plasma hemoglobin, heme, and arginase 1 disrupt endothelial function, drive oxidative and inflammatory stress, and have recently been referred to as erythrocyte damage-associated molecular pattern molecules (eDAMPs). Studies suggest that in addition to effects of cell free plasma hemoglobin on scavenging nitric oxide (NO) and generating reactive oxygen species (ROS), heme released from plasma hemoglobin can bind to the toll-like receptor 4 to activate the innate immune system. Persistent intravascular hemolysis over decades leads to chronic vasculopathy, with ∼10% of patients developing pulmonary hypertension. Progressive obstruction of small pulmonary arterioles, increase in pulmonary vascular resistance, decreased cardiac output, and eventual right heart failure causes death in many patients with this complication. This review provides an overview of the pathobiology of hemolysis-mediated endothelial dysfunction and eDAMPs and a summary of our present understanding of diagnosis and management of pulmonary hypertension in sickle cell disease, including a review of recent American Thoracic Society (ATS) consensus guidelines for risk stratification and management. PMID:25398989

  13. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment.

    PubMed

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, Alfons B A; Riccardi, Daniela; Kemp, Paul J; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2008-08-01

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive data on the nature of physiological stimuli for NEBs are lacking. This study aimed at developing an ex vivo mouse lung vibratome slice model for confocal live cell imaging of physiological reactions in identified NEBs and surrounding epithelial cells. Immunohistochemistry of fixed slices demonstrated that NEBs are almost completely shielded from the airway lumen by tight junction-linked Clara-like cells. Besides the unambiguous identification of NEBs, the fluorescent dye 4-Di-2-ASP allowed microscopic identification of ciliated cells, Clara cells, and Clara-like cells in live lung slices. Using the mitochondrial uncoupler FCCP and a mitochondrial membrane potential indicator, JC-1, increases in 4-Di-2-ASP fluorescence in NEB cells and ciliated cells were shown to represent alterations in mitochondrial membrane potential. Changes in the intracellular free calcium concentration ([Ca2+](i)) in NEBs and surrounding airway epithelial cells were simultaneously monitored using the calcium indicator Fluo-4. Application (5 s) of 50 mM extracellular potassium ([K+](o)) evoked a fast and reproducible [Ca2+](i) increase in NEB cells, while Clara-like cells displayed a delayed (+/- 4 s) [Ca2+](i) increase, suggestive of an indirect, NEB-mediated activation. The presented approach opens interesting new perspectives for unraveling the functional significance of pulmonary NEBs in control lungs and disease models, and for the first time allows direct visualization of local interactions within the NEB microenvironment. PMID:18367726

  14. Bone marrow–derived progenitor cells in pulmonary fibrosis

    PubMed Central

    Hashimoto, Naozumi; Jin, Hong; Liu, Tianju; Chensue, Stephen W.; Phan, Sem H.

    2004-01-01

    The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP+ cells to appear in active fibrotic lesions, while only a few GFP+ cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP+ cells in chimera mice and revealed a significant increase in GFP+ cells that also express type I collagen. GFP+ lung fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not α-smooth muscle actin. Treatment of isolated GFP+ fibroblasts with TGF-β failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell–derived factor-1α and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells. PMID:14722616

  15. Pulmonary hypertension in children and adolescents with sickle cell disease.

    PubMed

    Onyekwere, O C; Campbell, A; Teshome, M; Onyeagoro, S; Sylvan, C; Akintilo, A; Hutchinson, S; Ensing, G; Gaskin, P; Kato, G; Rana, S; Kwagyan, J; Gordeuk, V; Williams, J; Castro, O

    2008-03-01

    The prevalence of pulmonary hypertension (PHTN) in the pediatric sickle cell disease (SCD) population is not known despite its high prevalence in adult patients. Our hypothesis was that increased pulmonary artery pressures (PAPs) would be found in SCD children and adolescents, especially those with a history of pulmonary complications: acute chest syndrome, obstructive sleep apnea, asthma, and reactive airway disease. Fifty-two SCD children, 23 of whom had underlying pulmonary disease, were screened for PHTN, which was defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. Twenty-four (46.15%) SCD patients had increased PAP (i.e., TRV > or =2.5 m/s), and 6 (11.5%) had significant PHTN (i.e., TRV > or =3.0 m/s). Pulmonary disease was marginally associated with PHTN (odds ratio 2.80 and confidence interval 0.88 to 8.86; p = 0.0795). As in adult SCD patients with PHTN, this complication was correlated with the degree of hemolysis as manifested by significantly higher lactate dehydrogenase and bilirubin, lower hemoglobin and hematocrit levels, and a strong association with Hb-SS phenotype. However, after statistical adjustment for age and sex, increased serum LDH was not associated with the development of PHTN. Further studies are needed to clarify the prevalence and mechanisms of PHTN in pediatric and adolescent patients with SCD. PMID:17680298

  16. Pulmonary Metastasectomy 31 Years After Surgery for Renal Cell Carcinoma.

    PubMed

    Watanabe, Yui; Harada, Aya; Aoki, Masaya; Kamimura, Go; Wakida, Kazuhiro; Nagata, Toshiyuki; Yokomakura, Naoya; Kariatsumari, Kota; Nakamura, Yoshihiro; Sato, Masami

    2015-06-01

    An 82-year-old man underwent a left upper lobectomy for a solitary tumor on suspicion of lung cancer. Histopathologic findings of the resected specimen showed clear cell renal cell carcinoma, which was diagnosed as a metastasis from kidney cancer concealed for 31 years after nephrectomy. The Ki-67 labeling index of the metastatic tumor was high (36.1%). A few cases of recurrent renal cell carcinoma after a long interval from initial diagnosis have been seen. However, pulmonary metastasectomy more than 30 years after radical nephrectomy for renal cell carcinoma has not been reported. This remarkable case provides new and valuable clinical insights into metastatic renal cell carcinoma. PMID:26046874

  17. Synthesis of 3D graphite oxide-exfoliated carbon nanotube carbon composite and its application as catalyst support for fuel cells

    NASA Astrophysics Data System (ADS)

    Wang, Hailin; Kakade, Bhalchandra A.; Tamaki, Takanori; Yamaguchi, Takeo

    2014-08-01

    The restacking of graphene or reduced graphite oxide (r-GO) is commonly regarded as a severe obstacle for potential applications. We propose the application of exfoliated carbon nanotube (e-CNT) as an effective carbon spacer for fabricating a sandwich-like three-dimensional (3D) carbon composite with GO. The 3D carbon combination of GO + e-CNT is successfully prepared via homogenously mixing of GO and e-CNT in an aqueous dispersion in which carbon spacers are homogenously intercalated with graphene layers. With the addition of a carbon spacer, the BET surface area of 3D carbon (51.6 m2 g-1) is enhanced by a factor of three compared with r-GO (17.2 m2 g-1) after thermal reduction. In addition, the 3D GO + e-CNT supported PtPd catalyst (PtPd-GO + e-CNT) shows homogenous distribution of PtPd nanoparticles of 3.9 ± 0.6 nm in size, with an enlarged electrochemical active surface area (ECSA) value of 164 m2 g-1 and a mass activity of 690 mA mg-1 toward the methanol oxidation reaction (MOR), which is the typical anode reaction for direct methanol fuel cells (DMFC).

  18. Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis.

    PubMed

    Mourah, Samia; How-Kit, Alexandre; Meignin, Véronique; Gossot, Dominique; Lorillon, Gwenaël; Bugnet, Emmanuelle; Mauger, Florence; Lebbe, Celeste; Chevret, Sylvie; Tost, Jörg; Tazi, Abdellatif

    2016-06-01

    The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinases BRAF and MAP2K1 mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutated BRAF and MAP2K1 LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence of BRAF, MAP2K1, NRAS and KRAS mutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAF(V600E) mutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harboured NRAS(Q61K) (/R) mutations, whereas no NRAS mutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11 NRAS(Q61K) (/R)-mutated pulmonary LCH lesions, BRAF(V600) (E) mutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrent BRAF and NRAS mutations were carried by different cell clones. NRAS(Q61K) (/R) mutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrent BRAF(V600E) and NRAS(Q61K) (/R) mutations was significantly associated with patient outcome.These findings highlight the importance of NRAS genotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments. PMID:27076591

  19. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    ClinicalTrials.gov

    2005-06-23

    I Cell Disease; Fucosidosis; Globoid Cell Leukodystrophy; Adrenoleukodystrophy; Mannosidosis; Niemann-Pick Disease; Pulmonary Complications; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Metachromatic Leukodystrophy; Gaucher's Disease; Wolman Disease

  20. Is there any possible genotoxic effect in exfoliated bladder cells of rat under the exposure of 1800 MHz GSM-like modulated radio frequency radiation (RFR)?

    PubMed

    Gurbuz, Neslihan; Sirav, Bahriye; Yuvaci, Hilal Uslu; Turhan, Nilgun; Coskun, Zafer Kutay; Seyhan, Nesrin

    2010-08-01

    People are exposed to many carcinogenic and mutagenic chemicals in their everyday lives. These include antineoplastic drugs, Polycyclic aromatic hydrocarbons (PAH)s, aromatic amines, nitrosamines, metals, and electromagnetic radiation. Based on the state of knowledge acquired during the last 50 years of research on possible biological effects of electromagnetic fields (EMF), the majority of the scientific community is convinced that exposure to EMF below the existing security limits does not cause a risk to the health of the general public. However, this position is questioned by others, who are of the opinion that the available research data are contradictory or inconsistent and, therefore, unreliable. In this study, we aimed to investigate if there is any effect of 1800 MHz GSM modulated radio frequency radiation (RFR) on the number of micronucleus in exfoliated bladder cells of rat which will be informative about the genotoxic damage. Exposure period was 20 min/day, 5 days/week during a month. Six female Wistar rats were used for two groups: Group I (n=6): controls; Group II (n=6): 1.8 GHz exposed animals. 1800 MHz RFR did not showed a significant MN frequencies in rat bladder cells when compared with the control group (p>0.05). 1800 MHz RFR-exposed animals did not produce any genotoxic effect when compared with the control group ( p>0.05). Kinetic studies are important for any biomarker, especially those in which tissue differentiation and maturation processes will heavily influence the time between induction of damage and collection of damaged cells for micronucleus analysis. PMID:20707643

  1. Bone Marrow Stem Cell Contribution to Pulmonary Homeostasis and Disease

    PubMed Central

    McDonald, Lindsay T; LaRue, Amanda C

    2015-01-01

    The understanding of bone marrow stem cell plasticity and contribution of bone marrow stem cells to pathophysiology is evolving with the advent of innovative technologies. Recent data has led to new mechanistic insights in the field of mesenchymal stem cell (MSC) research, and an increased appreciation for the plasticity of the hematopoietic stem cell (HSC). In this review, we discuss current research examining the origin of pulmonary cell types from endogenous lung stem and progenitor cells as well as bone marrow-derived stem cells (MSCs and HSCs) and their contributions to lung homeostasis and pathology. We specifically highlight recent findings from our laboratory that demonstrate an HSC origin for pulmonary fibroblasts based on transplantation of a clonal population of cells derived from a single HSC. These findings demonstrate the importance of developing an understanding of the sources of effector cells in disease state. Finally, a perspective is given on the potential clinical implications of these studies and others addressing stem cell contributions to lung tissue homeostasis and pathology. PMID:26798846

  2. Directed Therapy for Exfoliation Syndrome

    PubMed Central

    Angelilli, Allison; Ritch, Robert

    2009-01-01

    Exfoliation syndrome (XFS) is an age-related disorder of the extracellular matrix that leads the production of abnormal fibrillar material that leads to elevated intraocular pressure and a relatively severe glaucoma. Exfoliation material is deposited in numerous ocular tissues and extraocular organs. XFS is associated with ocular ischemia, cerebrovascular disease, neurodegenerative disease and cardiovascular disease. Current modalities of treatment include intraocular pressure lowering with topical antihypertensives, laser trabeculoplasty and filtration surgery. The disease paradigm for XFS should be expanded to include directed therapy designed specifically to target the underlying disease process. Potential targets include preventing the formation or promoting the depolymerization of exfoliation material. Novel therapies targeting trabecular meshwork may prove particularly useful in the care of exfoliative glaucoma. The systemic and ocular associations of XFS underscore the need for a comprehensive search for neuroprotective agents in its treatment. PMID:19888433

  3. Characterization of cloned cells from an immortalized fetal pulmonary type II cell line

    SciTech Connect

    Henderson, R.F.; Waide, J.J.; Lechner, J.F.

    1995-12-01

    A cultured cell line that maintained expression of pulmonary type II cell markers of differentiation would be advantageous to generate a large number of homogenous cells in which to study the biochemical functions of type II cells. Type II epithelial cells are the source of pulmonary surfactant and a cell of origin for pulmonary adenomas. Last year our laboratory reported the induction of expression of two phenotypic markers of pulmonary type II cells (alkaline phosphatase activity and surfactant lipid synthesis) in cultured fetal rat lung epithelial (FRLE) cells, a spontaneously immortalized cell line of fetal rat lung type II cell origin. Subsequently, the induction of the ability to synthesize surfactant lipid became difficult to repeat. We hypothesized that the cell line was heterogenuous and some cells were more like type II cells than others. The purpose of this study was to test this hypothesis and to obtain a cultured cell line with type II cell phenotypic markers by cloning several FRLE cells and characterizing them for phenotypic markers of type II cells (alkaline phosphatase activity and presence of surfactant lipids). Thirty cloned cell lines were analyzed for induced alkaline phosphatase activity (on x-axis) and for percent of phospholipids that were disaturated (i.e., surfactant).

  4. Adult langerhans cell histiocytosis with hepatic and pulmonary involvement.

    PubMed

    Araujo, Bruno; Costa, Francisco; Lopes, Joanne; Castro, Ricardo

    2015-01-01

    Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of Langerhans cells of unknown etiology. It can involve multiple organ systems with different clinical presentation, which complicates the diagnosis. It can range from isolated to multisystem disease with different prognosis. Although common among children, liver involvement is relatively rare in adults and frequently overlooked. Natural history of liver LCH fits into two stages: an early stage with infiltration by histiocytes and a late stage with sclerosis of the biliary tree. Pulmonary findings are more common and include multiple nodules in different stages of cavitation, predominantly in the upper lobes. We present a case of adult LCH with pulmonary and biopsy proven liver involvement with resolution of the hepatic findings after treatment. PMID:25977828

  5. Pulmonary langerhans cell histiocytosis: case series and literature review.

    PubMed

    Wei, Ping; Lu, Hai-Wen; Jiang, Sen; Fan, Li-Chao; Li, Hui-Ping; Xu, Jin-Fu

    2014-11-01

    Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease with insidious onset and nonspecific manifestations. The objective of this article was to characterize the clinical manifestations and features of PLCH by retrospectively analyzing clinical data of patients with PLCH in addition to simultaneous review of literature.A retrospective analysis was conducted on clinical data of patients with PLCH (n = 7), whose conditions were diagnosed by biopsy from pulmonary tissue (n = 6) or enlarged lymph nodes in the neck (n = 1) and confirmed by PLCH typical radiological features on computed tomography (CT) scan, between January 2001 and September 2012 at the Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. The review of published reports was made to further emphasize the clinical manifestation and radiological features of PLCH.Long history of cigarette smoking was found in 6 patients. Two patients had recurrent pneumothorax and the other 2 had pulmonary arterial hypertension (World Health Organization group 5 pulmonary hypertension), diagnosed through ultrasonic cardiogram. The nodular shadows were revealed by chest CT scan in 5 patients, cystic shadows in 5 patients, and reticular shadows in 2 patients, as major manifestations, respectively; most of the lesions were located in the middle or upper segments of the lung. The obvious shrank of lesion was found in 1 patient after completely quitting smoking.The pathogenesis of PLCH might be closely associated with smoking. The cystic or nodular lesion was the typical radiological features. Further prospective studies with large sample size are required to further validate the study results and understand the clinical characteristics of PLCH to avoid misdiagnosis. PMID:25415669

  6. Pulmonary Langerhans Cell Histiocytosis: Case Series and Literature Review

    PubMed Central

    Wei, Ping; Lu, Hai-Wen; Jiang, Sen; Fan, Li-Chao; Li, Hui-Ping; Xu, Jin-Fu

    2014-01-01

    Abstract Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease with insidious onset and nonspecific manifestations. The objective of this article was to characterize the clinical manifestations and features of PLCH by retrospectively analyzing clinical data of patients with PLCH in addition to simultaneous review of literature. A retrospective analysis was conducted on clinical data of patients with PLCH (n = 7), whose conditions were diagnosed by biopsy from pulmonary tissue (n = 6) or enlarged lymph nodes in the neck (n = 1) and confirmed by PLCH typical radiological features on computed tomography (CT) scan, between January 2001 and September 2012 at the Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. The review of published reports was made to further emphasize the clinical manifestation and radiological features of PLCH. Long history of cigarette smoking was found in 6 patients. Two patients had recurrent pneumothorax and the other 2 had pulmonary arterial hypertension (World Health Organization group 5 pulmonary hypertension), diagnosed through ultrasonic cardiogram. The nodular shadows were revealed by chest CT scan in 5 patients, cystic shadows in 5 patients, and reticular shadows in 2 patients, as major manifestations, respectively; most of the lesions were located in the middle or upper segments of the lung. The obvious shrank of lesion was found in 1 patient after completely quitting smoking. The pathogenesis of PLCH might be closely associated with smoking. The cystic or nodular lesion was the typical radiological features. Further prospective studies with large sample size are required to further validate the study results and understand the clinical characteristics of PLCH to avoid misdiagnosis. PMID:25415669

  7. Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension

    PubMed Central

    LIU, JUNFENG; HAN, ZHIBO; HAN, ZHONGCHAO; HE, ZHIXU

    2015-01-01

    Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord-derived MSCs, which were cultured in serum-free medium, into a monocrotaline (MCT)-induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)-α in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT-induced PH, investigated in the present study, TNF-α expression levels were detected in the lung tissue, and the levels of TNF-α in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum-free medium, decreased the levels of TNF-α in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF-α, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs. PMID:26640533

  8. Oral cancer screening approach based on labeling exfoliated oral cells with molecularly-targeted optical contrast agents

    NASA Astrophysics Data System (ADS)

    Leautaud, Veronica; Horres, Charles R.; Bhattar, Vijayashree S.; Williams, Michelle D.; Gillenwater, Ann M.; Richards-Kortum, Rebecca R.

    2011-03-01

    Early detection is a potential key to improving the survival rates of oral cancer patients and reducing the morbidity associated with treatment. We seek to improve upon methods of detecting of early malignancies with oral brush biopsies by using immunofluorescence-based assessment of the expression of multiple well-described markers commonly overexpressed in oral cancers, such as Epidermal Growth Factor Receptor (EGFR) and Cytokeratin 8 (CK8). Furthermore, since abnormal cells are often scarce in brush biopsy samples, we seek to use magnetic microparticles targeted to these markers as a means of enriching the concentration of abnormal cells. Finally, we plan to conduct a small pilot study using these methods with brush biopsies from patients of the M. D. Anderson Cancer Center Head and Neck Clinic.

  9. Odontogenic ghost cell carcinoma with pulmonary metastasis

    PubMed Central

    Sukumaran, Renu; Somanathan, Thara; Kattoor, Jayasree

    2015-01-01

    Odontogenic ghost cell carcinoma (OGCC) is an exceptionally rare malignant odontogenic epithelial tumor. It is characterized by ameloblastic-like islands of epithelial cells with aberrant keratinization in the form of ghost cells with varying amounts of dysplastic dentin. Malignant histological characteristics include infiltration, cellular pleomorphism, numerous mitosis and necrosis. Its biological behavior varies from slow-growing locally invasive lesions to rapidly growing highly aggressive tumors. OGCC metastasizing to distant sites is extremely rare. Only three cases of metastasis have been reported in literature. We are reporting the case of a 54-year-old male patient who presented with tender swelling in the malar region. Histopathological examination revealed OGCC and he received postoperative radiotherapy. Two years later, he presented with a lung mass. Biopsy from the lung lesion showed the same morphology as that of maxillary tumor with scattered ghost cells. This case points to the aggressive behavior of OGCC and its metastatic potential. It also highlights the need for long-term follow-up of these patients. PMID:26980967

  10. Pulmonary Langerhans Cell Histiocytosis: An Update From the Pathologists' Perspective.

    PubMed

    Roden, Anja C; Yi, Eunhee S

    2016-03-01

    Context .- Pulmonary Langerhans cell histiocytosis (PLCH) is a rare histiocytic disorder that almost exclusively affects the lungs of smokers. PLCH is characterized by bronchiolocentric nodules and/or cysts in an upper and mid lung distribution with sparing of the costophrenic angles. The diagnosis can be challenging and often requires transbronchial biopsy or surgical lung biopsy. Pulmonary hypertension is a relatively common and sometimes severe complication of PLCH. The pathogenesis of PLCH is still debated. Recently, BRAF V600E mutation and BRAF expression have been identified in some patients with PLCH, suggesting that at least a subset of PLCH has a clonal proliferation. While smoking cessation is the first-line treatment of PLCH, some patients might require additional treatment and eventually transplant. Given that the lesional cells of PLCH express BRAF in some patients, MAPKinase pathway-targeted treatment might be useful for therapy-resistant patients. Objective . -To present the more recently recognized clinical and pathologic aspects of PLCH, including pulmonary hypertension in PLCH, pathogenesis, and treatment, as well as the basic diagnostic approach to PLCH. Data Sources .- Authors' own research, and search of literature database (PubMed) and UpToDate. Conclusions . -Despite the recent progress, more studies are needed to elucidate the biology of PLCH for identification of prognostic factors and appropriate treatment options, especially for therapy-refractory PLCH cases. PMID:26927717

  11. Sudden death of a patient with pulmonary Langerhans cell histiocytosis.

    PubMed

    Nakhla, Hassan; Jumbelic, Mary I

    2005-06-01

    We report a case of sudden death due to bilateral pneumothorax in a previously healthy 16-year-old adolescent white girl. She presented with sudden onset of shortness of breath followed by loss of consciousness. Postmortem chest radiograph showed bilateral pneumothoraces. Autopsy confirmed the bilateral pneumothorax and additionally showed emphysematous changes and bullae throughout the lung tissue. Microscopic sections of the lungs showed Langerhans cell histiocytosis. To the best of our knowledge, this is the first reported case of fatal presentation of pulmonary Langerhans cell histiocytosis. PMID:15913433

  12. Stem Cell-Based Therapy in Idiopathic Pulmonary Fibrosis.

    PubMed

    Barczyk, Marek; Schmidt, Matthias; Mattoli, Sabrina

    2015-08-01

    Idiopathic pulmonary fibrosis is a progressive fibrosing disorder for which there is no cure and no pharmacological treatment capable of increasing in a meaningful way the survival rate. Lung transplantation remains the only possible treatment for patients with advanced disease, although the increase in 5-year survival is only 45 %. Some preclinical studies have generated promising results about the therapeutic potential of exogenous stem cells. However, two initial clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or unrelated-donor, placenta-derived mesenchymal stem cells have not convincingly demonstrated that these treatments are acceptably safe. The results of other ongoing clinical trials may help to identify the best source and delivery route of mesenchymal stem cells and to estimate the risk of unwanted effects related to the mesenchymal nature of the transplanted cells. Considering that most of the therapeutic potential of these cells has been ascribed to paracrine signaling, the use of mesenchymal stem cell-derived secretome as an alternative to the transplantation of single cell suspension may circumvent many regulatory and clinical problems. Technical and safety concerns still limit the possibility of clinical applications of other promising interventions that are based on the use of human amnion stem cells, embryonic stem cells or induced pluripotent stem cells to replace or regenerate the dysfunctional alveolar epithelium. We summarize the current status of the field and identify major challenges and opportunities for the possible future integration of stem cell-based treatments into the currently recommended clinical management strategy for idiopathic pulmonary fibrosis. PMID:25896401

  13. Determining Proportion of Exfoliative Vaginal Cell during Various Stages of Estrus Cycle Using Vaginal Cytology Techniques in Aceh Cattle

    PubMed Central

    Siregar, Tongku N.; Melia, Juli; Rohaya; Thasmi, Cut Nila; Masyitha, Dian; Wahyuni, Sri; Rosa, Juliana; Nurhafni; Panjaitan, Budianto; Herrialfian

    2016-01-01

    The aim of this study was to investigate the period of estrus cycle in aceh cattle, Indonesia, based on vaginal cytology techniques. Four healthy females of aceh cattle with average weight of 250–300 kg, age of 5–7 years, and body condition score of 3-4 were used. All cattle were subjected to ultrasonography analysis for the occurrence of corpus luteum before being synchronized using intramuscular injections of PGF2 alpha 25 mg. A vaginal swab was collected from aceh cattle, stained with Giemsa 10%, and observed microscopically. Period of estrus cycle was predicted from day 1 to day 24 after estrus synchronization was confirmed using ultrasonography analysis at the same day. The result showed that parabasal, intermediary, and superficial epithelium were found in the vaginal swabs collected from proestrus, metestrus, and diestrus aceh cattle. Proportions of these cells in the particular period of estrus cycle were 36.22, 32.62, and 31.16 (proestrus); 21.33, 32.58, and 46.09 (estrus); 40.75, 37.58, and 21.67 (metestrus); and 41.07, 37.38, and 21.67 (diestrus), respectively. In conclusion, dominant proportion of superficial cell that occurred in estrus period might be used as the base for determining optimal time for insemination. PMID:26977335

  14. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema

    PubMed Central

    Ribeiro-Paes, João Tadeu; Bilaqui, Aldemir; Greco, Oswaldo T; Ruiz, Milton Artur; Marcelino, Monica Y; Stessuk, Talita; de Faria, Carolina A; Lago, Mario R

    2011-01-01

    Within the chronic obstructive pulmonary disease (COPD) spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs) arises as a new therapeutic approach, with a wide application potential. The purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea). After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC) were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease. This clinical trial was registered with ClinicalTrials.gov (NCT01110252) and was approved by the Brazilian National Committee of Ethics in Research (registration no. 14764, CONEP report 233/2009). PMID:21311694

  15. [Regulatory T cells in chronic obstructive pulmonary disease].

    PubMed

    Limón-Camacho, Leonardo; Solleiro-Villavicencio, Helena; Pupko-Sissa, Ilana; Lascurain, Ricardo; Vargas-Rojas, María Inés

    2013-01-01

    Exposition to tobacco smoke has been established as the main risk factor to develop chronic obstructive pulmonary disease (COPD), by inducing inflammation of the airways. Several cell populations participate in this inflammatory process. It has been accepted that a maladaptive modulation of inflammatory responses plays a critical role in the development of the disease. Regulatory T cells (Treg) are a subset of T CD4(+) lymphocytes that modulate the immune response through secretion of cytokines. The role of the Treg cells in chronic obstructive pulmonary disease is not clearly known, that is why it is important to focus in understanding their participation in the pathogenesis of the disease. To elaborate a systematic review of original articles in which we could describe Treg cells (their ontogeny, mechanisms of action) and their role in COPD, we made a systematic literature search in some data bases (MEDLINE, AMED, PubMed and Scielo) looking through the next keywords: "COPD and Regulatory T cells/EPOC y células T reguladoras", «Inflammation and COPD/Inflamación y EPOC», «Regulatory T cells/Células T reguladoras». We included basic science articles, controlled and non-controlled clinical trials, meta-analysis and guides. From this search we conclude that Treg cells are a subpopulation of T CD4(+) lymphocytes and their major functions are the suppression of immune responses and the maintenance of tolerance to self-antigens. A disruption in the regulatory mechanisms of the Treg cells leads to the development and perpetuation of inflammation in COPD. PMID:23474149

  16. Optical studies of oxidative stress in pulmonary artery endothelial cells

    NASA Astrophysics Data System (ADS)

    Ghanian, Zahra; Sepehr, Reyhaneh; Eis, Annie; Kondouri, Ganesh; Ranji, Mahsa

    2015-03-01

    Reactive oxygen species (ROS) play an essential role in facilitating signal transduction processes within the cell and modulating the injuries. However, the generation of ROS is tightly controlled both spatially and temporally within the cell, making the study of ROS dynamics particularly difficult. This study present a novel protocol to quantify the dynamic of the mitochondrial superoxide as a precursor of reactive oxygen species. To regulate the mitochondrial superoxide level, metabolic perturbation was induced by administration of potassium cyanide (KCN). The presented method was able to monitor and measure the superoxide production rate over time. Our results demonstrated that the metabolic inhibitor, potassium cyanide (KCN) induced a significant increase in the rate of superoxide production in mitochondria of fetal pulmonary artery endothelial cells (FPAEC). Presented method sets the stage to study different ROS mediated injuries in vitro.

  17. Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells.

    PubMed

    Zeid, N A; Muller, H K

    1995-07-01

    The density of zinc-iodide-osmium (ZIO) positive pulmonary Langerhans dendritic cells (LC) was increased about 20-fold in mice after passive exposure to tobacco smoke. This was associated with pulmonary changes consistent with the cigarette smoking-related clinical syndrome in humans, pulmonary Langerhans cell granulomatosis. The major feature was an interstitial peribronchial granuloma. The cellular infiltrate of the granuloma (lymphocytes, plasma cells, eosinophils, clusters of large histiocyte-like cells and macrophages) extended into the adjacent alveolar septum forming a star-shaped lesion. The histiocyte-like cells were large with pale acidophilic cytoplasm and many ill-defined short dendrites extending from the cell membrane. Bronchial epithelial metaplasia also developed. The interstitial changes were followed by the development of proliferative alveolar and bronchial lesions in 2 mice. The zinc-iodide-osmium positive cells were consistent with la positive pulmonary dendritic cells and their ultrastructure was similar to that of pulmonary Langerhans cells. After ceasing exposure to tobacco smoke the density of pulmonary Langerhans cells returned to that of the control level; interstitial granulomatous lesions disappeared, but the bronchial epithelial metaplasia did not reverse. Tobacco smoke exposure of mice produces interstitial granulomatous inflammation similar to Langerhans cell granulomatosis in humans. The elevated level of pulmonary Langerhans cells implicate these cells in the pathogenesis of these lesions. PMID:8532391

  18. IL-4 attenuates pulmonary epithelial cell-mediated suppression of T cell priming.

    PubMed

    Albrecht, Melanie; Arnhold, Markus; Lingner, Sandra; Mahapatra, Subhashree; Bruder, Dunja; Hansen, Gesine; Dittrich, Anna-Maria

    2012-01-01

    We have previously shown that Th2-polarized airway inflammation facilitates sensitization towards new, protein antigens. In this context, we could demonstrate that IL-4 needs to act on cells of the hematopoetic and the structural compartment in order to facilitate sensitization towards new antigens. We thus aimed to elucidate possible mechanisms of action of IL-4 on structural cells choosing to analyze pulmonary epithelial cells as an important part of the lung's structural system. We used a co-culture system of DC- or APC-dependent in vitro priming of T cells, co-cultivated on a layer of cells of a murine pulmonary epithelial cell line (LA-4) pretreated with or without IL-4. Effects on T cell priming were analyzed via CFSE-dilution and flow cytometric assessment of activation status. Pulmonary epithelial cells suppressed T cell proliferation in vitro but this effect was attenuated by pre-treatment of the epithelial cells with IL-4. Transwell experiments suggest that epithelial-mediated suppression of T cell activation is mostly cell-contact dependent and leads to attenuation in an early naive T cell phenotype. Secretion of soluble factors like TARC, TSLP, GM-CSF and CCL20 by epithelial cells did not change after IL-4 treatment. However, analysis of co-stimulatory expression on pulmonary epithelial cells revealed that pre-treatment of epithelial cells with IL-4 changed expression GITR-L, suggesting a possible mechanism for the effects observed. Our studies provide new insight into the role of IL-4 during the early phases of pulmonary sensitization: The inhibitory activity of pulmonary epithelial cells in homeostasis is reversed in the presence of IL-4, which is secreted in the context of Th2-dominated allergic airway inflammation. This mechanism might serve to explain facilitated sensitization in the clinical context of polysensitization where due to a pre-existing sensitization increased levels of IL-4 in the airways might facilitate T cell priming towards new

  19. Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations Following the Glenn Shunt

    PubMed Central

    Kavarana, Minoo N.; Mukherjee, Rupak; Eckhouse, Shaina R.; Rawls, William F.; Logdon, Christina; Stroud, Robert E.; Patel, Risha K.; Nadeau, Elizabeth K.; Spinale, Francis G.; Graham, Eric M.; Forbus, Geoffrey A.; Bradley, Scott M.; Ikonomidis, John S.; Jones, Jeffrey A.

    2014-01-01

    Background: Longevity of the superior cavopulmonary connection (SCPC) is limited by the development of pulmonary arteriovenous malformations (PAVM). The goal of this study was to determine whether phenotypic changes in pulmonary artery endothelial cells (PAEC) that favor angiogenesis occur with PAVM formation. Methods: A superior vena cava to right pulmonary artery connection was constructed in 5 pigs. Pulmonary arteries were harvested at 6-8 weeks following surgery to establish cultures of PAEC and smooth muscle cells, to determine cell proliferation, gene expression, and tubule formation. Abundance of proteins related to angiogenesis was measured in lung tissue. Results: Contrast echocardiography revealed right-to-left shunting, consistent with PAVM formation. While the proliferation of smooth muscle cells from the right pulmonary artery (RPA) (shunted side) and left pulmonary artery (LPA) (non- shunted side) were similar, right PAEC proliferation was significantly higher. Expression profiles of genes encoding cellular signaling proteins were higher in PAECs from the RPA vs. LPA. Protein abundance of angiopoietin-1, and Tie-2 (angiopoietin receptor) were increased in the right lung (both p<0.05). Tubule formation was increased in endothelial cells from the RPA compared to the LPA (404±16 vs. 199±71 tubules/mm2, respectively p<0.05). Conclusions: These findings demonstrate that PAVMs developed in a clinically relevant animal model of SCPC. This study found that PAVM development occurred concomitantly with differential changes in PAEC proliferative ability and phenotype. Moreover, there was a significant increase in the angiopoietin/Tie-2 complex in the right lung, which may provide novel therapeutic targets to attenuate PAVM formation following a SCPC. PMID:23968766

  20. Nestin-expressing vascular wall cells drive development of pulmonary hypertension.

    PubMed

    Saboor, Farhan; Reckmann, Ansgar N; Tomczyk, Claudia U M; Peters, Dorothea M; Weissmann, Norbert; Kaschtanow, Andre; Schermuly, Ralph T; Michurina, Tatyana V; Enikolopov, Grigori; Müller, Dieter; Mietens, Andrea; Middendorff, Ralf

    2016-03-01

    Nestin, a well-known marker of neuronal stem cells, was recently suggested to characterise stem cell-like progenitors in non-neuronal structures during development and tissue repair. Integrating novel morphological approaches (CLARITY), we investigate whether nestin expression defines the proliferating cell population that essentially drives vascular remodelling during development of pulmonary hypertension.The role of nestin was investigated in lungs of nestin-GFP (green fluorescent protein) mice, models of pulmonary hypertension (rat: monocrotaline, SU5416/hypoxia; mouse: hypoxia), samples from pulmonary hypertension patients and human pulmonary vascular smooth muscle cells (VSMCs).Nestin was solely found in lung vasculature and localised to proliferating VSMCs, but not bronchial smooth muscle cells. Nestin was shown to affect cell number and was significantly enhanced in lungs early during development of pulmonary hypertension, correlating well with increased VSMC proliferation, expression of phosphorylated (activated) platelet-derived growth factor receptor β and downregulation of the smooth muscle cell differentiation marker calponin. At later time points when pulmonary hypertension became clinically evident, nestin expression and proliferation returned to control levels. Increase of nestin-positive VSMCs was also found in human pulmonary hypertension, both in vessel media and neointima.Nestin expression seems to be obligatory for VSMC proliferation, and specifies lung vascular wall cells that drive remodelling and (re-)generation. Our data promise novel diagnostic tools and therapeutic targets for pulmonary hypertension. PMID:26699726

  1. A case of pulmonary Langerhans cell histiocytosis in a young woman with coeliac disease.

    PubMed

    Mastruzzo, Claudio; Vancheri, Carlo; Li Mura, Dario; Poletti, Venerino; Failla, Marco; Crimi, Nunzio

    2007-06-01

    Pulmonary Langerhans cells histiocytosis (pulmonary LCH) is an idiopathic unusual lung disease and its association with other systemic diseases has been rarely observed. Here, we describe a young non-smoking woman with concomitant pulmonary LCH and coeliac disease that, despite therapy, suddenly deteriorated. To the best of the authors' knowledge, this is the first report in the medical literature describing an association of coeliac disease with pulmonary LCH. Considering the concomitant occurrence of both diseases in our patient and the severe course of pulmonary LCH observed, we hypothesise that coeliac disease and pulmonary LCH might be related by a common disturbance in immunity and the onset and/or the course of pulmonary LCH could be influenced or markedly worsened by the presence of coeliac disease. PMID:17629812

  2. Multifunctional polymeric nanocomposites fabricated by incorporation of exfoliated graphene nanoplatelets and their application in bipolar plates for polymer electrolyte membrane fuel cells

    NASA Astrophysics Data System (ADS)

    Jiang, Xian

    The focus of this research is to investigate the potential of using exfoliated graphene nanoplatelets, GNP, as the multifunctional nano-reinforcement in fabricating polymer/GNP nanocomposites and then explore their prospective applications in bipolar plates for polymer electrolyte membrane (PEM) fuel cells. Firstly, HDPE (high density polyethylene)/GNP nanocomposites were fabricated using the conventional compounding method of melt-extrusion followed by injection molding. The mechanical properties, crystallization behaviors, thermal stability, thermal conductivity, and electrical conductivity of the resulting HDPE/GNP nanocomposites were evaluated as a function of GNP concentration. Results showed that HDPE/GNP nanocomposites exhibit equivalent flexural modulus and strength to HDPE composites filled with other commercial reinforcements but they have superior impact strength. By investigating the crystallization behavior of HDPE/GNP nanocomposites, it was found that GNP is a good nucleating agent at low loading levels and as a result can significantly increase crystallization temperature and crystallinity of HDPE. At high GNP loadings, however, the close proximity of GNP particles retards the crystallization process. The thermal stability and thermal conductivity of HDPE/GNP nanocomposites were significantly enhanced due to the excellent thermal properties of GNP. Meanwhile, results indicated that the percolation threshold of these nanocomposites prepared by the conventional melt-extrusion and injection molding is relatively high at around 10--15 vol% GNP loading. To enhance the electrical conductivity of HDPE/GNP nanocomposites, two special processing methods named solid state ball milling (SSBM) and solid state shear pulverization (SSSP) were studied. The mechanism by which SSBM and SSSP are capable of producing lower percolation or higher electrical conductivity is to coat the polymer surface by GNP platelets which facilitate the formation of conductive networks

  3. Pulmonary Extranodal Natural Killer/T-Cell Lymphoma (Nasal Type)

    PubMed Central

    Fei, Wang; Xiaohong, Wang; Hong, Zhu; Bei, He

    2015-01-01

    Abstract An 83-year-old woman presented with intermittent fever for 2 weeks. Chest radiography and computed tomography images showed multiple nodules and masses scattered in both lung fields. Tissue samples obtained by computed tomography-guided needle biopsy revealed extranodal natural killer/T-cell lymphoma (ENKL). The lung is the major site of involvement and the skin may be the primary site. The radiological imaging of this case is different from the cases reported before. Besides, we reviewed the medical records of our hospital and searched the Pubmed database and found 12 cases altogether (include the case presented), which were diagnosed with pulmonary ENKL, and the features of chest images were studied. To our knowledge, this is the first time that the chest imaging features of pulmonary ENKL were reviewed. We conclude that if the radiographic manifestations are multiple patchy consolidations or multiple nodules and masses in both lungs with or without bilateral pleural effusions, the diagnostic considerations should include ENKL. PMID:26402808

  4. Pulmonary Alveolar Type II Cells Isolated from Rats

    PubMed Central

    Dobbs, Leland G.; Mason, Robert J.

    1979-01-01

    It is unclear what factors control the secretion of pulmonary surface active material from alveolar type II cells in vivo. Other workers have suggested that cholinergic stimuli, adrenergic stimuli, and prostaglandins may all stimulate secretion. We isolated type II cells from the lungs of rats by treatment with elastase, discontinuous density centrifugation, and adherence in primary culture. β-Adrenergic agonists, but not cholinergic agonists, caused an increase in the release of [14C]disaturated phosphatidylcholine, the major component of surface-active material, from type II cells in culture. The β-adrenergic effect was stereo-selective, (−)-isoproterenol being 50 times more potent than (+)-isoproterenol. Terbutaline, 10 μM, a noncatecholamine β-2 adrenergic agonist, caused a release of 2.0±0.5 (mean±SD) times the basal release of [14C]disaturated phosphatidylcholine in 3 h; the concentration of terbutaline causing half maximal stimulation was 800 nM. The terbutaline effect was blocked by propranolol, a β-adrenergic antagonist (calculated Kd = 6 nM), but not by phentolamine, an α-adrenergic antagonist. Isobutylmethylxanthine, a phosphodiesterase inhibitor, and 8-Br cyclic AMP, but not 8-Br cyclic guanosine monophosphate, also stimulated release. We conclude that type II cells secrete disaturated phosphatidylcholine in response to treatment with adrenergic stimulation. PMID:34631

  5. ACTIVATION OF GATA-4 BY SEROTONIN IN PULMONARY ARTERY SMOOTH MUSCLE CELLS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin (5-HT) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension. Signal transduction initiated by 5-HT involves serotonin transporter (SERT)-dependent generation of reactive oxygen species (ROS) and activation of...

  6. Granite Exfoliation, Cosumnes River Watershed, Somerset, California

    NASA Astrophysics Data System (ADS)

    Crockett, I. Q.; Neiss-Cortez, M.

    2015-12-01

    In the Sierra Nevada foothills of California there are many exposed granite plutons within the greater Sierra Nevada batholith. As with most exposed parts of the batholith, these granite slabs exfoliate. It is important to understand exfoliation for issues of public safety as it can cause rock slides near homes, roads, and recreation areas. Through observation, measuring, and mapping we characterize exfoliation in our Cosumnes River watershed community.

  7. Pulmonary Lymphangitic Carcinomatosis due to Renal Cell Carcinoma

    PubMed Central

    Guddati, Achuta K.; Marak, Creticus P.

    2012-01-01

    Renal cell carcinoma is an aggressive disease with a high rate of mortality. It is known to metastasize to the lung, liver, bone and brain. However, manifestation through lymphatic spread to the lungs is rare. Lymphangitic carcinomatosis is commonly observed in malignancies of the breast, lung, pancreas, colon and cervix. It is unusual to observe lymphangitic carcinomatosis of the lungs due to renal cell carcinoma. Lymphangitic carcinomatosis of the lungs may result in severe respiratory distress and may be the direct cause of death. Currently, there are no known modalities of preventing or slowing lymphangitic carcinomatosis besides treating the primary tumor. However, early detection may change the course of the disease and may prolong survival. This is compounded by the difficulty involved in diagnosing lymphangitic carcinomatosis of the lung which frequently involves lung biopsy. Immunohistochemical studies are often used in conjunction with regular histochemistry in ascertaining the primary tumor and in differentiating it from pulmonary metastasis. In this case report, we describe the presentation and clinical course of renal cell carcinoma in a patient which manifested as lymphangitis carcinomatosa of the lungs. The patient underwent surgical resection of the primary tumor with lymph node resection but presented with a fulminant lymphangitic carcinomatosis of the lungs within two weeks. Immunohistochemistry of the tissue obtained by the biopsy confirmed the diagnosis which was subsequently corroborated during his autopsy. This case illustrates the necessity of an urgent follow-up of chemotherapy and immunotherapy in such patients. PMID:22679431

  8. Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia.

    PubMed

    Zhang, Qianlong; Fan, Kai; Wang, Peng; Yu, Juan; Liu, Ruxia; Qi, Hanping; Sun, Hongli; Cao, Yonggang

    2016-01-01

    The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension. PMID:26607464

  9. Separation medium containing thermally exfoliated graphite oxide

    NASA Technical Reports Server (NTRS)

    Prud'homme, Robert K. (Inventor); Aksay, Ilhan A. (Inventor); Herrera-Alonso, Margarita (Inventor)

    2012-01-01

    A separation medium, such as a chromatography filling or packing, containing a modified graphite oxide material, which is a thermally exfoliated graphite oxide with a surface area of from about 300 m.sup.2/g to 2600 m.sup.2/g, wherein the thermally exfoliated graphite oxide has a surface that has been at least partially functionalized.

  10. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension

    PubMed Central

    2014-01-01

    Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases. PMID:25085432

  11. Imbalance of mitochondrial-nuclear cross talk in isocyanate mediated pulmonary endothelial cell dysfunction☆

    PubMed Central

    Panwar, Hariom; Jain, Deepika; Khan, Saba; Pathak, Neelam; Raghuram, Gorantla V.; Bhargava, Arpit; Banerjee, Smita; Mishra, Pradyumna K.

    2013-01-01

    Mechanistic investigations coupled with epidemiology, case-control, cohort and observational studies have increasingly linked isocyanate exposure (both chronic and acute) with pulmonary morbidity and mortality. Though ascribed for impairment in endothelial cell function, molecular mechanisms of these significant adverse pulmonary outcomes remains poorly understood. As preliminary studies conducted in past have failed to demonstrate a cause-effect relationship between isocyanate toxicity and compromised pulmonary endothelial cell function, we hypothesized that direct exposure to isocyanate may disrupt endothelial structural lining, resulting in cellular damage. Based on this premise, we comprehensively evaluated the molecular repercussions of methyl isocyanate (MIC) exposure on human pulmonary arterial endothelial cells (HPAE-26). We examined MIC-induced mitochondrial oxidative stress, pro-inflammatory cytokine response, oxidative DNA damage response and apoptotic index. Our results demonstrate that exposure to MIC, augment mitochondrial reactive oxygen species production, depletion in antioxidant defense enzymes, elevated pro-inflammatory cytokine response and induced endothelial cell apoptosis via affecting the balance of mitochondrial-nuclear cross talk. We herein delineate the first and direct molecular cascade of isocyanate-induced pulmonary endothelial cell dysfunction. The results of our study might portray a connective link between associated respiratory morbidities with isocyanate exposure, and indeed facilitate to discern the exposure-phenotype relationship in observed deficits of pulmonary endothelial cell function. Further, understanding of inter- and intra-cellular signaling pathways involved in isocyanate-induced endothelial damage would not only aid in biomarker identification but also provide potential new avenues to target specific therapeutic interventions. PMID:24024149

  12. Mesenchymal Stromal Cells Expressing Heme Oxygenase-1 Reverse Pulmonary Hypertension

    PubMed Central

    Liang, Olin D.; Mitsialis, S. Alex; Chang, Mun Seog; Vergadi, Eleni; Lee, Changjin; Aslam, Muhammad; Fernandez-Gonzalez, Angeles; Liu, Xianlan; Baveja, Rajiv; Kourembanas, Stella

    2012-01-01

    Pulmonary arterial hypertension (PAH) remains a serious disease, and, while current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically-modified mouse lines, we tested the ability of bone marrow-derived stromal cells (MSCs), to treat chronic hypoxia-induced PAH. Recipient mice were exposed for five weeks to normobaric hypoxia (8%–10% O2), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or Heme Oxygenase-1 (HO-1) null mice (Hmox1KO) conferred partial protection from PAH when transplanted into WT or Hmox1KO recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SHO1 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1KO animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only upon doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulative, our results demonstrate that MSCs ameliorate chronic hypoxia – induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1 dependent and HO-1 independent protective pathways. PMID:20957739

  13. Pulmonary Rehabilitation in Improving Lung Function in Patients With Locally Advanced Non-Small Cell Lung Cancer Undergoing Chemoradiation

    ClinicalTrials.gov

    2015-03-17

    Cachexia; Fatigue; Pulmonary Complications; Radiation Toxicity; Recurrent Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  14. Pathogenic Actions of Cell Adhesion Molecule 1 in Pulmonary Emphysema and Atopic Dermatitis

    PubMed Central

    Yoneshige, Azusa; Hagiyama, Man; Fujita, Mitsugu; Ito, Akihiko

    2015-01-01

    Cell adhesion mediated by adhesion molecules is of central importance in the maintenance of tissue homeostasis. Therefore, altered expression of adhesion molecules leads to the development of various tissue disorders involving cell activation, degeneration, and apoptosis. Nevertheless, it still remains unclear what initiates the altered expression of adhesion molecules and how the subsequent pathological cascades proceed. In this regard, cell adhesion molecule 1 (CADM1) is one of the candidates that is involved in the development of pathological lesions; it is an intercellular adhesion molecule that is expressed in various types of cells such as pulmonary cells, neurons, and mast cells. Recent studies have revealed that alterations in the transcriptional or post-transcriptional expressions of CADM1 correlate with the pathogenesis of pulmonary diseases and allergic diseases. In this review, we specifically focus on how CADM1 is involved in the development of pathological lesions in pulmonary emphysema and atopic dermatitis. PMID:26636084

  15. Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.

    PubMed

    Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; Gonzalez De Los Santos, Francina; Phan, Sem H

    2016-07-01

    Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation. PMID:27206766

  16. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis

    PubMed Central

    Nicolls, Mark R.; Mizuno, Shiro; Taraseviciene-Stewart, Laima; Farkas, Laszlo; Drake, Jennnifer I.; Al Husseini, Aysar; Gomez-Arroyo, Jose G.; Voelkel, Norbert F.; Bogaard, Herman J.

    2012-01-01

    In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified

  17. Long-term improvement during tadalafil therapy in a patient with pulmonary hypertension secondary to pulmonary Langerhans cell histiocytosis.

    PubMed

    Nemoto, Kenji; Oh-Ishi, Shuji; Inui, Toshihide; Nakazawa, Mariko; Hyodo, Kentaro; Nakajima, Masayuki; Kanazawa, Jun; Miura, Yukiko; Takaku, Takio; Minami, Yuko; Hayashihara, Kenji; Saito, Takefumi; Kawabata, Yoshinori

    2016-01-01

    Pulmonary arterial hypertension (PAH) secondary to pulmonary Langerhans cell histiocytosis (PLCH) is known to be a relatively common complication and is associated with a poor prognosis. However, the optimal therapeutic approach for these cases remains to be established. A 57-year-old man visited our hospital because of a progressive dry cough. A thoracic computed tomography examination showed a combination of diffuse thick-walled cysts and reticulonodular shadows that were predominant in bilateral upper lobes of the lungs. He was diagnosed as having PLCH based on the results of video-assisted thoracoscopic lung biopsies. During a 3-year clinical course, his condition deteriorated despite smoking cessation. A systemic evaluation demonstrated precapillary PAH caused by PLCH (PAH-PLCH), and treatment with tadalafil, a phosphodiesterase-5 inhibitor, was started. During a 50-month period of treatment with tadalafil, improvements in his dyspnea, 6-min walking distance, and hemodynamics were maintained without either overt hypoxemia or pulmonary edema. We considered that tadalafil therapy may be a useful option in the treatment of patients with PAH-PLCH. PMID:27330952

  18. Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase

    PubMed Central

    Du, Jianhai; Xu, Hao; Bakhutashvili, Ivane; Eis, Annie; Shi, Yang; Pritchard, Kirkwood A.; Konduri, Girija G.

    2011-01-01

    Persistent pulmonary hypertension of the newborn (PPHN) is associated with decreased blood vessel density that contributes to increased pulmonary vascular resistance. Previous studies showed that uncoupled endothelial nitric oxide (NO) synthase (eNOS) activity and increased NADPH oxidase activity resulted in marked decreases in NO bioavailability and impaired angiogenesis in PPHN. In the present study, we hypothesize that loss of tetrahydrobiopterin (BH4), a critical cofactor for eNOS, induces uncoupled eNOS activity and impairs angiogenesis in PPHN. Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with PPHN (HTFL-PAEC) or control lambs (NFL-PAEC) were used to investigate the cellular mechanisms impairing angiogenesis in PPHN. Cellular mechanisms were examined with respect to BH4 levels, GTP-cyclohydrolase-1 (GCH-1) expression, eNOS dimer formation, and eNOS-heat shock protein 90 (hsp90) interactions under basal conditions and after sepiapterin (Sep) supplementation. Cellular levels of BH4, GCH-1 expression, and eNOS dimer formation were decreased in HTFL-PAEC compared with NFL-PAEC. Sep supplementation decreased apoptosis and increased in vitro angiogenesis in HTFL-PAEC and ex vivo pulmonary artery sprouting angiogenesis. Sep also increased cellular BH4 content, NO production, eNOS dimer formation, and eNOS-hsp90 association and decreased the superoxide formation in HTFL-PAEC. These data demonstrate that Sep improves NO production and angiogenic potential of HTFL-PAEC by recoupling eNOS activity. Increasing BH4 levels via Sep supplementation may be an important therapy for improving eNOS function and restoring angiogenesis in PPHN. PMID:21622842

  19. mTORC2 coordinates pulmonary artery smooth muscle cell metabolism, proliferation and survival in pulmonary arterial hypertension

    PubMed Central

    Goncharov, Dmitry A.; Kudryashova, Tatiana V.; Ziai, Houman; Ihida-Stansbury, Kaori; DeLisser, Horace; Krymskaya, Vera P.; Tuder, Rubin M.; Kawut, Steven M.; Goncharova, Elena A.

    2014-01-01

    Background Enhanced proliferation, resistance to apoptosis and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMC) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). The role of distinct mTOR complexes mTORC1 (mTOR-raptor) and mTORC2 (mTOR-rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance is unknown. Methods and Results Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly up-regulated in small remodeled PAs and isolated distal PAVSMC from IPAH subjects that have increased ATP levels, proliferation and survival that depend on glycolytic metabolism. siRNA- and pharmacological-based analysis showed that while both mTORC1 and mTORC2 contributing to proliferation, only mTORC2 is required for ATP generation and survival of IPAH PAVSMC. mTORC2 down-regulated energy sensor AMPK allowing activation of mTORC1-S6 and increased proliferation, and deficiency of pro-apoptotic protein Bim and IPAH PAVSMC survival. Nox4 protein levels were increased in IPAH PAVSMC that was necessary for mTORC2 activation, proliferation and survival. Nox4 levels and mTORC2 signaling were significantly up-regulated in small PAs from hypoxia-exposed rats at days 2-28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15-28 suppressed mTORC2, but not Nox4, induced SM-specific apoptosis in small PAs and reversed hypoxia-induced pulmonary vascular remodeling in rats. Conclusions These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via energy sensor AMPK to increased proliferation and survival of PAVSMC in PAH suggesting a new potential pathway for the therapeutic interventions. PMID:24270265

  20. The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma.

    PubMed

    Hiraki, Tsubasa; Goto, Yuko; Kitazono, Ikumi; Tasaki, Takashi; Higashi, Michiyo; Hatanaka, Kazuhito; Tanimoto, Akihide

    2016-04-01

    Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma. PMID:26519525

  1. Ultrasound exfoliation of inorganic analogues of graphene

    NASA Astrophysics Data System (ADS)

    Štengl, Václav; Henych, Jiří; Slušná, Michaela; Ecorchard, Petra

    2014-04-01

    High-intensity ultrasound exfoliation of a bulk-layered material is an attractive route for large-scale preparation of monolayers. The monolayer slices could potentially be prepared with a high yield (up to 100%) in a few minutes. Exfoliation of natural minerals (such as tungstenite and molybdenite) or bulk synthetic materials (including hexagonal boron nitride (h-BN), hexagonal boron carbon nitride (h-BCN), and graphitic carbon nitride (g-C3N4)) in liquids leads to the breakdown of the 3D graphitic structure into a 2D structure; the efficiency of this process is highly dependent upon the physical effects of the ultrasound. Atomic force microscopy (AFM), transmission electron microscopy (TEM), and selected area electron diffraction (SAED) were employed to verify the quality of the exfoliation. Herein, this new method of exfoliation with ultrasound assistance for application to mono- and bilayered materials in hydrophobic and hydrophilic environments is presented.

  2. Ultrasound exfoliation of inorganic analogues of graphene

    PubMed Central

    2014-01-01

    High-intensity ultrasound exfoliation of a bulk-layered material is an attractive route for large-scale preparation of monolayers. The monolayer slices could potentially be prepared with a high yield (up to 100%) in a few minutes. Exfoliation of natural minerals (such as tungstenite and molybdenite) or bulk synthetic materials (including hexagonal boron nitride (h-BN), hexagonal boron carbon nitride (h-BCN), and graphitic carbon nitride (g-C3N4)) in liquids leads to the breakdown of the 3D graphitic structure into a 2D structure; the efficiency of this process is highly dependent upon the physical effects of the ultrasound. Atomic force microscopy (AFM), transmission electron microscopy (TEM), and selected area electron diffraction (SAED) were employed to verify the quality of the exfoliation. Herein, this new method of exfoliation with ultrasound assistance for application to mono- and bilayered materials in hydrophobic and hydrophilic environments is presented. PMID:24708572

  3. Idiopathic pulmonary fibrosis: can cell mediated immunity markers predict clinical outcome?

    PubMed Central

    Meliconi, R; Lalli, E; Borzì, R M; Sturani, C; Galavotti, V; Gunella, G; Miniero, R; Facchini, A; Gasbarrini, G

    1990-01-01

    Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis. The three markers were: soluble CD8 (from activated suppressor-cytotoxic lymphocytes), soluble interleukin (IL)-2 receptors (from activated T cells and macrophages), and neopterin (from activated macrophages). Patients with idiopathic pulmonary fibrosis had higher levels of all three markers than the control subjects. Soluble IL-2 receptor and neopterin tended to be lower (though not significantly) in patients with idiopathic pulmonary fibrosis than in those with sarcoidosis, whereas soluble CD8 was similar in the two groups of patients. No correlation was found between soluble IL-2 receptors or soluble CD8 and the clinical, radiological, and physiological measures of disease activity or with clinical outcome (after a mean follow up of 23 months). Tumour necrosis factor levels were also determined. Only 30% of patients with idiopathic pulmonary fibrosis or sarcoidosis had detectable circulating tumour necrosis factor; these patients had a lower percentage of bronchoalveolar lavage fluid neutrophils in their lavage fluid. Tumour necrosis factor levels did not correlate with clinical measures of severity or outcome. Thus our data support the hypothesis that cell mediated alveolitis occurs in idiopathic pulmonary fibrosis. They do not, however, provide evidence to support the use of these markers of cell mediated immunity to monitor the clinical course in these patients. PMID:2118691

  4. Physiological functions of transient receptor potential channels in pulmonary arterial smooth muscle cells.

    PubMed

    Yang, Xiao-Ru; Lin, Mo-Jun; Sham, James S K

    2010-01-01

    The transient receptor potential (TRP) gene superfamily, which consists of 7 subfamilies with at least 28 mammalian homologues, is known to encode a wide variety of cation channels with diverse biophysical properties, activation mechanisms, and physiological functions. Recent studies have identified multiple TRP channel subtypes, belonging to the canonical (TRPC), melastatin-related (TRPM), and vanilloid-related (TRPV) subfamilies, in pulmonary arterial smooth muscle cells (PASMCs). They operate as specific Ca(2+) pathways responsive to stimuli, including Ca(2+) store depletion, receptor activation, reactive oxygen species, growth factors, and mechanical stress. Increasing evidence suggests that these channels play crucial roles in agonist-induced pulmonary vasoconstriction, hypoxic pulmonary vasoconstriction, smooth muscle cell proliferation, vascular remodeling, and pulmonary arterial hypertension. This chapter highlighted and discussed these putative physiological functions of TRP channels in pulmonary vasculatures. Since Ca(2+) ions regulate many cellular processes via specific Ca(2+) signals, future investigations of these novel channels will likely uncover more important regulatory mechanisms of pulmonary vascular functions in health and in disease states. PMID:20204726

  5. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanis...

  6. DNA-Assisted Exfoliation of Tungsten Dichalcogenides and Their Antibacterial Effect.

    PubMed

    Bang, Gyeong Sook; Cho, Suhyung; Son, Narae; Shim, Gi Woong; Cho, Byung-Kwan; Choi, Sung-Yool

    2016-01-27

    This study reports a method for the facile and high-yield exfoliation of WX2 (X = S, Se) by sonication under aqueous conditions using single-stranded DNA (abbreviated as ssDNA) of high molecular weight. The ssDNA provided a high degree of stabilization and prevented reaggregation, and it enhanced the exfoliation efficiency of WX2 nanosheets due to adsorption on the WX2 surface and the electrostatic repulsion of sugars in the ssDNA backbone. The exfoliation yield was higher with ssDNA (80%-90%) than without (2%-4%); the yield with ssDNA was also higher than the value previously reported for aqueous exfoliation (∼10%). Given that two-dimensional nanomaterials have potential health and environmental applications, we investigated antibacterial activity of exfoliated WX2-ssDNA nanosheets, relative to graphene oxide (GO), and found that WSe2-ssDNA nanosheets had higher antibacterial activity against Escherichia coli K-12 MG1655 cells than GO. Our method enables large-scale exfoliation in an aqueous environment in a single step with a short reaction time and under ambient conditions, and it can be used to produce surface-active or catalytic materials that have broad applications in biomedicine and other areas. PMID:26734845

  7. Imidazolium salts as small-molecule urinary bladder exfoliants in a murine model.

    PubMed

    Wagers, Patrick O; Tiemann, Kristin M; Shelton, Kerri L; Kofron, William G; Panzner, Matthew J; Wooley, Karen L; Youngs, Wiley J; Hunstad, David A

    2015-09-01

    We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties. PMID:26124168

  8. Imidazolium Salts as Small-Molecule Urinary Bladder Exfoliants in a Murine Model

    PubMed Central

    Wagers, Patrick O.; Tiemann, Kristin M.; Shelton, Kerri L.; Kofron, William G.; Panzner, Matthew J.; Wooley, Karen L.; Youngs, Wiley J.

    2015-01-01

    We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties. PMID:26124168

  9. Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Pizarro, Sandra; García-Lucio, Jéssica; Peinado, Víctor I.; Tura-Ceide, Olga; Díez, Marta; Blanco, Isabel; Sitges, Marta; Petriz, Jordi; Torralba, Yolanda; Marín, Pedro; Roca, Josep; Barberà, Joan Albert

    2014-01-01

    Background In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown. Objectives To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function. Methods 62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45+CD34+CD133+ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects. Results Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries. Conclusions Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit. PMID:25171153

  10. Pulmonary surfactant mitigates silver nanoparticle toxicity in human alveolar type-I-like epithelial cells.

    PubMed

    Sweeney, Sinbad; Leo, Bey Fen; Chen, Shu; Abraham-Thomas, Nisha; Thorley, Andrew J; Gow, Andrew; Schwander, Stephan; Zhang, Junfeng Jim; Shaffer, Milo S P; Chung, Kian Fan; Ryan, Mary P; Porter, Alexandra E; Tetley, Teresa D

    2016-09-01

    Accompanying increased commercial applications and production of silver nanomaterials is an increased probability of human exposure, with inhalation a key route. Nanomaterials that deposit in the pulmonary alveolar region following inhalation will interact firstly with pulmonary surfactant before they interact with the alveolar epithelium. It is therefore critical to understand the effects of human pulmonary surfactant when evaluating the inhalation toxicity of silver nanoparticles. In this study, we evaluated the toxicity of AgNPs on human alveolar type-I-like epithelial (TT1) cells in the absence and presence of Curosurf(®) (a natural pulmonary surfactant substitute), hypothesising that the pulmonary surfactant would act to modify toxicity. We demonstrated that 20nm citrate-capped AgNPs induce toxicity in human alveolar type I-like epithelial cells and, in agreement with our hypothesis, that pulmonary surfactant acts to mitigate this toxicity, possibly through reducing AgNP dissolution into cytotoxic Ag(+) ions. For example, IL-6 and IL-8 release by TT1 cells significantly increased 10.7- and 35-fold, respectively (P<0.01), 24h after treatment with 25μg/ml AgNPs. In contrast, following pre-incubation of AgNPs with Curosurf(®), this effect was almost completely abolished. We further determined that the mechanism of this toxicity is likely associated with Ag(+) ion release and lysosomal disruption, but not with increased reactive oxygen species generation. This study provides a critical understanding of the toxicity of AgNPs in target human alveolar type-I-like epithelial cells and the role of pulmonary surfactant in mitigating this toxicity. The observations reported have important implications for the manufacture and application of AgNPs, in particular for applications involving use of aerosolised AgNPs. PMID:27182651

  11. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension

    PubMed Central

    Sheikh, Abdul Q.; Misra, Ashish; Rosas, Ivan O.; Adams, Ralf H.; Greif, Daniel M.

    2015-01-01

    Excess and ectopic smooth muscle cells (SMCs) are central to cardiovascular disease pathogenesis, but underlying mechanisms are poorly defined. For instance, pulmonary hypertension (PH) or elevated pulmonary artery blood pressure is a devastating disease with distal extension of smooth muscle to normally unmuscularized pulmonary arterioles. We identify novel SMC progenitors that are located at the pulmonary arteriole muscular-unmuscular border and express both SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor-β (PDGFR-β). We term these cells “primed” because in hypoxia-induced PH, they express the pluripotency factor Kruppel-like factor 4 (KLF4), and in each arteriole, one of them migrates distally, dedifferentiates, and clonally expands, giving rise to the distal SMCs. Furthermore, hypoxia-induced expression of the ligand PDGF-B regulates primed cell KLF4 expression, and enhanced PDGF-B and KLF4 levels are required for distal arteriole muscularization and PH. Finally, in PH patients, KLF4 is markedly up-regulated in pulmonary arteriole smooth muscle, especially in proliferating SMCs. In sum, we have identified a pool of SMC progenitors that are critical for the pathogenesis of PH, and perhaps other vascular disorders, and therapeutic strategies targeting this cell type promise to have profound implications. PMID:26446956

  12. Pulmonary lymphoma of large B-cell type mimicking Wegener's granulomatosis.

    PubMed

    Miyahara, N; Eda, R; Umemori, Y; Murakami, T; Kunichika, N; Makihata, K; Aoe, K; Murakami, K; Takeyama, H; Harada, M

    2001-08-01

    A 27-year-old man with a primary pulmonary lymphoma of large B-cell type is described. Symptoms involved both the upper and lower respiratory tract. A chest roentgenogram showed a dense mass with cavitation. Transbronchial biopsy specimens revealed no atypical cells, rather they demonstrated granulomatous infiltration and vasculitis consistent with but not conclusively diagnostic of Wegener's granulomatosis. The pulmonary mass became smaller after sulfamethoxazole-trimethoprim therapy. These features suggested Wegener's granulomatosis. However, an open biopsy specimen was diagnostic for diffuse lymphoma of large B-cell type. High-grade pulmonary lymphoma should be considered in the differential diagnosis of patients with clinical and pathologic features suggesting Wegener's granulomatosis. PMID:11518126

  13. Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis

    PubMed Central

    Liu, Tianju; Yu, Hongfeng; Ding, Lin; Wu, Zhe; Gonzalez De Los Santos, Francina; Liu, Jianhua; Ullenbruch, Matthew; Hu, Biao; Martins, Vanessa; Phan, Sem H.

    2015-01-01

    Telomerase is typically expressed in cellular populations capable of extended replication, such as germ cells, tumor cells, and stem cells, but is also induced in tissue injury, repair and fibrosis. Its catalytic component, telomerase reverse transcriptase (TERT) is induced in lung fibroblasts from patients with fibrotic interstitial lung disease and in rodents with bleomycin-induced pulmonary fibrosis. To evaluate the fibroblast specific role of TERT in pulmonary fibrosis, transgenic mice bearing a floxed TERT allele were generated, and then crossed with an inducible collagen α2(I)-Cre mouse line to generate fibroblast specific TERT conditional knockout mice. TERT-specific deficiency in mesenchymal cells caused attenuation of pulmonary fibrosis as manifested by reduced lung hydroxyproline content, type I collagen and α-smooth muscle actin mRNA levels. The TERT-deficient mouse lung fibroblasts displayed decreased cell proliferative capacity and higher susceptibility to induced apoptosis compared with control cells. Additionally TERT deficiency was associated with heightened α-smooth muscle actin expression indicative of myofibroblast differentiation. However the impairment of cell proliferation and increased susceptibility to apoptosis would cause a reduction in the myofibroblast progenitor population necessary to mount a successful myofibroblast-dependent fibrotic response. These findings identified a key role for TERT in fibroblast proliferation and survival essential for pulmonary fibrosis. PMID:26555817

  14. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  15. Squamous Cell Carcinoma of the Oropharynx and Esophagus with Pulmonary Metastasis in a Backyard Laying Hen.

    PubMed

    Laura, Nordio; Marta, Vascellari; Giacomo, Berto; Luca, Bano

    2016-09-01

    A backyard laying hen exhibiting muscular atrophy, dyspnea, and absence of egg production was analyzed for diagnostic insights. Gross findings revealed the presence of a large ulcerated mass with irregular edges involving the caudal part of the oropharynx and the cranial part of the esophagus, occluding the lumen of the esophagus and compressing the trachea. Small nodular lesions were detected also in the lungs. Histologically, both esophageal and pulmonary masses were characterized by nests of pleomorphic epithelial cells with squamous differentiation. The diagnosis was of squamous cell carcinoma of the esophagus with the uncommon feature of pulmonary metastasis. PMID:27610733

  16. Pulmonary Mast Cell Tumor and Possible Paraganglioma in a Free-ranging Pacific Walrus ( Odobenus rosmarus divergens), Barrow, Alaska, USA.

    PubMed

    Seguel, Mauricio; Stimmelmayr, Raphaela; Howerth, Elizabeth; Gottdenker, Nicole

    2016-04-28

    We describe a pulmonary mast cell tumor in a subsistence-harvested free-ranging Pacific walrus (Odobenus rosmarus divergens). Neoplastic cells effacing a focal area of pulmonary parenchyma were characterized by rare metachromatic granules and positive staining for C-kit. We also report co-occurrence of a peribronchial mass with a morphologic and immunohistochemical profile compatible with paraganglioma. PMID:27054472

  17. Smooth muscle cell conditioned medium elevates angiotensin-converting enzyme of bovine pulmonary artery endothelial cells.

    PubMed

    Yu, F S; Lee, S L; Fanburg, B L

    1989-11-01

    Conditioned medium obtained from bovine pulmonary artery smooth muscle cells (SMC) in culture was found to elevate angiotensin-I-converting enzyme (ACE) of bovine pulmonary artery endothelial cells (EC) by 2- to 3-fold upon incubation for 24 to 48 h. The elevation in ACE was time dependent and inhibited by 10(-6) M cycloheximide, making it likely that the elevation was related to new protein synthesis by EC. Conditioned medium from EC failed to produce the same effect. The stimulatory effect of SMC conditioned medium on EC ACE was uninfluenced by exposures to anoxia as compared with room air, either during conditioning of medium or while assaying the effect of conditioned medium on EC ACE. Inhibitors of prostaglandin metabolism and calcium transport failed to influence the stimulatory effect of SMC conditioned medium on EC ACE. The stimulatory effect on EC ACE by conditioned medium was additive to that produced by Ca2+ ionophore A23187 and 3-isobutyl-1-methylxanthine and, similar to baseline ACE, was inhibited by 3 x 10(-8) M ouabain. Thus, SMC produce a factor that regulates the level of EC ACE. PMID:2484059

  18. Pulmonary Hypertension

    PubMed Central

    Newman, John H.

    2005-01-01

    The modern era in cardiopulmonary medicine began in the 1940s, when Cournand and Richards pioneered right-heart catheterization. Until that time, no direct measurement of central vascular pressure had been performed in humans. Right-heart catheterization ignited an explosion of insights into function and dysfunction of the pulmonary circulation, cardiac performance, ventilation–perfusion relationships, lung–heart interactions, valvular function, and congenital heart disease. It marked the beginnings of angiocardiography with its diagnostic implications for diseases of the left heart and peripheral circulation. Pulmonary hypertension was discovered to be the consequence of a large variety of diseases that either raised pressure downstream of the pulmonary capillaries, induced vasoconstriction, increased blood flow to the lung, or obstructed the pulmonary vessels, either by embolism or in situ fibrosis. Hypoxic vasoconstriction was found to be a major cause of acute and chronic pulmonary hypertension, and surprising vasoreactivity of the pulmonary vascular bed was discovered to be present in many cases of severe pulmonary hypertension, initially in mitral stenosis. Diseases as disparate as scleroderma, cystic fibrosis, kyphoscoliosis, sleep apnea, and sickle cell disease were found to have shared consequences in the pulmonary circulation. Some of the achievements of Cournand and Richards and their scientific descendents are discussed in this article, including success in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and management of hypoxic pulmonary hypertension. PMID:15994464

  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. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention

    SciTech Connect

    Mehta, Vivek . E-mail: Vivek.Mehta@swedish.org

    2005-09-01

    Although radiotherapy improves locoregional control and survival in patients with non-small-cell lung cancer, radiation pneumonitis is a common treatment-related toxicity. Many pulmonary function tests are not significantly altered by pulmonary toxicity of irradiation, but reductions in DL{sub CO}, the diffusing capacity of carbon monoxide, are more commonly associated with pneumonitis. Several patient-specific factors (e.g. age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g. chemotherapy regimen and dose) have been proposed as potential predictors of the risk of radiation pneumonitis, but these have not been consistently demonstrated across different studies. The risk of radiation pneumonitis also seems to increase as the cumulative dose of radiation to normal lung tissue increases, as measured by dose-volume histograms. However, controversy persists about which dosimetric parameter optimally predicts the risk of radiation pneumonitis, and whether the volume of lung or the dose of radiation is more important. Radiation oncologists ought to consider these dosimetric factors when designing radiation treatment plans for all patients who receive thoracic radiotherapy. Newer radiotherapy techniques and technologies may reduce the exposure of normal lung to irradiation. Several medications have also been evaluated for their ability to reduce radiation pneumonitis in animals and humans, including corticosteroids, amifostine, ACE inhibitors or angiotensin II type 1 receptor blockers, pentoxifylline, melatonin, carvedilol, and manganese superoxide dismutase-plasmid/liposome. Additional research is warranted to determine the efficacy of these medications and identify nonpharmacologic strategies to predict and prevent radiation pneumonitis.

  1. Pulmonary Alveolar Type II Epithelial Cells and Adult Respiratory Distress Syndrome

    PubMed Central

    Mason, Robert J.

    1985-01-01

    During the past ten years, functions of alveolar type II cells have been well characterized with isolated cells in vitro. Some of the functions were well known from studies in vivo, but others such as transepithelial sodium transport were unsuspected. A better understanding of this important pulmonary cell type improves our knowledge of the pathophysiology of adult respiratory distress syndrome and may in time lead to new therapeutic strategies. ImagesFigure 1.Figure 2.Figure 3.Figure 4. PMID:3909639

  2. The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

    PubMed Central

    Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P.; Williams, David B.; Kamp, David W.

    2015-01-01

    Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. PMID:26370974

  3. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

    PubMed Central

    Champion, Hunter C.; Campbell-Lee, Sally A.; Bivalacqua, Trinity J.; Manci, Elizabeth A.; Diwan, Bhalchandra A.; Schimel, Daniel M.; Cochard, Audrey E.; Wang, Xunde; Schechter, Alan N.; Noguchi, Constance T.; Gladwin, Mark T.

    2007-01-01

    Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO. PMID:17158223

  4. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

    PubMed Central

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  5. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens.

    PubMed

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4(+) or CD8(+) T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b(+) myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b(+) myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  6. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells

    PubMed Central

    Jacobsen, Elizabeth A.; Ochkur, Sergei I.; Pero, Ralph S.; Taranova, Anna G.; Protheroe, Cheryl A.; Colbert, Dana C.; Lee, Nancy A.; Lee, James J.

    2008-01-01

    The current paradigm surrounding allergen-mediated T helper type 2 (Th2) immune responses in the lung suggests an almost hegemonic role for T cells. Our studies propose an alternative hypothesis implicating eosinophils in the regulation of pulmonary T cell responses. In particular, ovalbumin (OVA)-sensitized/challenged mice devoid of eosinophils (the transgenic line PHIL) have reduced airway levels of Th2 cytokines relative to the OVA-treated wild type that correlated with a reduced ability to recruit effector T cells to the lung. Adoptive transfer of Th2-polarized OVA-specific transgenic T cells (OT-II) alone into OVA-challenged PHIL recipient mice failed to restore Th2 cytokines, airway histopathologies, and, most importantly, the recruitment of pulmonary effector T cells. In contrast, the combined transfer of OT-II cells and eosinophils into PHIL mice resulted in the accumulation of effector T cells and a concomitant increase in both airway Th2 immune responses and histopathologies. Moreover, we show that eosinophils elicit the expression of the Th2 chemokines thymus- and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in the lung after allergen challenge, and blockade of these chemokines inhibited the recruitment of effector T cells. In summary, the data suggest that pulmonary eosinophils are required for the localized recruitment of effector T cells. PMID:18316417

  7. COMPARATIVE TOXICITY OF DIFFERENT EMISSION PARTICLES IN MURINE PULMONARY EPITHELIAL CELLS AND MACROPHAGES

    EPA Science Inventory

    Comparative Toxicity of Different Emission Particles in Murine Pulmonary Epithelial Cells and Macrophages. T Stevens1, M Daniels2, P Singh2, M I Gilmour2. 1 UNC, Chapel Hill 27599 2Experimental Toxicology Division, NHEERL, RTP, NC 27711

    Epidemiological studies have shown ...

  8. Puerarin Induces Mitochondria-Dependent Apoptosis in Hypoxic Human Pulmonary Arterial Smooth Muscle Cells

    PubMed Central

    Chen, Chan; Chen, Chun; Wang, Zhiyi; Wang, Liangxing; Yang, Lehe; Ding, Minjiao; Ding, Cheng; Sun, Yu; Lin, Quan; Huang, Xiaoying; Du, Xiaohong; Zhao, Xiaowei; Wang, Chuangyi

    2012-01-01

    Background Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial hypertension (PAH) is caused in part by decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Puerarin, an isoflavone purified from the Chinese medicinal herb kudzu, ameliorates chronic hypoxic PAH in animal models. Here we investigated the effects of puerarin on apoptosis of hypoxic human PASMCs (HPASMCs), and to determine the possible underlying mechanisms. Methodology/Principal Findings HPASMCs were cultured for 24 h in normoxia or hypoxia (5% O2) conditions with and without puerarin. Cell number and viability were determined with a hemacytometer or a cell counting kit. Apoptosis was detected with a TUNEL test, rhodamine-123 (R-123) fluorescence, a colorimetric assay, western blots, immunohistochemical staining and RT-PCR. Hypoxia inhibited mitochondria-dependent apoptosis and promoted HPASMC growth. In contrast, after puerarin (50 µM or more) intervention, cell growth was inhibited and apoptosis was observed. Puerarin-induced apoptosis in hypoxic HPASMCs was accompanied by reduced mitochondrial membrane potential, cytochrome c release from the mitochondria, caspase-9 activation, and Bcl-2 down-regulation with concurrent Bax up-regulation. Conclusions/Significance Puerarin promoted apoptosis in hypoxic HPASMCs by acting on the mitochondria-dependent pathway. These results suggest a new mechanism of puerarin relevant to the management of clinical hypoxic pulmonary hypertension. PMID:22457823

  9. Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening.

    PubMed

    Bilek, Anastacia M; Dee, Kay C; Gaver, Donald P

    2003-02-01

    Airway collapse and reopening due to mechanical ventilation exerts mechanical stress on airway walls and injures surfactant-compromised lungs. The reopening of a collapsed airway was modeled experimentally and computationally by the progression of a semi-infinite bubble in a narrow fluid-occluded channel. The extent of injury caused by bubble progression to pulmonary epithelial cells lining the channel was evaluated. Counterintuitively, cell damage increased with decreasing opening velocity. The presence of pulmonary surfactant, Infasurf, completely abated the injury. These results support the hypotheses that mechanical stresses associated with airway reopening injure pulmonary epithelial cells and that pulmonary surfactant protects the epithelium from this injury. Computational simulations identified the magnitudes of components of the stress cycle associated with airway reopening (shear stress, pressure, shear stress gradient, or pressure gradient) that may be injurious to the epithelial cells. By comparing these magnitudes to the observed damage, we conclude that the steep pressure gradient near the bubble front was the most likely cause of the observed cellular damage. PMID:12433851

  10. Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients

    PubMed Central

    Maioli, Maria Christina Paixão; Soares, Andrea Ribeiro; Bedirian, Ricardo; Alves, Ursula David; de Lima Marinho, Cirlene; Lopes, Agnaldo José

    2015-01-01

    Objective To evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases. Methods Fifty-nine adults were included in this cross-sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography. Results Abnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p-value < 0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value = 0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p-value = 0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p-value = 0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography. Conclusion A significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases. PMID:26969771

  11. Fabrication of Boron Nitride Nanosheets by Exfoliation.

    PubMed

    Wang, Zifeng; Tang, Zijie; Xue, Qi; Huang, Yan; Huang, Yang; Zhu, Minshen; Pei, Zengxia; Li, Hongfei; Jiang, Hongbo; Fu, Chenxi; Zhi, Chunyi

    2016-06-01

    Nanomaterials with layered structures, with their intriguing properties, are of great research interest nowadays. As one of the primary two-dimensional nanomaterials, the hexagonal boron nitride nanosheet (BNNS, also called white graphene), which is an analogue of graphene, possesses various attractive properties, such as high intrinsic thermal conductivity, excellent chemical and thermal stability, and electrical insulation properties. After being discovered, it has been one of the most intensively studied two-dimensional non-carbon nanomaterials and has been applied in a wide range of applications. To support the exploration of applications of BNNSs, exfoliation, as one of the most promising approaches to realize large-scale production of BNNSs, has been intensively investigated. In this review, methods to yield BNNSs by exfoliation will be summarized and compared with other potential fabrication methods of BNNSs. In addition, the future prospects of the exfoliation of h-BN will also be discussed. PMID:27062213

  12. Management of exfoliative glaucoma: challenges and solutions

    PubMed Central

    Holló, Gábor; Katsanos, Andreas; Konstas, Anastasios GP

    2015-01-01

    Exfoliative glaucoma is the most common type of secondary open-angle glaucoma worldwide. It is characterized by high intraocular pressure (IOP) and worse 24-hour IOP characteristics. In order to minimize progression, treatment of exfoliative glaucoma has to provide a low long-term mean IOP and good 24-hour IOP control. To achieve these goals, fixed-dose combination eye drops, argon and selective laser trabeculoplasty, and various forms of surgery (trabeculectomy, deep sclerectomy, viscocanalostomy, ab interno trabeculotomy, trabecular aspiration, and cataract surgery) all need to be considered during the long-term management of the disease. Since exfoliative glaucoma is a disease of the elderly, and is frequently associated with systemic vascular disease, interdisciplinary consultations are of great clinical importance. These management aspects and the current medical, laser, and surgical results are covered in this review, with a special focus on the needs of the general ophthalmologist. PMID:26045655

  13. Management of exfoliative glaucoma: challenges and solutions.

    PubMed

    Holló, Gábor; Katsanos, Andreas; Konstas, Anastasios Gp

    2015-01-01

    Exfoliative glaucoma is the most common type of secondary open-angle glaucoma worldwide. It is characterized by high intraocular pressure (IOP) and worse 24-hour IOP characteristics. In order to minimize progression, treatment of exfoliative glaucoma has to provide a low long-term mean IOP and good 24-hour IOP control. To achieve these goals, fixed-dose combination eye drops, argon and selective laser trabeculoplasty, and various forms of surgery (trabeculectomy, deep sclerectomy, viscocanalostomy, ab interno trabeculotomy, trabecular aspiration, and cataract surgery) all need to be considered during the long-term management of the disease. Since exfoliative glaucoma is a disease of the elderly, and is frequently associated with systemic vascular disease, interdisciplinary consultations are of great clinical importance. These management aspects and the current medical, laser, and surgical results are covered in this review, with a special focus on the needs of the general ophthalmologist. PMID:26045655

  14. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    PubMed Central

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  15. Longitudinal analysis of pulmonary function in adults with sickle cell disease

    PubMed Central

    Field, Joshua J.; Glassberg, Jeffrey; Gilmore, Annette; Howard, Joanna; Patankar, Sameer; Yan, Yan; Davies, Sally C.; DeBaun, Michael R.; Strunk, Robert C.

    2013-01-01

    Among adults with sickle cell disease (SCD), pulmonary complications are a leading cause of death. Yet, the natural history of lung function in adults with SCD is not well established. We conducted a retrospective cohort study of adults with SCD who had repeated pulmonary function tests performed over 20 years of age. Ninety-two adults were included in this cohort. Rate of decline in FEV1 for men and women with SCD was 49 cc/year (compared with 20–26 cc/year in the general population). Further studies are needed to identify factors which impact the rate of lung function decline in adults with SCD. PMID:18383325

  16. Imaging of diffuse metastatic and dystrophic pulmonary calcification in children after haematopoietic stem cell transplantation.

    PubMed

    Guermazi, A; Espérou, H; Selimi, F; Gluckman, E

    2005-08-01

    The authors describe three cases of diffuse pulmonary calcification; two metastatic in children with acute transitory renal failure and the other dystrophic in a child with leukaemia. All three patients underwent haematopoietic stem cell transplantation (HSCT). Chest radiographs disclosed diffuse calcification within the lungs. The distribution of this calcification was bilateral but asymmetric. Diagnosis was made in two cases by high resolution computed tomography (HRCT) and in one case by HRCT and bone scan. Radiological characteristics, scintigraphic features, pathological mechanism and clinical outcome of such pulmonary calcification are discussed. PMID:16046422

  17. Pulmonary Artery Agenesis Associated With Emphysema and Multiple Invasive Non-Small Cell Lung Cancers.

    PubMed

    Makdisi, George; Edell, Eric S; Maleszewski, Joseph J; Molina, Julian R; Deschamps, Claude

    2015-06-01

    Pulmonary artery (PA) agenesis in the absence of associated cardiac abnormalities is a rare congenital abnormality. It may remain undiagnosed until adulthood when patients present with respiratory symptoms such as hemoptysis, dyspnea, repeated respiratory infections, or pulmonary hypertension. Herein we present a case of a 50-year-old woman who was found to have multiple, morphologically distinct non-small cell lung cancers in association with agenesis of the PA. This instance represents the fourth reported case of such association in the English literature. PMID:26046873

  18. Stable liquid crystalline phases of colloidally dispersed exfoliated layered niobates.

    PubMed

    Nakato, Teruyuki; Miyamoto, Nobuyoshi; Harada, Akiko

    2004-01-01

    Colloidally dispersed niobium oxide nanosheets obtained by exfoliation of layered niobates HNb(3)O(8) and HTiNbO(5) formed stable liquid crystalline phases; their liquid crystallinity was dependent on the niobate species exfoliated. PMID:14737341

  19. Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells.

    PubMed

    Yang, Jun; Li, Xiaohui; Li, Ying; Southwood, Mark; Ye, Lingying; Long, Lu; Al-Lamki, Rafia S; Morrell, Nicholas W

    2013-08-15

    Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1-4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli. PMID:23771884

  20. Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

    PubMed Central

    Yang, Jun; Li, Xiaohui; Li, Ying; Southwood, Mark; Ye, Lingying; Long, Lu; Al-Lamki, Rafia S.

    2013-01-01

    Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1–4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1–4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli. PMID:23771884

  1. Preparation and characterization of solar exfoliated graphene

    SciTech Connect

    M, Sreejesh S, Nagaraja H.; K, Udaya Bhat

    2014-10-15

    Hummer's method was used for the chemical synthesis of graphite oxide from graphite flakes. Simultaneous exfoliation and reduction of graphite oxide to Graphene was achieved through focused solar light irradiation using a convex lens. The morphological characteristics were studied using SEM and TEM. Layered morphology of Graphene was observed through TEM. Raman spectra and FTIR were used for the structural characterization of Graphene. EDAX analysis showed the drop in oxygen content during exfoliation. The method offered a faster, easier and environmental friendly method to produce Graphene for potential applications.

  2. Exfoliative cheilitis: report of a case.

    PubMed

    Mani, Shani Ann; Shareef, Ban Tawfeek

    2007-09-01

    Exfoliative cheilitis, one of a spectrum of diseases that affect the vermilion border of the lips, is uncommon and has no known cause. However, factors such as stress and some psychiatric conditions are associated with the onset of the disease. This condition is disabling because esthetics and normal functions such as eating, speaking and smiling are compromised. The lack of specific treatment makes exfoliative cheilitis a chronic disease that radically affects a person"s life. This report attempts to further investigate the clinical course of the disease and provides detailed illustrations of the cyclical nature of the disease. PMID:17868515

  3. Method for exfoliation of hexagonal boron nitride

    NASA Technical Reports Server (NTRS)

    Lin, Yi (Inventor); Connell, John W. (Inventor)

    2012-01-01

    A new method is disclosed for the exfoliation of hexagonal boron nitride into mono- and few-layered nanosheets (or nanoplatelets, nanomesh, nanoribbons). The method does not necessarily require high temperature or vacuum, but uses commercially available h-BN powders (or those derived from these materials, bulk crystals) and only requires wet chemical processing. The method is facile, cost efficient, and scalable. The resultant exfoliated h-BN is dispersible in an organic solvent or water thus amenable for solution processing for unique microelectronic or composite applications.

  4. Preparation and characterization of solar exfoliated graphene

    NASA Astrophysics Data System (ADS)

    M, Sreejesh; K, Udaya Bhat; S, Nagaraja H.

    2014-10-01

    Hummer's method was used for the chemical synthesis of graphite oxide from graphite flakes. Simultaneous exfoliation and reduction of graphite oxide to Graphene was achieved through focused solar light irradiation using a convex lens. The morphological characteristics were studied using SEM and TEM. Layered morphology of Graphene was observed through TEM. Raman spectra and FTIR were used for the structural characterization of Graphene. EDAX analysis showed the drop in oxygen content during exfoliation. The method offered a faster, easier and environmental friendly method to produce Graphene for potential applications.

  5. Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis.

    PubMed

    Tazi, A; Montcelly, L; Bergeron, A; Valeyre, D; Battesti, J P; Hance, A J

    1998-06-01

    In most patients with pulmonary Langerhans cell histiocytosis (LCH), clinical and radiological abnormalities initially either stabilize or regress, often without treatment. Little information is available, however, concerning the subsequent evolution of disease in patients who initially follow a benign course. We describe four patients with biopsy-confirmed pulmonary LCH whose initial course was characterized by regression of parenchymal nodular lesions, but who subsequently developed one or more episodes of active disease 7 mo to 7.5 yr after their initial presentation. In each case, the subsequent episodes of active disease were characterized by the reappearance or marked increase in nodular radiographic abnormalities, whose presence was confirmed by high-resolution computed tomography (HRCT). Thus, initial regression of nodular lesions in pulmonary LCH does not preclude the reappearance of one or more episodes of active disease, and may have important consequences on the long-term prognosis of these patients. PMID:9620939

  6. High Diagnostic Yield of Dedicated Pulmonary Screening before Hematopoietic Cell Transplantation in Children.

    PubMed

    Versluys, Anne Birgitta; van der Ent, Korstiaan; Boelens, Jaap J; Wolfs, Tom; de Jong, Pim; Bierings, Marc B

    2015-09-01

    Pulmonary complications are an important cause for treatment-related morbidity and mortality in hematopoietic cell transplantation (HCT) in children. The aim of this study was to investigate the yield of our pre-HCT pulmonary screening program. We also describe our management guidelines based on these findings and correlate them with symptomatic lung injury after HCT. Since 2008, all patients undergo a dedicated pulmonary screening consisting of pulmonary function test (PFT), chest high-resolution computed tomography (HRCT), and bronchial alveolar lavage (BAL) before HCT. We systematically evaluated the yield during the first 5 years of our screening program. We included 142 consecutive children. In 74% of patients, abnormalities were found. In 66% of patients, 1 or more PFT results were <80% of normal. Chest HRCT showed abnormalities in 55%; 19% of these abnormalities were considered "clinically significant." BAL was abnormal in 43% of patients; respiratory viruses (PCR) were found in 35 patients, fungi (antigen or culture) in 21, and bacteria (culture) in 22. All 3 screening tests contributed separately to clinically relevant information regarding pulmonary status in these pre-HCT children. In 46 patients (33%), screening results had diagnostic and/or therapeutic implications. We found an association between pre-SCT HRCT findings and lung injury after transplantation. Pre-HCT screening with the combination of 3 modalities, reflecting different domains of respiratory status (function, structure, and microbial colonization), reveals important abnormalities in a substantial number of patients. Whether this improves patient outcome requires further investigation. PMID:26071867

  7. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease.

    PubMed

    Minniti, Caterina P; Machado, Roberto F; Coles, Wynona A; Sachdev, Vandana; Gladwin, Mark T; Kato, Gregory J

    2009-12-01

    Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD. PMID:19775299

  8. Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow.

    PubMed

    Datar, Sanjeev A; Gong, Wenhui; He, Youping; Johengen, Michael; Kameny, Rebecca J; Raff, Gary W; Maltepe, Emin; Oishi, Peter E; Fineman, Jeffrey R

    2016-07-01

    Associated abnormalities of the lymphatic circulation are well described in congenital heart disease. However, their mechanisms remain poorly elucidated. Using a clinically relevant ovine model of a congenital cardiac defect with chronically increased pulmonary blood flow (shunt), we previously demonstrated that exposure to chronically elevated pulmonary lymph flow is associated with: 1) decreased bioavailable nitric oxide (NO) in pulmonary lymph; and 2) attenuated endothelium-dependent relaxation of thoracic duct rings, suggesting disrupted lymphatic endothelial NO signaling in shunt lambs. To further elucidate the mechanisms responsible for this altered NO signaling, primary lymphatic endothelial cells (LECs) were isolated from the efferent lymphatic of the caudal mediastinal node in 4-wk-old control and shunt lambs. We found that shunt LECs (n = 3) had decreased bioavailable NO and decreased endothelial nitric oxide synthase (eNOS) mRNA and protein expression compared with control LECs (n = 3). eNOS activity was also low in shunt LECs, but, interestingly, inducible nitric oxide synthase (iNOS) expression and activity were increased in shunt LECs, as were total cellular nitration, including eNOS-specific nitration, and accumulation of reactive oxygen species (ROS). Pharmacological inhibition of iNOS reduced ROS in shunt LECs to levels measured in control LECs. These data support the conclusion that NOS signaling is disrupted in the lymphatic endothelium of lambs exposed to chronically increased pulmonary blood and lymph flow and may contribute to decreased pulmonary lymphatic bioavailable NO. PMID:27199125

  9. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Neuroendocrine Hyperplasia of Infancy.

    PubMed

    Carr, Laurie L; Kern, Jeffrey A; Deutsch, Gail H

    2016-09-01

    Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes. PMID:27514602

  10. Familial Occurrence of Pulmonary Embolism after Intravenous, Adipose Tissue-Derived Stem Cell Therapy

    PubMed Central

    Jung, Jae Woo; Kwon, Minsuk; Choi, Jae Chol; Shin, Jong Wook; Park, In Won; Choi, Byoung Whui

    2013-01-01

    The therapeutic potential of human multipotent mesenchymal stromal cells, especially human adipose tissue-derived stem cells (hASC), is promising. However, there are concerns about the safety of infusion of hASC in human. Recently, we have experienced pulmonary embolism and infarct among family members who have taken multiple infusions of intravenous autologous hASC therapy. A 41-year-old man presented with chest pain for one month. Chest CT showed multiple pulmonary artery embolism and infarct at right lung. Serum D-dimer was 0.8 µg/mL (normal; 0-0.5 µg/mL). He had received intravenous autologous adipose tissue-derived stem cell therapy for cervical herniated intervertebral disc three times (one, two, and three months prior to the visit). His parents also received the same therapy five times and their chest CT also showed multiple pulmonary embolism. These cases represent artificial pulmonary embolisms and infarct after IV injection of hASC. Follow-up chest CT showed spontaneous resolution of lesions in all three patients. PMID:23918585

  11. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    PubMed

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  12. Cell Permeable Peptide Conjugated Nanoerythrosomes of Fasudil Prolong Pulmonary Arterial Vasodilation in PAH Rats

    PubMed Central

    Gupta, Nilesh; Patel, Brijeshkumar; Nahar, Kamrun; Ahsan, Fakhrul

    2014-01-01

    In this study, we tested the hypothesis that a cell permeable peptide, CARSKNKDC (CAR), conjugated nanoerythrosomes (NERs) containing fasudil, a rho-kinase (ROCK) inhibitor, produces prolonged pulmonary preferential vasodilation. CAR conjugated NERs containing fasudil were prepared by hypotonic lysis and extrusion method, optimized for various physicochemical properties in-vitro. The formulations were then used to study the hemodynamic efficacy in a monocrotaline-induced rodent model of pulmonary arterial hypertension (PAH). CAR-NERs-Fasudil was spherical in shape with an average vesicle size and entrapment efficiency of 161.3±1.37nm and 48.81±1.96%, respectively. Formulations were stable for ~3 weeks when stored at 4°C and the drug was released in a controlled fashion for >48 hrs. The uptake of CAR-NERs-Fasudil by TGF-β activated pulmonary arterial smooth muscle cell was ~1.5 fold greater than the uptake of NERs-Fasudil. CAR-NERs-Fasudil inhibited ROCK activity and 5-hydroxytryptamine induced cell proliferation. In terms of reduction of pulmonary arterial pressure, intratracheal administration of CAR-NERs-Fasudil was ~2-fold more specific to the lungs compared with plain fasudil. Overall, CAR peptide grafted nanoerythrosomes offers a new platform for improving the therapeutic efficacy of a rho-kinase inhibitor, fasudil, without affecting peripheral vasodilation. PMID:25460151

  13. Genotoxic Evaluation of Mexican Welders Occupationally Exposed to Welding-Fumes Using the Micronucleus Test on Exfoliated Oral Mucosa Cells: A Cross-Sectional, Case-Control Study

    PubMed Central

    Jara-Ettinger, Ana Cecilia; López-Tavera, Juan Carlos; Zavala-Cerna, María Guadalupe; Torres-Bugarín, Olivia

    2015-01-01

    Background An estimated 800,000 people worldwide are occupationally exposed to welding-fumes. Previous studies show that the exposure to such fumes is associated with damage to genetic material and increased cancer risk. In this study, we evaluate the genotoxic effect of welding-fumes using the Micronucleus Test on oral mucosa cells of Mexican welders. Material and Methods We conducted a cross-sectional, matched case-control study of n = 66 (33 exposed welders, and 33 healthy controls). Buccal mucosa smears were collected and stained with acridine orange, observed under 100x optical amplification with a fluorescence lamp, and a single-blinded observer counted the number of micronuclei and other nuclear abnormalities per 2,000 observed cells. We compared the frequencies of micronuclei and other nuclear abnormalities, and fitted generalised linear models to investigate the interactions between nuclear abnormalities and the exposure to welding-fumes, while controlling for smoking and age. Results Binucleated cells and condensed-chromatin cells showed statistically significant differences between cases and controls. The frequency of micronuclei and the rest of nuclear abnormalities (lobed-nuclei, pyknosis, karyolysis, and karyorrhexis) did not differ significantly between the groups. After adjusting for smoking, the regression results showed that the occurrence of binucleated cells could be predicted by the exposure to welding-fumes plus the presence of tobacco consumption; for the condensed-chromatin cells, our model showed that the exposure to welding-fumes is the only reliable predictor. Conclusions Our findings suggest that Mexican welders who are occupationally exposed to welding-fumes have increased counts of binucleated and condensed-chromatin cells. Nevertheless, the frequencies of micronuclei and the rest of nuclear abnormalities did not differ between cases and controls. Further studies should shed more light on this subject. PMID:26244938

  14. Hypoxia promotes cell proliferation by modulating E2F1 in chicken pulmonary arterial smooth muscle cells

    PubMed Central

    2013-01-01

    In this study, we sought to investigate the expression of the transcription factor E2F1 in chicken pulmonary arterial smooth muscle cells upon hypoxia exposure, as well as the role that E2F1 played in the regulation of cell proliferation. Isolated chicken pulmonary arterial smooth muscle cells were subjected to hypoxia or normoxia for indicated time points. Cell viability, DNA synthesis, cell cycle profile, and expression of E2F1 were analyzed. The results showed that hypoxia promoted cell proliferation and DNA synthesis which was accompanied by an increased S phase entry and upregulation of E2F1 at mRNA and protein levels. Using siRNA technology, we demonstrated that gene inactivation of endogenous E2F1 abolished hypoxia-induced cell proliferation, DNA synthesis, and S phase entry compared with negative siRNA transfected cells. These results suggest that hypoxia-induced proliferation is mediated by inducing E2F1 in chicken pulmonary arterial smooth muscle cells. PMID:23902684

  15. Mesenchymal stem cell-conditioned media suppresses inflammation-associated overproliferation of pulmonary artery smooth muscle cells in a rat model of pulmonary hypertension

    PubMed Central

    LIU, JUNFENG; HAN, ZHIBO; HAN, ZHONGCHAO; HE, ZHIXU

    2016-01-01

    Inflammation-associated overproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered to be involved in the pathogenesis of pulmonary hypertension (PH). The administration of mesenchymal stem cell-conditioned media (MSC-CM) has displayed benefits in the treatment of PH, however, the exact mechanism has yet to be elucidated. The present study aimed to determine whether MSC-CM is able to suppress overproliferation of PASMCs in PH via immunoregulation. By the administration of MSC-CM to monocrotaline (MCT)-induced PH rats, and the development of an in vitro co-culture system comprised of PASMCs and activated T cells, the therapeutic effects of MSC-CM on PH, and the changes in the expression of correlated factors, including TNF-α, calcineurin (CaN) and nuclear factor of activated T cells (NFAT), were assessed. Immunohistochemical staining results indicated that MSC-CM was able to significantly suppress the production of TNF-α in MCT-induced PH and co-culture systems; and reverse transcription-quantitative polymerase chain reaction results showed significant downregulation of the expression of CaN and NFATc2 in PASMCs (P<0.01). Furthermore, MSC-CM was able to significantly suppress CaN activity and NFATc2 activation (P<0.01), thus inhibiting the overproliferation of PASMCs. Finally, MSC-CM improved abnormalities in hemodynamics and pulmonary histology in MCT-induced PH. In conclusion, the findings of the current study suggest that administration of MSC-CM has the potential to suppress inflammation-associated overproliferation of PASMCs due to its immunosuppressive effects in PH and, thus, may serve as a beneficial therapeutic strategy. PMID:26893632

  16. [Cytogenetic and other cariological parameters of exfoliative buccal cells in Vietnamese children from areas where dioxin-containing herbicides were applied].

    PubMed

    Sycheva, L P; Mozhaeva, T E; Umnova, N V; Zhuchenko, N A; Diep, Vu Hong; Tuyet, Hoang Anh

    2008-01-01

    In a cohort of 69 South Vietnam children, full cariological analysis of buccal epithelial cells was performed. In order to evaluate the significance of cariological changes, all the parameters under study were divided into three groups: cytogenetic indices, apoptotic indices, and indirect indices of proliferation; integral indexes in each group were determined and the relations between them were found while assessing the effects of environment pollution on public health. The number of cells with cytogenetic alterations (micronuclei and protrusions) was increased, the process of tissue proliferation was intensified, and the apoptotic process was decelerated in children li-ing in areas polluted with Agent Orange/dioxins, which evidenced that the complex of environmental factors these superecotoxicants were part of had a harmful effect on the population. The parameters studied did not depend on age and sex of the children; the number of congenital morphogenetic variants per one child significantly correlated with the sum of cells with cytogenetic alterations. PMID:18318151

  17. Proliferation of pulmonary artery smooth muscle cells in the development of ascites syndrome in broilers induced by low ambient temperature.

    PubMed

    Wang, J; Qiao, J; Zhao, L H; Li, K; Wang, H; Xu, T; Tian, Y; Gao, M; Wang, X

    2007-12-01

    Pulmonary vascular remodelling, mainly characterized by arterial medial thickening, is an important pathological feature of broiler ascites syndrome (AS). Since vascular smooth muscle cells (VSMC) form the major cellular component of arterial medial layer, we speculate that VSMC proliferation is one of the causes of pulmonary arterial medial thickening in ascitic broilers. Hence, the present study was designed to investigate the role of VSMC proliferation in pulmonary vascular remodelling in development of AS induced by low ambient temperature. Broilers in control group (22 +/- 1.5 degrees C) and low temperature group (11 +/- 2 degrees C) were sampled every week at 15-50 days of age. Proliferative indexes of VSMC in pulmonary arteries were assessed with proliferating cell nuclear antigen, and the relative medial thickness (RMT) and relative wall area (RWA), as indexes of pulmonary vascular remodelling, were examined by computer-image analysing system. The results showed that the high incidence (18.75%) of AS was induced by low temperature, and a significantly increased VSMC proliferation was observed in pulmonary arteries in the low temperature group at 22-50 days of age (P < 0.05). In addition, RMT and RWA in pulmonary arteries were significantly elevated in the low temperature group from 36 days of age (P < 0.05), indicating that pulmonary vascular remodelling occurred following VSMC proliferation in AS. Our data suggest that proliferation of VSMC may facilitate pulmonary vascular remodelling and have a pivotal role in AS induced by low ambient temperature. PMID:18045340

  18. Caveolae-Dependent and -Independent Uptake of Albumin in Cultured Rodent Pulmonary Endothelial Cells

    PubMed Central

    Li, Hui-Hua; Li, Jin; Wasserloos, Karla J.; Wallace, Callen; Sullivan, Mara G.; Bauer, Philip M.; Stolz, Donna B.; Lee, Janet S.; Watkins, Simon C.; St Croix, Claudette M.; Pitt, Bruce R.; Zhang, Li-Ming

    2013-01-01

    Although a critical role for caveolae-mediated albumin transcytosis in pulmonary endothelium is well established, considerably less is known about caveolae-independent pathways. In this current study, we confirmed that cultured rat pulmonary microvascular (RPMEC) and pulmonary artery (RPAEC) endothelium endocytosed Alexa488-labeled albumin in a saturable, temperature-sensitive mode and internalization resulted in co-localization by fluorescence microscopy with cholera B toxin and caveolin-1. Although siRNA to caveolin-1 (cav-1) in RPAEC significantly inhibited albumin uptake, a remnant portion of albumin uptake was cav-1-independent, suggesting alternative pathways for albumin uptake. Thus, we isolated and cultured mouse lung endothelial cells (MLEC) from wild type and cav-1-/- mice and noted that ~ 65% of albumin uptake, as determined by confocal imaging or live cell total internal reflectance fluorescence microscopy (TIRF), persisted in total absence of cav-1. Uptake of colloidal gold labeled albumin was evaluated by electron microscopy and demonstrated that albumin uptake in MLEC from cav-1-/- mice was through caveolae-independent pathway(s) including clathrin-coated pits that resulted in endosomal accumulation of albumin. Finally, we noted that albumin uptake in RPMEC was in part sensitive to pharmacological agents (amiloride [sodium transport inhibitor], Gö6976 [protein kinase C inhibitor], and cytochalasin D [inhibitor of actin polymerization]) consistent with a macropinocytosis-like process. The amiloride sensitivity accounting for macropinocytosis also exists in albumin uptake by both wild type and cav-1-/- MLEC. We conclude from these studies that in addition to the well described caveolar-dependent pulmonary endothelial cell endocytosis of albumin, a portion of overall uptake in pulmonary endothelial cells is cav-1 insensitive and appears to involve clathrin-mediated endocytosis and macropinocytosis-like process. PMID:24312378

  19. Selective biological response of human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells on cold-plasma-modified polyester vascular prostheses.

    PubMed

    Blanchemain, N; Aguilar, M R; Chai, F; Jimenez, M; Jean-Baptiste, E; El-Achari, A; Martel, B; Hildebrand, H F; Roman, J San

    2011-12-01

    The aim of this work was to improve the hemocompatibility and the selectivity according to cells of non-woven poly(ethylene terephthalate) (PET) membranes. Non-woven PET membranes were modified by a combined plasma-chemical process. The surface of these materials was pre-activated by cold-plasma treatment and poly(acrylic acid) (PAA) was grafted by the in situ free radical polymerization of acrylic acid (AA). The extent of this reaction and the number of carboxylic groups incorporated were evaluated by colorimetric titration using toluidine blue O. All samples were characterized by SEM, AFM and thermogravimetric analysis, and the mechanical properties of the PAA grafted sample were determined. A selective cell response was observed when human pulmonary artery smooth muscle cells (HPASMC) or human pulmonary micro vascular endothelial cells (HPMEC) were seeded on the modified surfaces. HPASMC proliferation decreased about 60%, while HPMEC proliferation was just reduced about 10%. PAA grafted samples did not present hemolytic activity and the platelet adhesion decreased about 28% on PAA grafted surfaces. PMID:22002636

  20. The trabecular meshwork in normal eyes and in exfoliation glaucoma.

    PubMed

    Rasmussen, Carol A; Kaufman, Paul L

    2014-01-01

    Trabecular meshwork (TM) and ciliary muscle contraction and relaxation function together to provide control of outflow. The active role the TM plays in the regulation of intraocular pressure (IOP) is mediated by cytoskeletal and contractility mechanisms as well as signal/transduction factors that mediate its response to stressors. This complex system is altered with age and the glaucomas, and it can be difficult to differentiate between the various etiological effects/agents. Factors such as a compromised antioxidant defense system and altered extracellular matrix metabolism are known to contribute to impaired outflow and may be common to primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma (XFG). Genes differentially expressed in diseased ocular tissue or in cultured HTM cell models, and thus implicated in the disease process, include SOD2, ALDH1A1, MGST1, LOX, and LOXL1, elements of the transforming growth factor-β/bone morphogenetic protein/SMAD signaling pathways, connective tissue growth factor, matrix metalloproteinase-2, a tissue inhibitor of metalloproteinases also known as TIMP-2, and endothelin-1 (ET-1). In exfoliation syndrome and XFG fibrillar, proteinaceous extracellular material is produced in excess and accumulates in both outflow pathways but does not always lead to elevated IOP. Locally produced material may accumulate in the intertrabecular spaces, juxtacanalicular (JCT) meshwork, and the inner wall of Schlemm's canal as a result of a combination of both excessive synthesis and insufficient degradation. An increase in JCT plaque and decreased cellularity in the TM are thought to contribute to decreased outflow facility in glaucoma patients, but XFG patient specimens show reduced extracellular plaque material in the JCT, and the structural integrity of trabecular endothelial cells is mostly retained and cellularity remains unchanged. The distinctions between causes/effects of structural changes leading to reduced outflow

  1. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production

    PubMed Central

    Chen, Gang; Korfhagen, Thomas R.; Xu, Yan; Kitzmiller, Joseph; Wert, Susan E.; Maeda, Yutaka; Gregorieff, Alexander; Clevers, Hans; Whitsett, Jeffrey A.

    2009-01-01

    Various acute and chronic inflammatory stimuli increase the number and activity of pulmonary mucus-producing goblet cells, and goblet cell hyperplasia and excess mucus production are central to the pathogenesis of chronic pulmonary diseases. However, little is known about the transcriptional programs that regulate goblet cell differentiation. Here, we show that SAM-pointed domain–containing Ets-like factor (SPDEF) controls a transcriptional program critical for pulmonary goblet cell differentiation in mice. Initial cell-lineage–tracing analysis identified nonciliated secretory epithelial cells, known as Clara cells, as the progenitors of goblet cells induced by pulmonary allergen exposure in vivo. Furthermore, in vivo expression of SPDEF in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation. This was associated with enhanced expression of genes regulating goblet cell differentiation and protein glycosylation, including forkhead box A3 (Foxa3), anterior gradient 2 (Agr2), and glucosaminyl (N-acetyl) transferase 3, mucin type (Gcnt3). Consistent with these findings, levels of SPDEF and FOXA3 were increased in mouse goblet cells after sensitization with pulmonary allergen, and the proteins were colocalized in goblet cells lining the airways of patients with chronic lung diseases. Deletion of the mouse Spdef gene resulted in the absence of goblet cells in tracheal/laryngeal submucosal glands and in the conducting airway epithelium after pulmonary allergen exposure in vivo. These data show that SPDEF plays a critical role in regulating a transcriptional network mediating the goblet cell differentiation and mucus hyperproduction associated with chronic pulmonary disorders. PMID:19759516

  2. Hydrogen Selective Exfoliated Zeolite Membranes

    SciTech Connect

    Tsapatsis, Michael; Daoutidis, Prodromos; Elyassi, Bahman; Lima, Fernando; Iyer, Aparna; Agrawal, Kumar; Sabnis, Sanket

    2015-04-06

    The objective of this project was to develop and evaluate an innovative membrane technology at process conditions that would be representative of Integrated Gasification Combined Cycle (IGCC) advanced power generation with pre-combustion capture of carbon dioxide (CO2). This research focused on hydrogen (H2)-selective zeolite membranes that could be utilized to separate conditioned syngas into H2-rich and CO2-rich components. Both experiments and process design and optimization calculations were performed to evaluate the concept of ultra-thin membranes made from zeolites nanosheets. In this work, efforts in the laboratory were made to tackle two fundamental challenges in application of zeolite membranes in harsh industrial environments, namely, membrane thickness and membrane stability. Conventional zeolite membranes have thicknesses in the micron range, limiting their performance. In this research, we developed a method for fabrication of ultimately thin zeolite membranes based on zeolite nanosheets. A range of layered zeolites (MWW, RWR, NSI structure types) suitable for hydrogen separation was successfully exfoliated to their constituent nanosheets. Further, membranes were made from one of these zeolites, MWW, to demonstrate the potential of this group of materials. Moreover, long-term steam stability of these zeolites (up to 6 months) was investigated in high concentrations of steam (35 mol% and 95 mole%), high pressure (10 barg), and high temperatures (350 °C and 600 °C) relevant to conditions of water-gas-shift and steam methane reforming reactions. It was found that certain nanosheets are stable, and that stability depends on the concentration of structural defects. Additionally, models that represent a water-gas-shift (WGS) membrane reactor equipped with the zeolite membrane were developed for systems studies. These studies had the aim of analyzing the effect of the membrane reactor integration into IGCC plants

  3. Adverse effects of industrial multiwalled carbon nanotubes on human pulmonary cells

    PubMed Central

    Tabet, Lyes; Bussy, Cyrill; Amara, Nadia; Setyan, Ari; Grodet, Alain; Rossi, Michel J.; Pairon, Jean-Claude; Boczkowski, Jorge; Lanone, Sophie

    2009-01-01

    The aim of this study was to evaluate adverse effects of multi-walled carbon nanotubes (MWCNT) produced for industrial purposes, on the human epithelial cell line A549. MWCNT were dispersed in dipalmitoyl lecithin (DPL), a component of pulmonary surfactant, and the effects of dispersion in DPL were compared to those in 2 other media: ethanol (EtOH) and phosphate buffer saline (PBS). Effects of MWCNT were also compared to those of 2 asbestos fibers (chrysotile and crocidolite) and carbon black (CB) nanoparticles, not only in A549 cells, but also on mesothelial cells (MeT5A human cell line), used as an asbestos-sensitive cell type. MWCNT formed agglomerates on top of both cell lines (surface area 15–35 μm2), that were significantly larger and more numerous in PBS than in EtOH and DPL. Whatever the dispersion media, incubation with 100 μg/ml MWCNT induced a similar decrease in metabolic activity without changing cell membrane permeability or apoptosis. Neither MWCNT cellular internalization nor oxidative stress were observed. In contrast, asbestos fibers penetrated into the cells, decreased metabolic activity but not cell membrane permeability and increased apoptosis, without decreasing cell number. CB was internalized without any adverse effects. In conclusion, this study demonstrates that MWCNT produced for industrial purposes exert adverse effects without being internalized by human epithelial and mesothelial pulmonary cell lines. PMID:19034795

  4. Tire containing thermally exfoliated graphite oxide

    NASA Technical Reports Server (NTRS)

    Prud'homme, Robert K. (Inventor); Aksay, Ilhan A. (Inventor)

    2011-01-01

    A tire, tire lining or inner tube, containing a polymer composite, made of at least one rubber and/or at least one elastomer and a modified graphite oxide material, which is a thermally exfoliated graphite oxide with a surface area of from about 300 sq m/g to 2600 sq m/g.

  5. Pulmonary Langerhans Cell Histiocytosis in an Adult Diagnosed with Solitary Inguinal Lymphadenopathy.

    PubMed

    Luo, Wei; Li, Ya-lun; Jia, Lian; Liu, Chun-tao

    2015-01-01

    We herein report an extremely rare case of pulmonary Langerhans cell histiocytosis with a solitary enlarged inguinal lymph node. A 19-year-old man presented with a non-productive cough lasting for over a five-month period and an enlarged left inguinal lymph node that had persisted for four months. A histopathological study of the lymph node specimens found Langerhans cells coupled with eosinophils. Positive immunohistochemical staining for langerin, Cluster of Differentiation 1a, S100 in the Langerhans cells confirmed the diagnosis, and a mildly impaired ventilation function in addition to multiple peripheral pulmonary cystic lesions were detected. The patient was managed with prednisone (0.5 mg/kg daily), with slow tapering over several months. PMID:26134198

  6. [Pulmonary Langerhans cell histiocytosis in a non-smoking Japanese woman].

    PubMed

    Tadokoro, Akira; Ishii, Tomoya; Bandoh, Shuji; Yokomise, Hiroyasu; Haba, Reiji; Ishida, Toshihiko

    2011-03-01

    A 44-year-old Japanese woman was admitted to our hospital because of dry cough and dyspnea on exertion. She had never smoked. She had been passively exposed to smoking by her husband and co-workers from the age of 21 (1984) to 33 (1996). She had previously developed pneumothorax twice, in 1985. On admission, computed tomography (CT) of the chest showed reticulonodular opacities predominant in bilateral upper lung fields, and pulmonary function tests revealed a decrease in vital capacity. The differential diagnoses were sarcoidosis, idiopathic pulmonary fibrosis and pulmonary Langerhans cell histiocytosis (PLCH). Video-assisted thoracic surgery was performed to make a definitive diagnosis. A histological specimen revealed the presence of CD1a-positive Langerhans cells in bronchiolocentric nodular lesions, leading to a diagnosis of PLCH. She was given 0.5 mg/kg bodyweight/ day oral prednisolone. Her symptoms disappeared with steroid maintenance therapy, and her vital capacity on pulmonary function testing was prevented from further deterioration. Based on the pathogenesis of PLCH, this case suggested that not only active smoking, but also passive smoking, played an important role in the development of PLCH. PMID:21485154

  7. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders.

    PubMed Central

    Inoue, Y.; King, T. E.; Tinkle, S. S.; Dockstader, K.; Newman, L. S.

    1996-01-01

    Mast cells (MCs) are abundant in fibrotic tissue, although their role in fibrogenesis remains obscure. Recent studies suggest MCs may produce basic fibroblast growth factor (bFGF). To evaluate the hypothesis that MC bFGF contributes to the fibrotic response in human interstitial lung disease, we studied lung tissue, bronchoalveolar lavage fluid and serum in 1) idiopathic pulmonary fibrosis, 2) chronic beryllium disease and sarcoidosis, 3) control subjects with no disease or who were beryllium sensitized with normal lung histology. Diseased subjects underwent clinical assessments to stage disease severity. We determined that most bFGF+ cells in lung interstitium are MCs and are most abundant in idiopathic pulmonary fibrosis. Distribution of bFGF+ MCs matched that of extracellular matrix deposition and correlated with the extent of fibrosis morphometrically. Only one bFGF isoform (17.8 kd) was found in idiopathic pulmonary fibrosis and chronic beryllium disease lung tissues and interacted with heparin-like molecules in the lung. Using a human MC line, we verified that MCs express bFGF mRNA and protein that localizes to cytoplasmic granules. Clinically, bFGF concentrations in bronchoalveolar lavage fluid and serum were highest in disease states and correlated with bronchoalveolar lavage cellularity and severity of gas exchange abnormalities, supporting a role for MC bFGF in the pulmonary fibrotic response and its clinical consequence. Images Figure 1 Figure 2 Figure 7 Figure 10 Figure 11 Figure 12 PMID:8952537

  8. Adoptive Immunotherapy of Established Pulmonary Metastases with LAK Cells and Recombinant Interleukin-2

    NASA Astrophysics Data System (ADS)

    Mule, James J.; Shu, Suyu; Schwarz, Susan L.; Rosenberg, Steven A.

    1984-09-01

    The activation of human peripheral blood leukocytes or murine splenocytes with interleukin-2 (IL-2) generated cells that were lytic in vitro for a variety of fresh tumor cells. The adoptive transfer of such lymphokine-activated killer (LAK) cells to mice with established pulmonary sarcoma metastases was highly effective in reducing the number (and size) of these tumor nodules when combined with repeated injections of recombinant IL-2. These findings provide a rationale for clinical trials of the infusion of human LAK cells generated with recombinant IL-2 as well as Phase I trials of the infusion of recombinant IL-2 systemically into humans.

  9. Mitigation of Late Renal and Pulmonary Injury After Hematopoietic Stem Cell Transplantation

    SciTech Connect

    Cohen, Eric P.; Bedi, Manpreet; Irving, Amy A.; Jacobs, Elizabeth; Tomic, Rade; Klein, John; Lawton, Colleen A.; Moulder, John E.

    2012-05-01

    Purpose: To update the results of a clinical trial that assessed whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure and pulmonary-related mortality in subjects undergoing total body irradiation (TBI) in preparation for hematopoietic stem cell transplantation (HSCT). Methods and Materials: Updated records of the 55 subjects who were enrolled in this randomized controlled trial were analyzed. Twenty-eight patients received captopril, and 27 patients received placebo. Definitions of TBI-HSCT-related chronic renal failure (and relapse) were the same as those in the 2007 analysis. Pulmonary-related mortality was based on clinical or autopsy findings of pulmonary failure or infection as the primary cause of death. Follow-up data for overall and pulmonary-related mortality were supplemented by use of the National Death Index. Results: The risk of TBI-HSCT-related chronic renal failure was lower in the captopril group (11% at 4 years) than in the placebo group (17% at 4 years), but this was not statistically significant (p > 0.2). Analysis of mortality was greatly extended by use of the National Death Index, and no patients were lost to follow-up for reasons other than death prior to 67 months. Patient survival was higher in the captopril group than in the placebo group, but this was not statistically significant (p > 0.2). The improvement in survival was influenced more by a decrease in pulmonary mortality (11% risk at 4 years in the captopril group vs. 26% in the placebo group, p = 0.15) than by a decrease in chronic renal failure. There was no adverse effect on relapse risk (p = 0.4). Conclusions: Captopril therapy produces no detectable adverse effects when given after TBI. Captopril therapy reduces overall and pulmonary-related mortality after radiation-based HSCT, and there is a trend toward mitigation of chronic renal failure.

  10. Pulmonary aspergilloma

    MedlinePlus

    ... Coccidioidomycosis Cystic fibrosis Histoplasmosis Lung abscess Lung cancer Sarcoidosis See also: Aspergillosis Symptoms You may not have ... fibrosis Histoplasmosis Lung cancer - small cell Pulmonary tuberculosis Sarcoidosis Update Date 8/31/2014 Updated by: Jatin ...

  11. Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis.

    PubMed Central

    Forrester, J M; Newman, L S; Wang, Y; King, T E; Kotzin, B L

    1993-01-01

    Sarcoidosis is a multisystem disease of unknown etiology characterized by the presence of noncaseating granulomas in involved tissues. To investigate a potential role for gamma/delta T cells in the pathogenesis of pulmonary sarcoidosis, we studied lung and blood T cells from patients for preferential expression of particular gamma/delta T cell receptors. An abnormally high percentage of gamma/delta cells was found in the blood of some patients. However, the increased percentage did not reflect an increase in absolute number, and appeared to be secondary to a decrease in T cells expressing alpha/beta receptors. Furthermore, as in normals, the circulating gamma/delta cells in patients predominantly expressed V gamma 9/V delta 2 receptors, a subset that was not enriched at the site of disease. In contrast, in the lung, an increased percentage of gamma/delta cells expressing V delta 1 was found in a subset of patients. Importantly, these cells demonstrated evidence of prior activation by selectively expanding in vitro in the presence of interleukin 2. Furthermore, an analysis of junctional region sequences revealed their clonal nature. These clonal expansions of V delta 1+ cells in pulmonary sarcoidosis provide evidence for a disease process that involves specific recognition of a local antigen by T cells, and contributes new information regarding the nature of the as yet undefined antigenic stimulus. PMID:8423227

  12. Primary pulmonary germ cell tumor with blastomatous differentiation.

    PubMed

    Miller, R R; Champagne, K; Murray, R C

    1994-11-01

    We describe the clinical and pathologic findings of a patient with mixed blastoma-germ cell malignancy primary in the lung. Serum alpha-fetoprotein levels were elevated at presentation, and normalized with anti-germ cell chemotherapy. The resection specimen contained massively necrotic germ cell tumor with viable mature neural tissue, plus viable biphasic blastoma with stromal bone and skeletal muscle differentiation. It is not clear whether the germ cell component represents unusual differentiation of a somatic cell line or whether the blastoma component represents an unusual pattern of teratomatous differentiation. PMID:7525163

  13. The regulatory role of interferon-γ producing gamma delta T cells via the suppression of T helper 17 cell activity in bleomycin-induced pulmonary fibrosis.

    PubMed

    Segawa, S; Goto, D; Iizuka, A; Kaneko, S; Yokosawa, M; Kondo, Y; Matsumoto, I; Sumida, T

    2016-09-01

    Interstitial pneumonia (IP) is a chronic progressive interstitial lung disease associated with poor prognosis and high mortality. However, the pathogenesis of IP remains to be elucidated. The aim of this study was to clarify the role of pulmonary γδT cells in IP. In wild-type (WT) mice exposed to bleomycin, pulmonary γδT cells were expanded and produced large amounts of interferon (IFN)-γ and interleukin (IL)-17A. Histological and biochemical analyses showed that bleomycin-induced IP was more severe in T cell receptor (TCR-δ-deficient (TCRδ(-/-) ) mice than WT mice. In TCRδ(-/-) mice, pulmonary IL-17A(+) CD4(+) Τ cells expanded at days 7 and 14 after bleomycin exposure. In TCRδ(-/-) mice infused with γδT cells from WT mice, the number of pulmonary IL-17A(+) CD4(+) T cells was lower than in TCRδ(-/-) mice. The examination of IL-17A(-/-) TCRδ(-/-) mice indicated that γδT cells suppressed pulmonary fibrosis through the suppression of IL-17A(+) CD4(+) T cells. The differentiation of T helper (Th)17 cells was determined in vitro, and CD4(+) cells isolated from TCRδ(-/-) mice showed normal differentiation of Th17 cells compared with WT mice. Th17 cell differentiation was suppressed in the presence of IFN-γ producing γδT cells in vitro. Pulmonary fibrosis was attenuated by IFN-γ-producing γδT cells through the suppression of pulmonary IL-17A(+) CD4(+) T cells. These results suggested that pulmonary γδT cells seem to play a regulatory role in the development of bleomycin-induced IP mouse model via the suppression of IL-17A production. PMID:27083148

  14. Sequestration of inhaled particulate antigens by lung phagocytes. A mechanism for the effective inhibition of pulmonary cell-mediated immunity.

    PubMed Central

    MacLean, J. A.; Xia, W.; Pinto, C. E.; Zhao, L.; Liu, H. W.; Kradin, R. L.

    1996-01-01

    Dendritic cells (DCs) have emerged as the dominant antigen-presenting cells (APCs) of the lung, playing a vital role in the induction of cell-mediated immunity to inhaled antigens. We have previously demonstrated that an airway challenge with the soluble antigen hen egg lysozyme yields rapid acquisition of specific antigen-presenting cell activity by purified pulmonary DCs and a cell-mediated immune response in the lung upon secondary challenge. To examine how a particulate antigen leads to a cell-mediated response in vivo, graded concentrations of heat-killed Listeria (HKL) were injected intratracheally into Lewis rats. The bacteria were rapidly ingested by lung macrophages and polymorphonuclear leukocytes. The ability of purified pulmonary DCs pulsed in vivo by an airway challenge with HKL to subsequently stimulate HKL-specific responses ex vivo showed a threshold response, requiring a dose in excess of 10(9) organisms/rat. By contrast, all dosages of HKL yielded specific sensitization of lymphocytes in the draining bilar nodes. Pulmonary DCs purified from rats after a secondary in vivo airway challenge with HKL at day 14 were ineffective antigen-presenting cells except at high dosages of antigen. The generation of cell-mediated pulmonary inflammation paralleled the antigen-presenting cell activity of pulmonary DCs and was observed only at high antigen dosages. Hen egg lysozyme immobilized onto polystyrene beads and injected intratracheally yielded comparable results to those observed with HKL. We suggest that a pulmonary cellular immune response is generated to an inhaled particulate antigen when the protective phagocytic capacities of the lung are exceeded and antigen is able to interact directly with interstitial DCs. The diversion of particulate antigens by pulmonary phagocytes may help to limit undesirable pulmonary inflammation while allowing the generation of antigen-specific immune lymphocytes in vivo. Images Figure 2 Figure 4 Figure 5 Figure 7 Figure 9

  15. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    PubMed Central

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  16. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia.

    PubMed

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C; Sellati, Timothy J; Harton, Jonathan A

    2016-03-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  17. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia

    PubMed Central

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C.; Sellati, Timothy J.; Harton, Jonathan A.

    2016-01-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  18. Epithelial Sodium Channels in Pulmonary Epithelial Progenitor and Stem Cells

    PubMed Central

    Liu, Yang; Jiang, Bi-Jie; Zhao, Run-Zhen; Ji, Hong-Long

    2016-01-01

    Regeneration of the epithelium of mammalian lungs is essential for restoring normal function following injury, and various cells and mechanisms contribute to this regeneration and repair. Club cells, bronchioalveolar stem cells (BASCs), and alveolar type II epithelial cells (ATII) are dominant stem/progenitor cells for maintaining epithelial turnover and repair. Epithelial Na+ channels (ENaC), a critical pathway for transapical salt and fluid transport, are expressed in lung epithelial progenitors, including club and ATII cells. Since ENaC activity and expression are development- and differentiation-dependent, apically located ENaC activity has therefore been used as a functional biomarker of lung injury repair. ENaC activity may be involved in the migration and differentiation of local and circulating stem/progenitor cells with diverse functions, eventually benefiting stem cells spreading to re-epithelialize injured lungs. This review summarizes the potential roles of ENaC expressed in native progenitor and stem cells in the development and regeneration of the respiratory epithelium. PMID:27570489

  19. Theophylline prevents NAD{sup +} depletion via PARP-1 inhibition in human pulmonary epithelial cells

    SciTech Connect

    Moonen, Harald J.J. . E-mail: h.moonen@grat.unimaas.nl; Geraets, Liesbeth; Vaarhorst, Anika; Bast, Aalt; Wouters, Emiel F.M.; Hageman, Geja J.

    2005-12-30

    Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD{sup +}, resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD{sup +} pool, and of NAD{sup +}-dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD{sup +} levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies.

  20. Intravascular large B-cell lymphoma complicated by invasive pulmonary aspergillosis: a rare presentation

    PubMed Central

    Mahasneh, Tamadur; Harrington, Zinta; Williamson, Jonathan; Alkhawaja, Darweesh; Duflou, Jo; Shin, Joo-Shik

    2014-01-01

    We describe a patient with persisting fevers, a progressive pulmonary infiltrate, and high levels of serum lactate dehydrogenase. No underlying cause for these changes was found prior to her death despite extensive investigations. Postmortem tissue revealed invasive pulmonary aspergillosis and subsequent brain examination revealed vascular changes in keeping with intravascular large B-cell lymphoma (IVLBCL). On review, subtle yet extensive lymphomatous infiltrates involved the vasculature of multiple other organs, including the lungs. Aspergillosis is a relatively rare presenting feature of lymphoproliferative disorders, and IVLBCL is a rare subtype of diffuse large B-cell non-Hodgkin's lymphoma with, to our knowledge, very few case reports to date. Lymphoma should be considered in patients presenting with pneumonitis with bilateral lung infiltrates on imaging, with a high serum level of lactate dehydrogenase. PMID:25473570

  1. Pulmonary Langerhans cell histiocytosis with cervical lymph node involvement, and coexistence with pulmonary tuberculosis and right pneumothorax: a case report and review of literature

    PubMed Central

    Gao, Limin; Li, Huifang; Li, Gandi; Liu, Weiping; Li, Jinnan; Zhang, Wenyan

    2015-01-01

    We report an uncommon 22-year-old male Pulmonary Langerhans Cell Histiocytosis (PLCH) case which co-existed with pulmonary tuberculosis (TB). Unlike the common PLCH cases, this PLCH case has cervical lymph node involvement and right pneumothorax. The diagnosis was established by the imaging of lung and the biopsies of the lung and left neck lymph node. Imaging of the chest showed characteristic small nodules and thin-walled cysts and right pneumothorax. The LCH cells in the lung and left neck lymph node were characterized by large convoluted nuclei with cerebriform indentations of the nuclear envelope and longitudinal grooves. The nuclei contained small eosinophilic nucleoli and moderate amount cytoplasm. Immunohistochemically, the histiocytoid cells were positive for Langerin, CD1a and S-100. Acid-fast bacilli were found in sputum and lung biopsy tissue. To the best of our knowledge, this is the first case of PLCH with cervical lymph node involvement, and coexisted with pulmonary tuberculosis, right pneumothorax. A contribution of this case and review three of the five cases of PLCH with extrapulmonary involvement to lymph nodes resolved spontaneously after smoking cessation constitute a novel addition that it is inappropriate to regard pulmonary/nodal LCH as multi-organ or disseminated disease, and the treatment methods are the same whether the PLCH patient with lymph node involvement or not. PMID:25973117

  2. Pulmonary Langerhans cell histiocytosis with cervical lymph node involvement, and coexistence with pulmonary tuberculosis and right pneumothorax: a case report and review of literature.

    PubMed

    Gao, Limin; Li, Huifang; Li, Gandi; Liu, Weiping; Li, Jinnan; Zhang, Wenyan

    2015-01-01

    We report an uncommon 22-year-old male Pulmonary Langerhans Cell Histiocytosis (PLCH) case which co-existed with pulmonary tuberculosis (TB). Unlike the common PLCH cases, this PLCH case has cervical lymph node involvement and right pneumothorax. The diagnosis was established by the imaging of lung and the biopsies of the lung and left neck lymph node. Imaging of the chest showed characteristic small nodules and thin-walled cysts and right pneumothorax. The LCH cells in the lung and left neck lymph node were characterized by large convoluted nuclei with cerebriform indentations of the nuclear envelope and longitudinal grooves. The nuclei contained small eosinophilic nucleoli and moderate amount cytoplasm. Immunohistochemically, the histiocytoid cells were positive for Langerin, CD1a and S-100. Acid-fast bacilli were found in sputum and lung biopsy tissue. To the best of our knowledge, this is the first case of PLCH with cervical lymph node involvement, and coexisted with pulmonary tuberculosis, right pneumothorax. A contribution of this case and review three of the five cases of PLCH with extrapulmonary involvement to lymph nodes resolved spontaneously after smoking cessation constitute a novel addition that it is inappropriate to regard pulmonary/nodal LCH as multi-organ or disseminated disease, and the treatment methods are the same whether the PLCH patient with lymph node involvement or not. PMID:25973117

  3. Inhibition of Excessive Cell Proliferation by Calcilytics in Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Yamamura, Aya; Ohara, Naoki; Tsukamoto, Kikuo

    2015-01-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease of unknown pathogenesis. Vascular remodeling due to excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a critical pathogenic event that leads to early morbidity and mortality. The excessive cell proliferation is closely linked to the augmented Ca2+ signaling in PASMCs. More recently, we have shown by an siRNA knockdown method that the Ca2+-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, involved in the enhanced Ca2+ response and subsequent excessive cell proliferation. In this study, we examined whether pharmacological blockade of CaSR attenuated the excessive proliferation of PASMCs from IPAH patients by MTT assay. The proliferation rate of PASMCs from IPAH patients was much higher (~1.5-fold) than that of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Treatment with NPS2143, an antagonist of CaSR or calcilytic, clearly suppressed the cell proliferation in a concentration-dependent manner (IC50 = 2.64 μM) in IPAH-PASMCs, but not in normal and CTEPH PASMCs. Another calcilytic, Calhex 231, which is structurally unrelated to NPS2143, also concentration-dependently inhibited the excessive proliferation of IPAH-PASMCs (IC50 = 1.89 μM). In contrast, R568, an activator of CaSR or calcimimetic, significantly facilitated the proliferation of IPAH-PASMCs (EC50 = 0.33 μM). Similar results were obtained by BrdU incorporation assay. These results reveal that the excessive PASMC proliferation was modulated by pharmacological tools of CaSR, showing us that calcilytics are useful for a novel therapeutic approach for pulmonary arterial hypertension. PMID:26375676

  4. Changes of Number and Function of Late Endothelial Progenitor Cells in Peripheral Blood of COPD Patients Combined with Pulmonary Hypertension.

    PubMed

    Liu, Pei; Zhang, Hongmei; Liu, Jianxin; Sheng, Chunfeng; Zhang, Linlin; Zeng, Yanjun

    2016-06-01

    Objective The objective of this study was to investigate the changes of number and function of late endothelial progenitor cells (EPCs) in peripheral blood of chronic obstructive pulmonary disease (COPD) patients combined with pulmonary hypertension. Subjects and Methods The study enrolled 120 cases including 40 non-COPD and pulmonary arterial hypertension (PAH) patients (non-COPD group), 40 COPD non-PAH patients (COPD group), and 40 COPD patients combined with PAH (COPD + PAH group). Peripheral blood mononuclear cells were separated by density gradient centrifugation, cultured for 21 days, and then identified as late endothelial progenitor cells. The cell colonies were counted. MTT assay, modified Boyden chamber assay, and human fibronectin plates were used to measure the proliferation, migration, and adhesion functions of the late endothelial progenitor cells, respectively. Results Compared with non-COPD and COPD groups, the number of peripheral blood late EPCs in COPD + PAH group was significantly reduced, and the proliferation, adhesion, and migration capacities were significantly lowered; the differences were statistically significant (p < 0.05). The number and function of late EPCs decreased with the increase of pulmonary artery pressure (p < 0.05). Conclusion The number of late EPCs in COPD patients combined with pulmonary hypertension was reduced, which implies the impaired cell functions. The changes of number and function were negatively correlated with the severity of pulmonary hypertension. PMID:25226359

  5. Hypoxia inhibits pulmonary artery endothelial cell apoptosis via the e-selectin/biliverdin reductase pathway.

    PubMed

    Song, Shasha; Yi, Zhi; Zhang, Min; Mao, Min; Fu, Li; Zhao, Xijuan; Liu, Zizhen; Gao, Jiayin; Cao, Weiwei; Liu, Yumei; Shi, Hengyuan; Zhu, Daling

    2016-07-01

    Hypoxia-induced inhibition of apoptosis in pulmonary artery endothelial cells (PAECs) has an important role in pulmonary arterial remodeling leading to aggravated hypoxic pulmonary arterial hypertension. However, the mechanisms involved in the hypoxia-induced inhibition of PAEC apoptosis have not been elucidated. e-selectin and biliverdin reductase (BVR) have been reported to contribute to the cascade of apoptosis in several cell lines but not in PAECs. In the present study, we show that the expression of e-selectin and BVR was both up-regulated by hypoxia in PAECs. Moreover, hypoxia attenuated the decreased cell survival and apoptotic protein expression, and increased DNA fragmentation induced by serum deprivation in the PAECs, which was mediated by the e-selectin/BVR pathway. In addition, by examining the mitochondrial membrane potential and mitochondrial membrane proteins (Bcl-2 and BAX), we show that the mitochondrial-dependent apoptosis pathway was necessary for the e-selectin/BVR pathway inducing the anti-apoptotic effect of hypoxia in PAECs. Taken all together, our data show that the e-selectin/BVR pathway participates in the inhibitory process of hypoxia in PAEC apoptosis which is mediated by the mitochondrial-dependent apoptosis pathway. PMID:27033411

  6. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation‑induced pulmonary fibrosis.

    PubMed

    Choi, Seo-Hyun; Kim, Miseon; Lee, Hae-June; Kim, Eun-Ho; Kim, Chun-Ho; Lee, Yoon-Jin

    2016-05-01

    Lung fibrosis is a major complication in radiation‑induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre‑treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, ‑2 or ‑4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1‑specific inhibitor suppressed radiation‑induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation‑induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  7. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis

    PubMed Central

    CHOI, SEO-HYUN; KIM, MISEON; LEE, HAE-JUNE; KIM, EUN-HO; KIM, CHUN-HO; LEE, YOON-JIN

    2016-01-01

    Lung fibrosis is a major complication in radiation-induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre-treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, -2 or -4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1-specific inhibitor suppressed radiation-induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation-induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  8. The Effect of a Retinoic Acid Derivative on Cell-Growth Inhibition in a Pulmonary Carcinoma Cell Line.

    PubMed

    Akita, Tomomi; Horiguchi, Michiko; Ozawa, Chihiro; Terada, Hiroshi; Yamashita, Chikamasa

    2016-01-01

    Pulmonary carcinoma is a major cause of cancer-related death worldwide. Because the prognosis remains poor, the development of novel therapeutic approaches is highly desirable. In this study, we investigated the effect of Tamibarotene (Am80), a retinoic acid derivative, on the growth of human lung adenocarcinoma cell line A549. Our ultimate goal in this study is to provide pulmonary carcinoma therapy with a new approach. First, we treated A549 cells with Am80 to clarify the effect of cell-growth inhibition. Am80 significantly reduced the viability of A549 cells in a dose- and time-dependent manner. The IC50 value, which was determined using CellTiter-Glo Luminescent Cell Viability assay, of Am80 and all-trans retinoic acid (ATRA) against A549 cells at 6 d was 49.1±8.1 µM and 92.3±8.0 µM, respectively. Furthermore, Am80 reduced the anchorage-independent cell-growth ability of A549 cells. However, it was not an apoptosis-mediated mechanism. These results suggest that Am80 can be used as an effective, novel cell-growth inhibitor in lung adenocarcinoma. PMID:26934924

  9. Pyrogallol induces the death of human pulmonary fibroblast cells through ROS increase and GSH depletion.

    PubMed

    Park, Woo Hyun

    2016-08-01

    Pyrogallol (PG) inhibits the growth of various cells via stimulating O2•--mediated death. This study investigated the effects of PG on cell death in human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. PG inhibited the growth of HPF cells with an IC50 of ~50-100 µM at 24 h. PG induced a G1 phase arrest of the cell cycle and also triggered cell death accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm), Bcl-2 decrease, p53 increase and the activation of caspase-3. PG increased O2•- level in HPF cells and depleted GSH content in these cells. Z-VAD (a pan-caspase inhibitor) did not significantly change cell growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells. N-acetylcysteine (NAC) attenuated growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells and it decreased O2•- level in these cells as well. However, L-buthionine sulfoximine (BSO) strongly increased ROS level in PG-treated HPF cells and it intensified growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion in these cells. In conclusion, PG-induced HPF cell death was closely related to increases in ROS level and GSH depletion. PMID:27278810

  10. Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus

    PubMed Central

    Behar, Samuel M.; Carpenter, Stephen M.; Booty, Matthew G.; Barber, Daniel L.; Jayaraman, Pushpa

    2014-01-01

    Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID:25311810

  11. Pulmonary Platelet Thrombi and Vascular Pathology in Acute Chest Syndrome in Patients with Sickle Cell Disease

    PubMed Central

    Anea, Ciprian B.; Lyon, Matthew; Lee, Itia; Gonzales, Joyce N.; Adeyemi, Amidat; Falls, Greer; Kutlar, Abdullah; Brittain, Julia E.

    2015-01-01

    A growing body of evidence suggests a role for platelets in sickle cell disease (SCD). Despite the pro-inflammatory, occlusive nature of platelets, a role for platelets in acute chest syndrome (ACS), however, remains understudied. To provide evidence and potentially describe contributory factors for a putative link between ACS and platelets, we performed an autopsy study of 20 SCD cases – 10 of whom died from ACS and 10 whose deaths were not ACS-related. Pulmonary histopathology and case history were collected. We discovered that disseminated pulmonary platelet thrombi were present in 3 out of 10 of cases with ACS, but none of the matched cases without ACS. Those cases with detected thrombi were associated with significant deposition of endothelial vWF and detection of large vWF aggregates adhered to endothelium. Potential clinical risk factors were younger age and higher platelet count at presentation. However, we also noted a sharp and significant decline in platelet count prior to death in each case with platelet thrombi in the lungs. In this study, neither hydroxyurea use nor perimortem transfusion was associated with platelet thrombi. Surprisingly, in all cases, there was profound pulmonary artery remodeling with both thrombotic and proliferative pulmonary plexiform lesions. The severity of remodeling was not associated with a severe history of ACS, or hydroxyurea use, but was inversely correlated with age. We thus provide evidence of undocumented presence of platelet thrombi in cases of fatal ACS describe clinical correlates. We also provide novel correlates of pulmonary remodeling in SCD. PMID:26492581

  12. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2011-01-01

    Background Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored. Methods Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies. Results There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling. Conclusions The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the

  13. Variations of chromosomes 2 and 3 gene expression profiles among pulmonary telocytes, pneumocytes, airway cells, mesenchymal stem cells and lymphocytes

    PubMed Central

    Zheng, Minghuan; Sun, Xiaoru; Zhang, Miaomiao; Qian, Mengjia; Zheng, Yonghua; Li, Meiyi; Cretoiu, Sanda M; Chen, Chengshui; Chen, Luonan; Cretoiu, Dragos; Popescu, Laurentiu M; Fang, Hao; Wang, Xiangdong

    2014-01-01

    Telocytes (TCs) were identified as a distinct cellular type of the interstitial tissue and defined as cells with extremely long telopodes (Tps). Our previous data demonstrated patterns of mouse TC-specific gene profiles on chromosome 1. The present study focuses on the identification of characters and patterns of TC-specific or TC-dominated gene expression profiles in chromosome 2 and 3, the network of principle genes and potential functional association. We compared gene expression profiles of pulmonary TCs, mesenchymal stem cells, fibroblasts, alveolar type II cells, airway basal cells, proximal airway cells, CD8+T cells from bronchial lymph nodes (T-BL), and CD8+ T cells from lungs (T-LL). We identified that 26 or 80 genes of TCs in chromosome 2 and 13 or 59 genes of TCs up-or down-regulated in chromosome 3, as compared with other cells respectively. Obvious overexpression of Myl9 in chromosome 2 of TCs different from other cells, indicates that biological functions of TCs are mainly associated with tissue/organ injury and ageing, while down-expression of Pltp implies that TCs may be associated with inhibition or reduction of inflammation in the lung. Dominant overexpression of Sh3glb1, Tm4sf1 or Csf1 in chromosome 3 of TCs is mainly associated with tumour promotion in lung cancer, while most down-expression of Pde5 may be involved in the development of pulmonary fibrosis and other acute and chronic interstitial lung disease. PMID:25278030

  14. Anisotropic Thermal Conductivity of Exfoliated Black Phosphorus.

    PubMed

    Jang, Hyejin; Wood, Joshua D; Ryder, Christopher R; Hersam, Mark C; Cahill, David G

    2015-12-22

    The anisotropic thermal conductivity of passivated black phosphorus (BP), a reactive two-dimensional material with strong in-plane anisotropy, is ascertained. The room-temperature thermal conductivity for three crystalline axes of exfoliated BP is measured by time-domain thermo-reflectance. The thermal conductivity along the zigzag direction is ≈2.5 times higher than that of the armchair direction. PMID:26516073

  15. Response of hemopoietic, progenitor, and multipotent mesenchymal stromal cells to administration of ketanserin during pulmonary fibrosis.

    PubMed

    Dygai, A M; Skurikhin, E G; Pershina, O V; Stepanova, I E; Khmelevskaya, E S; Ermakova, N N; Reztsova, A M; Krupin, V A; Reikhart, D V; Goldberg, V E

    2014-11-01

    We studied the effect of ketanserin on hemopoietic progenitor cells (Lin(-)Sca-1(+)c-Kit(+)CD34- and Lin(-)Sca-1(+)c-Kit(+)CD34(+)), progenitor hemopoietic cells (Lin(-)Sca-1(+)c-kit(+)), and multipotent mesenchymal stromal cells (CD45(-)CD73(+)CD106(+)) in C57Bl/6 mice during pulmonary fibrosis. It was shown that the blocker of 5-HT2A receptors lowers the activity of bleomycin-induced inflammation in the lungs and prevents the infiltration of alveolar interstitium and alveolar ducts by hemopoietic stem and hemopoietic progenitor cells; in this case, they are more numerous in the bone marrow of sick animals. Ketanserin reduces the capacity for self-renewal of lung multipotent mesenchymal stromal cells in the fibrotic phase of the disease and inhibits their differentiation into stromal cell lines (adipocytes, chondrocytes, and fibroblasts) simultaneously with the decrease in the percentage of connective tissue in the lung parenchyma. PMID:25403389

  16. Photostability of thin exfoliated black phosphorus

    NASA Astrophysics Data System (ADS)

    Favron, Alexandre; Francoeur, Sébastien; Leonelli, Richard; Martel, Richard

    2014-03-01

    In its bulk form, black phosphorus has a direct gap of about 0.3 eV. Because of its lamellar structure, similar to that of graphite, black phosphorus can be exfoliated down to a single monolayer. The interesting properties is the possible tuning of the energy gap in the Near-IR using control of the layer thickness, which is of great interesting to develop sensors and other Near-IR optoelectronic devices. Preliminary studies on thin exfoliated layers revealed a fast photo-induced oxidation of black phosphorus, in room condition with an excitation higher than 1.8 eV. Using Raman spectroscopy as a probe of the quality and integrity of exfoliated layers, we present in this talk the results of a dynamical study of the photo-oxidation process at room temperature in a controlled atmosphere with the presence of the oxygen-water redox couple. A photo-induced charge transfer from black phosphorus to the redox couple is found to be responsible of the fast deterioration of the structure. Finally, we present Raman and Photoluminescence results on un-oxidized thin-layers measured at low temperature using different passivation schemes.

  17. Interleukin 17-Producing γδ T Cells Increased in Patients with Active Pulmonary Tuberculosis

    PubMed Central

    Peng, Meiyu; Wang, Zhaohua; Yao, Chunyan; Jiang, Lina; Jin, Qili; Wang, Jing; Li, Baiqing

    2008-01-01

    Although it has been known that γδ T cells may play an important role in the immune response to infection of Mycobacterium tuberculosis (M. tb), the mechanisms by which the γδ T cells participate in the innate and/or acquired immunity to tuberculosis (TB) have not been full elucidated. In the present study, 27 patients with active pulmonary TB and 16 healthy donors (HD) were performed. We found that proportion of IL-17-producing cells among lymphocyte was similar between TB patients and HD, whereas the proportions of γδ T cells in IL-17-producing cells (59.2%) and IL-17-producing cells in γδ T cells (19.4%) in peripheral blood were markedly increased in TB patients when compared to those in HD (43.9% and 7.7%, respectively). In addition, the proportions of IFN-γ-producing γδ T cells in TB patients were obviously lower than that in HD. Upon re-stimulated with M. tb heat-treated antigen (M. tb-HAg) in vitro, fewer IL-17-producing γδ T cells were generated from HD and TB patients, whereas IFN-γ-producing γδ T cells were increased in TB patients compared to that in HD. Our findings in TB patients and healthy human were consistent with other murine investigation that the IL-17-producing γδ T cells were main source of IL-17 in mouse model of BCG infection, suggesting that γδ T cells might be involved in the formation of tubercular granuloma in pulmonary TB patients, but need further identification. PMID:18582402

  18. Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

    PubMed Central

    Walters, Mark C.; Hardy, Karen; Edwards, Sandie; Adamkiewicz, Thomas; Barkovich, James; Bernaudin, Francoise; Buchanan, George R.; Bunin, Nancy; Dickerhoff, Roswitha; Giller, Roger; Haut, Paul R.; Horan, John; Hsu, Lewis L.; Kamani, Naynesh; Levine, John E.; Margolis, David; Ohene-Frempong, Kwaku; Patience, Melinda; Redding-Lallinger, Rupa; Roberts, Irene A. G.; Rogers, Zora R.; Sanders, Jean E.; Scott, J. Paul; Sullivan, Keith M.

    2010-01-01

    We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease. PMID:19822218

  19. On the exfoliating polymeric cellular dosage forms for immediate drug release.

    PubMed

    Blaesi, Aron H; Saka, Nannaji

    2016-06-01

    The most prevalent pharmaceutical dosage forms at present-the oral immediate-release tablets and capsules-are granular solids. Though effective in releasing drug rapidly, development and manufacture of such dosage forms are fraught with difficulties inherent to particulate processing. Predictable dosage form manufacture could be achieved by liquid-based processing, but cast solid dosage forms are not suitable for immediate drug release due to their resistance to fluid percolation. To overcome this limitation, we have recently introduced cellular dosage forms that can be readily prepared from polymeric melts. It has been shown that open-cell structures comprising polyethylene glycol 8000 (PEG 8k) excipient and a drug exfoliate upon immersion in a dissolution medium. The drug is then released rapidly due to the large specific surface area of the exfoliations. In this work, we vary the molecular weight of the PEG excipient and investigate its effect on the drug release kinetics of structures with predominantly open-cell topology. We demonstrate that the exfoliation rate decreases substantially if the excipient molecular weight is increased from 12 to 100kg/mol, which causes the drug dissolution time to increase by more than a factor of ten. A model is then developed to elucidate the exfoliation behavior of cellular structures. Diverse transport processes are considered: percolation due to capillarity, diffusion of dissolution medium through the cell walls, and viscous flow of the saturated excipient. It is found that the lower exfoliation rate and the longer dissolution time of the dosage forms with higher excipient molecular weight are primarily due to the greater viscosity of the cell walls after fluid penetration. PMID:27045468

  20. Pulmonary langerhans cell histiocytosis: PET/CT for initial workup and treatment response evaluation.

    PubMed

    Hansen, Neil J; Hankins, Jordan H

    2015-02-01

    A 40-year-old man underwent pan-endoscopy owing to abdominal pain. Biopsies of the gastrointestinal tract demonstrated diffuse Langerhans cell histiocytosis. PET/CT was done, with CT demonstrating classic pulmonary manifestations of Langerhans cell histiocytosis that had association with intense FDG uptake on PET. Bowel appeared normal. Treatment was initiated with smoking cessation and 6 cycles of cytarabine. Follow-up PET/CT after initial treatment demonstrated improvement of parenchymal abnormalities seen on CT, with resolution of hypermetabolic activity. Maintenance chemotherapy was initiated. PET/CT is increasingly being used for initial staging and treatment response assessment in this rare disorder. PMID:24999688

  1. The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice

    SciTech Connect

    Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang; Han, Zhaozhong

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

  2. Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.

    PubMed

    Branchfield, Kelsey; Nantie, Leah; Verheyden, Jamie M; Sui, Pengfei; Wienhold, Mark D; Sun, Xin

    2016-02-12

    The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression. PMID:26743624

  3. Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells.

    PubMed

    Csiszar, Anna; Labinskyy, Nazar; Jo, Hanjoong; Ballabh, Praveen; Ungvari, Zoltan

    2008-08-01

    There is increasing evidence that TGF-beta family member cytokine bone morphogenetic protein (BMP)-4 plays different pathophysiological roles in the pulmonary and systemic circulation. Upregulation of BMP-4 has been linked to atherosclerosis and hypertension in the systemic circulation, whereas disruption of BMP-4 signaling is associated with the development of pulmonary hypertension. To test the hypothesis that BMP-4 elicits differential effects in the pulmonary and systemic circulation, we compared the prooxidant and proinflammatory effects of BMP-4 in cultured human coronary arterial endothelial cells (CAECs) and pulmonary arterial endothelial cells (PAECs). We found that BMP-4 (from 0.3 to 10 ng/ml) in CAECs increased O(2)(*-) and H(2)O(2) generation, induced NF-kappaB activation, upregulated ICAM-1, and induced monocyte adhesiveness to ECs. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O(2)(*-) production in cultured rat carotid arteries, whereas cultured rat pulmonary arteries were protected from these adverse effects of BMP-4. Thus, we propose that BMP-4 exerts prooxidant, prohypertensive, and proinflammatory effects only in the systemic circulation, whereas pulmonary arteries are protected from these adverse effects of BMP-4. The vascular bed-specific endothelial effects of BMP-4 are likely to contribute to its differential pathophysiological role in the systemic and pulmonary circulation. PMID:18539760

  4. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  5. Development of confocal immunofluorescence FRET microscopy to Investigate eNOS and GSNOR localization and interaction in pulmonary endothelial cells

    NASA Astrophysics Data System (ADS)

    Rehman, Shagufta; Brown-Steinke, Kathleen; Palmer, Lisa; Periasamy, Ammasi

    2015-03-01

    Confocal FRET microscopy is a widely used technique for studying protein-protein interactions in live or fixed cells. Endothelial nitric oxide synthase (eNOS) and S-nitrosoglutathione reductase (GSNOR) are enzymes involved in regulating the bioavailability of S-nitrosothiols (SNOs) in the pulmonary endothelium and have roles in the development of pulmonary arterial hypertension. Labeling of endogenous proteins to better understand a disease process can be challenging. We have used immunofluorescence to detect endogenous eNOS and GSNOR in primary pulmonary endothelial cells to co-localize these proteins as well as to study their interaction by FRET. The challenge has been in selecting the right immunofluorescence labeling condition, right antibody, the right blocking reagent, the right FRET pair and eliminating cross-reactivity of secondary antibodies. We have used Alexa488 and Alexa568 as a FRET pair. After a series of optimizations, the data from Confocal Laser Scanning Microscopy (CLSM) demonstrate co-localization of eNOS and GSNOR in the perinuclear region of the pulmonary endothelial cell primarily within the cis-Golgi with lower levels of co-localization seen within the trans-Golgi. FRET studies demonstrate, for the first time, interaction between eNOS and GSNOR in both murine and bovine pulmonary endothelial cells. Further characterization of eNOSGSNOR interaction and the subcellular location of this interaction will provide mechanistic insight into the importance of S-nitrosothiol signaling in pulmonary biology, physiology and pathology.

  6. The gasotransmitter hydrogen sulphide decreases Na⁺ transport across pulmonary epithelial cells.

    PubMed

    Althaus, M; Urness, K D; Clauss, W G; Baines, D L; Fronius, M

    2012-07-01

    BACKGROUND AND PURPOSE The transepithelial absorption of Na(+) in the lungs is crucial for the maintenance of the volume and composition of epithelial lining fluid. The regulation of Na(+) transport is essential, because hypo- or hyperabsorption of Na(+) is associated with lung diseases such as pulmonary oedema or cystic fibrosis. This study investigated the effects of the gaseous signalling molecule hydrogen sulphide (H(2) S) on Na(+) absorption across pulmonary epithelial cells. EXPERIMENTAL APPROACH Ion transport processes were electrophysiologically assessed in Ussing chambers on H441 cells grown on permeable supports at air/liquid interface and on native tracheal preparations of pigs and mice. The effects of H(2)S were further investigated on Na(+) channels expressed in Xenopus oocytes and Na(+) /K(+)-ATPase activity in vitro. Membrane abundance of Na(+) /K(+)-ATPase was determined by surface biotinylation and Western blot. Cellular ATP concentrations were measured colorimetrically, and cytosolic Ca(2+) concentrations were measured with Fura-2. KEY RESULTS H(2)S rapidly and reversibly inhibited Na(+) transport in all the models employed. H(2)S had no effect on Na(+) channels, whereas it decreased Na(+) /K(+)-ATPase currents. H(2)S did not affect the membrane abundance of Na(+) /K(+)-ATPase, its metabolic or calcium-dependent regulation, or its direct activity. However, H(2)S inhibited basolateral calcium-dependent K(+) channels, which consequently decreased Na(+) absorption by H441 monolayers. CONCLUSIONS AND IMPLICATIONS H(2) S impairs pulmonary transepithelial Na(+) absorption, mainly by inhibiting basolateral Ca(2+)-dependent K(+) channels. These data suggest that the H(2)S signalling system might represent a novel pharmacological target for modifying pulmonary transepithelial Na(+) transport. PMID:22352810

  7. Pulmonary Langerhans cell histiocytosis: analysis of 14 patients and literature review

    PubMed Central

    Li, Cheng-Wei; Li, Man-Hui; Li, Jiang-Xiong; Tao, Ru-Jia; Xu, Jin-Fu

    2016-01-01

    Background Pulmonary Langerhans cell histiocytosis (PLCH) is an orphan disease in respiratory medicine, which most affects adult smokers. The purpose of this article was to discuss the clinical features, especially the radiologic features of PLCH patients during their hospitalization through a retrospective analysis on clinical data. Furthermore, the current literature was also reviewed. Methods Between December 2008 and June 2012, 14 patients with PLCH were assessed at Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Among these patients, seven patients were diagnosed through tissue biopsy from the lung and one patient from enlarged cervical lymph nodes; the rest of six patients were diagnosed based on the clinical-radiological data. The data consisting of demographics, clinical presentation, smoking habits, pulmonary function tests (PFTs) and radiographic image from the medical records was analyzed retrospectively. Results The average age of patients (11 males and 3 females) was 42.79 (±13.71) years old. All male patients and one female patient had a long smoking history. The common manifestations were cough and exertional dyspnea. Spontaneous pneumothorax was found in three patients. Varieties of pulmonary shadows such as nodular, cystic, patch-like and cord-like were revealed by chest computed tomography (CT) examination. Large Langerhans cells (LCs) were discovered in biopsy tissue by immunohistochemical stains. Conclusions PLCH is still an orphan disease and maybe related to smoking. Clinical symptoms such as cough and exertional dyspnea are non-specific. We shall pay attention to recurrent pneumothorax as clinically it is associated with PLCH. The characteristic radiological manifestation is cystic or nodular shadow in the lungs, which plays crucial roles in diagnosing PLCH. PMID:27293848

  8. Role of IL-7 in the shaping of the pulmonary gamma delta T cell repertoire.

    PubMed

    Hayes, S M; Sirr, A; Jacob, S; Sim, G K; Augustin, A

    1996-04-15

    Gamma delta T cells bearing the canonical fetal-type V gamma 6/V delta 1 rearrangements are the predominant gamma delta T cells in the lungs of adult mice. In contrast, these V gamma 6/V delta 1 T cells are virtually absent in the pulmonary epithelia of nude mice. The intraepithelial dominance of gamma delta T cells that express this particular TCR is thought to result from a preferred thymic pathway of gene rearrangement and not from TCR-mediated positive selection. We now show that gamma delta T cell precursors in the lung epithelium of both euthymic and athymic neonatal mice generate this rearrangement in situ. In athymic mice, these clonotypes do not survive, but can be rescued in vitro and in vivo by the lymphokine IL-7. PMID:8609389

  9. Bilateral Bronchiectasis as a Presentation Form of Pulmonary Marginal Zone B-Cell Lymphoma of Bronchus Associated Lymphoid Tissue

    PubMed Central

    Ernst, Glenda; Torres, Carla; Borsini, Eduardo; Vigovich, Félix; Downey, Daniel; Salvado, Alajandro; Bosio, Martín

    2015-01-01

    The pulmonary marginal zone B-cell lymphoma of bronchus associated lymphoid tissue of the lung (BALT) is a rare illness that can remain without symptoms. Radiological findings of pulmonary lymphoma are heterogeneous. In literature, bronchiectasis is only described in one patient who also had besides adenomegalies. We reported on a 48-year-old female patient. She showed symptoms consistent with dyspnea with productive cough; there were crepitant sounds in the auscultation. Pulmonary functional test has shown a severe restrictive pattern with a low FVC and DLCO. CT scan showed bronchiectasis in the medium lobule without adenomegalies. Echocardiogram was normal, and the laboratory findings only showed leukocytosis. There were no findings in the bronchoscopy, but the lung biopsy showed a B-cell pulmonary lymphoma (positive to CD20 and CD79a in immunostaining). A wide variety of radiological manifestations has been previously described; however, we have presented this rare case, with bronchiectasis, as unique radiological finding. PMID:26839723

  10. Gold-Mediated Exfoliation of Ultralarge Optoelectronically-Perfect Monolayers.

    PubMed

    Desai, Sujay B; Madhvapathy, Surabhi R; Amani, Matin; Kiriya, Daisuke; Hettick, Mark; Tosun, Mahmut; Zhou, Yuzhi; Dubey, Madan; Ager, Joel W; Chrzan, Daryl; Javey, Ali

    2016-06-01

    Gold-mediated exfoliation of ultralarge optoelectronically perfect monolayers with lateral dimensions up to ≈500 μm is reported. Electrical, optical, and X-ray photo-electron spectroscopy characterization show that the quality of the gold-exfoliated flakes is similar to that of tape-exfoliated flakes. Large-area flakes allow manufacturing of large-area mono-layer transition metal dichalcogenide electronics. PMID:27007751

  11. Modulating the dysregulated migration of pulmonary arterial hypertensive smooth muscle cells with motif mimicking cell permeable peptides

    PubMed Central

    Wilson, Jamie L.; Rupasinghe, Chamila; Usheva, Anny; Warburton, Rod; Kaplan, Chloe; Taylor, Linda; Hill, Nicholas; Mierke, Dale F.; Polgar, Peter

    2016-01-01

    Migration of vascular smooth muscle cells is a key element in remodeling during pulmonary arterial hypertension (PAH). We are observing key alterations in the migratory characteristics of human pulmonary artery smooth muscle cells (HPASMC) isolated from transplanted lungs of subjects with PAH. Using wound migration and barrier removal assays, we demonstrate that the PAH cells migrate under quiescent growth conditions and in the absence of pro-migratory factors such as platelet derived growth factor (PDGF). Under the same conditions, in the absence of PDGF, non-PAH HPASMC show negligible migration. The dysregulated migration initiates, in part, through phosphorylation events signaled through the unstimulated PDGF receptor via focal adhesion kinase (FAK) whose total basal expression and phosphorylation at tyrosine 391 is markedly increased in the PAH cells and is inhibited by a motif mimicking cell-permeable peptide (MMCPP) targeting the Tyr751 region of the PDGF receptor and by imatinib. However, exposure of the PAH cells to PDGF further promotes migration. Inhibition of p21 activated kinases (PAK), LIM kinases (LIMK), c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK) reduces both the dysregulated and the PDGF-stimulated migration. Immunofluorescence microscopy confirms these observations showing activated JNK and p38 MAPK at the edge of the wound but not in the rest of the culture in the PAH cells. The upstream inhibitors FAK (PF-573228) and imatinib block this activation of JNK and p38 at the edge of the site of injury and correspondingly inhibit migration. MMCPP which inhibit the activation of downstream effectors of migration, cofilin and caldesmon, also limit the dysregulated migration. These results highlight key pathways which point to potential targets for future therapies of pulmonary hypertension with MMCPP.

  12. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension.

    PubMed

    Veith, Christine; Schermuly, Ralph T; Brandes, Ralf P; Weissmann, Norbert

    2016-03-01

    Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID:26228924

  13. Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis

    PubMed Central

    Bazan, Silvia B.; Costa, Tania A.; de Araújo, Eliseu Frank; Feriotti, Claudia; Loures, Flávio V.; Pretel, Fernando D.; Calich, Vera L. G.

    2015-01-01

    Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3GFP knock-in mice and immunodeficient Rag1-/- mice, respectively, which were intratracheally infected with 106 yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3GFP transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1-/- mice subsequently infected by the pulmonary route demonstrated that isolated CD4+Foxp3+ Treg cells were able to confer some degree of immunoprotection and that CD4+Foxp3- T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation. PMID:26512987

  14. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis.

    PubMed

    Marmai, Cecilia; Sutherland, Rachel E; Kim, Kevin K; Dolganov, Gregory M; Fang, Xiaohui; Kim, Sophia S; Jiang, Shuwei; Golden, Jeffery A; Hoopes, Charles W; Matthay, Michael A; Chapman, Harold A; Wolters, Paul J

    2011-07-01

    Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process. PMID:21498628

  15. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis

    PubMed Central

    Marmai, Cecilia; Sutherland, Rachel E.; Kim, Kevin K.; Dolganov, Gregory M.; Fang, Xiaohui; Kim, Sophia S.; Jiang, Shuwei; Golden, Jeffery A.; Hoopes, Charles W.; Matthay, Michael A.; Chapman, Harold A.

    2011-01-01

    Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process. PMID:21498628

  16. Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4.

    PubMed

    Lukic, Ana; Ji, Jie; Idborg, Helena; Samuelsson, Bengt; Palmberg, Lena; Gabrielsson, Susanne; Rådmark, Olof

    2016-09-01

    Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4 In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product. LTC4 released from the myeloid cells was further transformed by the epithelial cells in a transcellular manner. Formation of LTD4 was rapid when catalyzed by γ-glutamyl transpeptidase (GGT)1 in the A549 epithelial lung cancer cell line, but considerably slower when catalyzed by GGT5 in primary bronchial epithelial cells. When A549 cells were cultured in the presence of IL-1β, GGT1 expression increased about 2-fold. Also exosomes from A549 cells contained GGT1 and augmented LTD4 formation. Serine-borate complex (SBC), an inhibitor of GGT, inhibited conversion of LTC4 to LTD4 Unexpectedly, SBC also upregulated translocation of 5-lipoxygenase (LO) to the nucleus in Mono Mac 6 cells, and 5-LO activity. Our results demonstrate an active role for epithelial cells in biosynthesis of LTD4, which may be of particular relevance in the lung. PMID:27436590

  17. Stretch-activated channels in pulmonary arterial smooth muscle cells from normoxic and chronically hypoxic rats.

    PubMed

    Ducret, Thomas; El Arrouchi, Jalila; Courtois, Arnaud; Quignard, Jean-François; Marthan, Roger; Savineau, Jean-Pierre

    2010-11-01

    Stretch-activated channels (SACs) act as membrane mechanotransducers since they convert physical forces into biological signals and hence into a cell response. Pulmonary arterial smooth muscle cells (PASMCs) are continuously exposed to mechanical stimulations e.g., compression and stretch, that are enhanced under conditions of pulmonary arterial hypertension (PAH). Using the patch-clamp technique (cell-attached configuration) in PASMCs, we showed that applying graded negative pressures (from 0 to -60 mmHg) to the back end of the patch pipette increases occurrence and activity of SACs. The current-voltage relationship (from -80 to +40 mV) was almost linear with a reversal potential of 1 mV and a slope conductance of 34 pS. SACs were inhibited in the presence of GsMTx-4, a specific SACs blocker. Using microspectrofluorimetry (indo-1), we found that hypotonic-induced cell swelling increases intracellular Ca(2+) concentration ([Ca(2+)](i)). This [Ca(2+)](i) increase was markedly inhibited in the absence of external Ca(2+) or in the presence of the following blockers of SACs: gadolinium, streptomycin, and GsMTx-4. Interestingly, in chronically hypoxic rats, an animal model of PAH, SACs were more active and hypotonic-induced calcium response in PASMCs was significantly higher (nearly a two-fold increase). Moreover, unlike in normoxic rats, intrapulmonary artery rings from hypoxic rats mounted in a Mulvany myograph, exhibited a myogenic tone sensitive to SAC blockers. In conclusion, this work demonstrates that SACs in rat PASMCs can be activated by membrane stretch as well as hypotonic stimulation and are responsible for [Ca(2+)](i) increase. The link between SACs activation-induced calcium response and myogenic tone in chronically hypoxic rats suggests that SACs are an important element for the increased pulmonary vascular tone in PAH and that they may represent a molecular target for PAH treatment. PMID:21035852

  18. Receptor-mediated binding of C1 q on pulmonary endothelial cells

    SciTech Connect

    Zhang, S.C.; Schultz, D.; Ryan, U.

    1986-03-01

    Normal undamaged pulmonary endothelial cells (EC) do not express receptors for C3b or the Fc portion of IgG, but both receptors become unmasked after viral infection or exposure to white cell lysates. Here, highly purified human C1q was labeled with /sup 125/I, and the globular subunits were separated from the collagenous portion by collagenase digestion and chromatography. Bovine pulmonary artery EC were cultured without exposure to proteolytic enzymes. Binding assays were carried out at 0/sup 0/C, pH 7.4, ..mu.. = 0.15. Results showed that /sup 125/I-C1q binds to EC, the binding is dose-dependent, and the receptor is saturable. Saturation was approached at a C1q concentration of ca 0.1 ug. By Scatchard analysis, maximum binding was 0.219 pmoles in a volume of 250 ..mu..l for 7 x 10/sup 5/ cells, and the average number of binding sites per cell was 1.88 x 10/sup 5/. Isolated /sup 125/I-C1q heads do not bind, and when native /sup 125/I-C1q was bound to EC radioactivity was eliminated after collagenase treatment for 4 h at 37/sup 0/C. Thus, C1q binds to EC via the collagenous portion. That Fc receptors (globular heads) are exposed was shown by rosette formation with EA and EC bound C1q. Using similar conditions, native C1(C1w x 2C1r x 2C1s) did not bind to EC. These results suggest a mechanism for localizing immune complexes on undamaged pulmonary vessels which may be important for initiation of the inflammatory response.

  19. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice.

    PubMed

    Shivshankar, Pooja; Brampton, Christopher; Miyasato, Shelley; Kasper, Michael; Thannickal, Victor J; Le Saux, Claude Jourdan

    2012-07-01

    Idiopathic pulmonary fibrosis is associated with a decreased expression of caveolin-1 (cav-1), yet its role remains unclear. To investigate the role of cav-1, we induced pulmonary fibrosis in wild-type (WT) and cav-1-deficient (cav-1(-/-)) mice using intratracheal instillation of bleomycin. Contrary to expectations, significantly less collagen deposition was measured in tissue from cav-1(-/-) mice than in their WT counterparts, consistent with reduced mRNA expression of procollagen1a2 and procollagen3a1. Moreover, cav-1(-/-) mice demonstrated 77% less α-smooth muscle actin staining, suggesting reduced mesenchymal cell activation. Levels of pulmonary injury, assessed by tenascin-C mRNA expression and CD44v10 detection, were significantly increased at Day 21 after injury in WT mice, an effect significantly attenuated in cav-1(-/-) mice. The apparent protective effect against bleomycin-induced fibrosis in cav-1(-/-) mice was attributed to reduce cellular senescence and apoptosis in cav-1(-/-) epithelial cells during the early phase of lung injury. Reduced matrix metalloproteinase (MMP)-2 and MMP-9 expressions indicated a low profile of senescence-associated secretory phenotype (SASP) in the bleomycin-injured cav-1(-/-) mice. However, IL-6 and macrophage inflammatory protein 2 were increased in WT and cav-1(-/-) mice after bleomycin challenge, suggesting that bleomycin-induced inflammatory response substantiated the SASP pool. Thus, loss of cav-1 attenuates early injury response to bleomycin by limiting stress-induced cellular senescence/apoptosis in epithelial cells. In contrast, decreased cav-1 expression promotes fibroblast activation and collagen deposition, effects that may be relevant in later stages of reparative response. Hence, therapeutic strategies to modulate the expression of cav-1 should take into account cell-specific effects in the regenerative responses of the lung epithelium to injury. PMID:22362388

  20. NHERF2 is crucial in ERM phosphorylation in pulmonary endothelial cells

    PubMed Central

    2013-01-01

    Background EBP50 and NHERF2 adaptor proteins are incriminated in various signaling pathways of the cell. They can bind ERM proteins and mediate ERM-membrane protein interactions. Results Binding of ERM to EBP50 and NHERF2 was compared in pulmonary artery endothelial cells by immunoprecipitation. NHERF2 associates with all three ERM, but EBP50 appeared to be a weak binding partner if at all. Furthermore, we detected co-localization of NHERF2 and phospho-ERM at the cell membrane and in the filopodia of dividing cells. Silencing of NHERF2 prevented agonist or angiogenesis induced phosphorylation of ERM, while overexpression of the adaptor elevated the phosphorylation level of ERM, likely catalyzed by Rho kinase 2, which co-immunoprecipitated with NHERF2/ERM in control EC, but did not bind to ERM in NHERF2 depleted cells. Dependence of ERM phosphorylation on NHERF2 was also shown in Matrigel tube formation assay, and NHERF2 was proved to be important in angiogenesis as well. Furthermore, when NHERF2 was depleted or cells were overexpressing a mutant form of NHERF2 unable to bind ERM, we found attenuated cell attachment with ECIS measurements, while it was supported by overexpression of wild type NHERF2. Conclusions Pivotal role of NHERF2 in the phosphorylation process of ERM in pulmonary artery endothelial cells is shown. We propose that NHERF2 provides a common anchoring surface for ERM and Rho kinase 2. Our results demonstrate the essential role of NHERF2 in endothelial cell adhesion/migration and angiogenesis. PMID:24364877

  1. Pulmonary natural killer T cells play an essential role in mediating hyperoxic acute lung injury.

    PubMed

    Nowak-Machen, Martina; Schmelzle, Moritz; Hanidziar, Dusan; Junger, Wolfgang; Exley, Mark; Otterbein, Leo; Wu, Yan; Csizmadia, Eva; Doherty, Glen; Sitkovsky, Michail; Robson, Simon C

    2013-05-01

    Critically ill patients are routinely exposed to high concentrations of supplemental oxygen for prolonged periods of time, which can be life-saving in the short term, but such exposure also causes severe lung injury and increases mortality. To address this therapeutic dilemma, we studied the mechanisms of the tissue-damaging effects of oxygen in mice. We show that pulmonary invariant natural killer T (iNKT) cells are unexpectedly crucial in the development of acute oxygen-induced lung injury. iNKT cells express high concentrations of the ectonucleotidase CD39, which regulates their state of activation. Both iNKT cell-deficient (Jα18(-/-)) and CD39-null mice tolerate hyperoxia, compared with wild-type control mice that exhibit severe lung injury. An adoptive transfer of wild-type iNKT cells into Jα18(-/-) mice results in hyperoxic lung injury, whereas the transfer of CD39-null iNKT cells does not. Pulmonary iNKT cell activation and proliferation are modulated by ATP-dependent purinergic signaling responses. Hyperoxic lung injury can be induced by selective P2X7-receptor blockade in CD39-null mice. Our data indicate that iNKT cells are involved in the pathogenesis of hyperoxic lung injury, and that tissue protection can be mediated through ATP-induced P2X7 receptor signaling, resulting in iNKT cell death. In conclusion, our data suggest that iNKT cells and purinergic signaling should be evaluated as potential novel therapeutic targets to prevent hyperoxic lung injury. PMID:23349052

  2. Prolonged B Cell Depletion With Rituximab is Effective in Treating Refractory Pulmonary Granulomatous Inflammation in Granulomatosis With Polyangiitis (GPA)

    PubMed Central

    Henderson, Scott R.; Copley, Susan J.; Pusey, Charles D.; Ind, Philip W.; Salama, Alan D.

    2014-01-01

    Abstract Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22–52) years. Pulmonary nodules (median 4, range 2–6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/μL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P = <0.0001) and largest nodule diameter (P = <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion. PMID:25501085

  3. Stent Implantation for Malignant Pulmonary Artery Stenosis in a Metastasizing Non-Small Cell Bronchial Carcinoma

    SciTech Connect

    Gutzeit, A.; Koch, S.; Meier, U. R.; Zollikofer, Ch.

    2008-07-15

    A 58-year-old patient with recently diagnosed non-small cell bronchial carcinoma was referred to us with increasing shortness of breath and orthopnea by her family practitioner. To exclude the possibility of a pulmonary embolism, contrast medium-enhanced angio-CT of the thorax was performed. This showed a large mediastinal tumor, which, on the one hand, infiltrated and occluded the left upper lobe bronchus and, on the other, constricted the left pulmonary artery over a considerable part of its length. In view of the palliative situation and massively increasing dyspnea, balloon dilatation of the obstructed left pulmonary artery followed by stent placement was performed. This resulted in an immediate improvement of the symptoms. The originally strongly oxygen-dependent and heavily dyspneic patient could be relieved of the external supply of oxygen and was able to sleep normally without additional medication within 24 h. The patient was able ambulate freely within 2 days, with a markedly improved quality of life.

  4. Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function

    PubMed Central

    Denney, Laura; Byrne, Adam J.; Shea, Thomas J.; Buckley, James S.; Pease, James E.; Herledan, Gaelle M.F.; Walker, Simone A.; Gregory, Lisa G.; Lloyd, Clare M.

    2015-01-01

    Summary Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions. PMID:26588780

  5. A protocol proposition of cell therapy for the treatment of chronic obstructive pulmonary disease.

    PubMed

    Ribeiro-Paes, J T; Stessuk, T; Marcelino, M; Faria, C; Marinelli, T; Ribeiro-Paes, M J

    2014-01-01

    The main feature of pulmonary emphysema is airflow obstruction resulting from the destruction of the alveolar walls distal to the terminal bronchioles. Existing clinical approaches have improved and extended the quality of life of emphysema patients. However, no treatment currently exists that can change the disease course and cure the patient. The different therapeutic approaches that are available aim to increase survival and/or enhance the quality of life of emphysema patients. In this context, cell therapy is a promising therapeutic approach with great potential for degenerative pulmonary diseases. In this protocol proposition, all patients will be submitted to laboratory tests, such as evaluation of heart and lung function and routine examinations. Stem cells will be harvested by means of 10 punctures on each anterior iliac crest, collecting a total volume of 200mL bone marrow. After preparation, separation, counting and labeling (optional) of the mononuclear cells, the patients will receive an intravenous infusion from the pool of Bone Marrow Mononuclear Cells (BMMC). This article proposes a rational and safe clinical cellular therapy protocol which has the potential for developing new projects and can serve as a methodological reference for formulating clinical application protocols related to the use of cellular therapy in COPD. This study protocol was submitted and approved by the Brazilian National Committee of Ethics in Research (CONEP - Brazil) registration number 14764. It is also registered in ClinicalTrials.gov (NCT01110252). PMID:24287082

  6. Effect of spiperone on mesenchymal multipotent stromal and hemopoietic stem cells under conditions of pulmonary fibrosis.

    PubMed

    Skurikhin, E G; Khmelevskaya, E S; Ermakova, N N; Pershina, O V; Reztsova, A M; Krupin, V A; Stepanova, I E; Reztsova, V M; Reikhart, D V; Dygai, A M

    2014-05-01

    The antifibrotic properties of spiperone and its effect on stem and progenitor cells were studied on the model of reversible bleomycin-induced pulmonary fibrosis in C57Bl/6 mice. Spiperone reduced infiltration of the alveolar interstitium and alveolar ducts with inflammatory cells and prevented the growth of the connective tissue in the parenchyma of bleomycin lungs. Apart from anti-inflammatory effect, spiperone suppressed bone marrow hemopoietic cells (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119)-, Sca-1+, c-Kit+, CD34- and progenitor hemopoietic cells (granulocyte-erythroid-macrophage-megakaryocytic and granulocyte CFU). Spiperone-induced disturbances of fi brogenesis were paralleled by restoration of endothelial cells in the lung parenchyma, reduction of the number of circulating bone marrow cells and lung mesenchymopoietic cells (mesenchymal multipotent stromal cells (CD31-, CD34-, CD45-, CD44+, CD73+, CD90+, CD106+) and progenitor fi broblast cells), and suppression of multilineage differentiation of multipotent mesenchymal stromal cells (including fi broblast-lineage cells). PMID:24913578

  7. Cyclic-radiation response of murine fibrosarcoma cells grown as pulmonary nodules

    SciTech Connect

    Grdina, D.J.; Hunter, N.

    1982-10-01

    The radiation age response of murine fibrosarcoma (FSa) cells grown as pulmonary nodules in C/sub 3/Hf/Kam mice was determined. FSa cells were irradiated in vivo either with 10 Gy as 14 day-old lung tumors (i.e., artificial macrometastases) prior to cell separation or with 5 Gy as single cells trapped in the lungs of recipient mice (i.e., artificial micrometastases) following cell separation and synchronization by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine cell-cycle parameters and the relative synchrony of the separated populations, as well as the percent contamination of normal diploid cells in each of the tumor cell populations. Tumor populations containing up to 90% G/sub 1/, 60% S-, and 75% G/sub 2/+M-phase tumor cells were obtained. Cell clonogenicity, determined using a lung colony assay, ranged from 0.7 to 6% for control FSa cells from the various elutriator fractions. The radiation sensitivity of these separated cell populations varied by a factor of 6, regardless of whether the cells were irradiated as artificial micro or macro-metastases. In each experiment, tumor populations most enriched in s-phase cells exhibited the greatest radiation sensitivity. To confirm that these populations were highly enriched in S-phase cells and to demonstrate that they were more radiosensitive than FSa cells in other parts of the cell cycle, the elutriated tumor populations were exposed to either suicide labeling by high specific activity tritiated thymidine or hydroxyurea. The resultant age response curves were qualitatively similar to those obtained following irradiation and reflected the S-phase sensitivity of FSa cells to these agents.

  8. Lung Metastasis of Renal Cell Carcinoma: ACase Report of Pulmonary Sarcomatoid Carcinoma.

    PubMed

    Fan, Tao; Song, Ying-Jie

    2016-06-01

    Pulmonary sarcomatoid carcinoma (PSC) is a rare malignant cancer composed of sarcoma and sarcoma-like elements with spindle or giant cell features. We report the case of a 60-year-old male with past medical history of right renal cell carcinoma 2 years earlier. Apulmonary nodule was detected in the left upper lobe, 23 months after nephrectomy. Systemic positron emission tomography-computerized tomography (PET-CT) revealed one high metabolic mass shadow in the left upper lobe. Chest CTscan with contrast revealed a left upper lobe mass (2.9 x 2.5 cm). The case was suspected to be a lung metastasis of renal cell carcinoma. After surgery, the pathology revealed PSC-giant cell carcinoma. The tumor's pathology and treatment methods are discussed. PMID:27376226

  9. Transcatheter Arterial Embolization With Spherical Embolic Agent for Pulmonary Metastases From Renal Cell Carcinoma

    SciTech Connect

    Seki, Akihiko Hori, Shinichi Sueyoshi, Satoru Hori, Atsushi Kono, Michihiko Murata, Shinichi Maeda, Masahiko

    2013-12-15

    Purpose: This retrospective study aimed to evaluate the safety and local efficacy of transcatheter arterial embolization (TAE) with superabsorbent polymer microspheres (SAP-MS) in patients with pulmonary metastases from renal cell carcinoma (RCC). Methods: Sixteen patients with unresectable pulmonary metastases from RCC refractory to standard therapy were enrolled to undergo TAE with the purpose of mass reduction and/or palliation. The prepared SAP-MS swell to approximately two times larger than their dry-state size (100-150 {mu}m [n = 14], 50-100 {mu}m [n = 2]). Forty-nine pulmonary nodules (lung n = 22, mediastinal lymph node n = 17, and hilar lymph node n = 10) were selected as target lesions for evaluation. Local tumor response was evaluated 3 months after TAE according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The relationship between tumor enhancement ratio by CT during selective angiography and local tumor response was evaluated. Results: The number of TAE sessions per patient ranged from 1 to 5 (median 2.9). Embolized arteries at initial TAE were bronchial arteries in 14 patients (87.5 %) and nonbronchial systemic arteries in 11 patients (68.8 %). Nodule-based evaluation showed that 5 (10.2 %) nodules had complete response, 17 (34.7 %) had partial response, 15 (30.6 %) had stable disease, and 12 (24.5 %) had progressive disease. The response rate was significantly greater in 22 lesions that had a high tumor enhancement ratio than in 27 lesions that had a slight or moderate ratio (90.9 vs. 7.4 %, p = 0.01). Severe TAE-related adverse events did not occur. Conclusion: TAE with SAP-MS might be a well-tolerated and locally efficacious palliative option for patients with pulmonary metastases from RCC.

  10. [Commemorative lecture of receiving Imamura Memorial Prize. NK cell in pulmonary tuberculosis from basic and clinical point of view].

    PubMed

    Yoneda, T

    1996-11-01

    Although natural killer (NK) cells, which lyse certain tumors in vitro, have been shown to provide early defense mechanism against cancer growth and viral infection, possible role in the host defense against pulmonary tuberculosis remains undefined. A series of my studies have recently provided several evidence supporting the involvement of NK cells in the immunopathology of pulmonary tuberculosis. NK cell activity in patients with active pulmonary tuberculosis was significantly augmented compared with that in age-, sex- matched healthy controls, which suggests NK cells are activated in vivo in pulmonary tuberculosis. Lung NK cells from BCG-infected mice also are shown to be activated. Asialo GM 1 was demonstrated to be a novel surface marker of mice NK cells, which inhibited activation of NK cells by interferon. Chronic intractable tuberculosis was classified with a combination of NK cell activity and delayed-type hypersensitivity reaction to 2, 4-dinitrochrolbenzene. Subgroup defined with high NK cell activity and normal delayed-type hypersensitivity was characterized with moderate radiographical lesions and stable clinical course, suggesting the immune-spectrum classification was associated with clinical manifestations. Malnutrition has been suggested to be a risk factor associated with the development and reactivation of pulmonary tuberculosis. NK cell activity was significantly correlated with visceral proteins. IL-2 producing capability was significantly decreased in patients with serum albumin less than 3.5 g/dl. More recently, I established an in vitro system evaluating quantitative capability for intracellular killing by human monocytes, in which monocyte phagocytize Mycobacterium tuberculosis and subsequently inhibit intracellular replication of the organisms by adding some cytokines or cells. Purified NK cells by using discontinuous gradient centrifugation and magnetic separation technique were added to M. tuberculosis-infected monocytes monolayer

  11. Activation of the Wnt/Planar Cell Polarity Pathway Is Required for Pericyte Recruitment during Pulmonary Angiogenesis

    PubMed Central

    Yuan, Ke; Orcholski, Mark E.; Panaroni, Cristina; Shuffle, Eric M.; Huang, Ngan F.; Jiang, Xinguo; Tian, Wen; Vladar, Eszter K.; Wang, Lingli; Nicolls, Mark R.; Wu, Joy Y.; de Jesus Perez, Vinicio A.

    2016-01-01

    Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial–pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G–coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward endothelium via live-imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. PAH pericytes had reduced expression of frizzled 7 (Fzd7) and cdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes in vitro and in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial–pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH. PMID:25447046

  12. Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep.

    PubMed

    Rozance, Paul J; Seedorf, Gregory J; Brown, Alicia; Roe, Gates; O'Meara, Meghan C; Gien, Jason; Tang, Jen-Ruey; Abman, Steven H

    2011-12-01

    Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR. PMID:21873446

  13. Maturation of intracellular calcium homeostasis in sheep pulmonary arterial smooth muscle cells.

    PubMed

    Goyal, Ravi; Creel, Kara D; Chavis, Erica; Smith, Gregory D; Longo, Lawrence D; Wilson, Sean M

    2008-11-01

    Cytosolic Ca(2+) signaling dynamics are important to pulmonary arterial reactivity, and alterations are implicated in pulmonary vascular disorders. Yet, adaptations in cellular Ca(2+) homeostasis and receptor-mediated Ca(2+) signaling with maturation from fetal to adult life in pulmonary arterial smooth muscle cells (PASMCs) are not known. The present study tested the hypothesis that cytosolic Ca(2+) homeostasis and receptor-generated Ca(2+) signaling adapt with maturation in sheep PASMCs. Digitalized fluorescence microscopy was performed using isolated PASMCs from fetal and adult sheep that were loaded with the Ca(2+) indicator fura 2. The results show that basal cytosolic and sarcoplasmic reticulum Ca(2+) levels are attained before birth. Similarly, Ca(2+) efflux pathways from the cytosol and basal as well as capacitative Ca(2+) entry (CCE) are also developed before birth. However, receptor-mediated Ca(2+) signaling adapts with maturation. Prominently, serotonin stimulation elicited Ca(2+) elevations in very few fetal compared with adult PASMCs; in contrast, phenylephrine elevated Ca(2+) in a similar percentage of fetal and adult PASMCs. Serotonin and phenylephrine elicited Ca(2+) increases of a similar magnitude in reactive cells of fetus and adult, supporting the assertion that inositol trisphosphate signaling is intact. Caffeine and ATP elevated Ca(2+) in equivalent numbers of fetal and adult PASMCs. However, the caffeine-induced cytosolic Ca(2+) increase was significantly greater in fetal PASMCs, whereas the ATP-elicited increase was greater in adult cells. Overall, the results of this study demonstrate selective adaptations in receptor-mediated Ca(2+) signaling, but not in cellular Ca(2+) homeostasis. PMID:18776056

  14. Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs.

    PubMed

    Tadokoro, Kent S; Rana, Ujala; Jing, Xigang; Konduri, G Ganesh; Miao, Qing R; Teng, Ru-Jeng

    2016-06-01

    Nogo-B and its receptor (NgBR) are involved in blood vessel growth in developing lungs, but their role in pulmonary artery smooth muscle cell (PASMC) growth is unknown. We hypothesized that NgBR regulates growth of PASMCs by modulating the function of endoplasmic reticulum (ER) and formation of reactive oxygen species (ROS). In utero constriction of the ductus arteriosus created pulmonary hypertension in fetal lambs (hypertensive fetal lamb [HTFL]). PASMCs isolated 8 days after surgery were assessed for the alteration of protein levels by immunoblots and ROS formation by dihydroethidium and Cell ROX deep red fluorescence. NgBR small interfering RNA and plasmid DNA were used to manipulate NgBR levels. Proliferation and wound healing were assessed by cell counts and scratch recovery assay, respectively. Acute ER stress was induced by tunicamycin. Differences of mitogen-activated protein kinase and Akt pathway activation in HTFL versus control PASMCs were evaluated. Results showed that HTFL PASMCs had decreased NgBR levels and increased proliferation, wound healing, ER stress, and ROS formation compared with controls. Knockdown of NgBR in control PASMCs generated a phenotype similar to HTFL, and overexpression in HTFL restored the defective phenotype to control. Decreased NgBR levels were associated with increased ROS formation in HTFL PASMCs. Subsequently, scavenging ROS decreased proliferation and wound healing. Mechanistically, ROS formation decreases NgBR expression, which induces ER stress. This leads to extracellular signal-regulated kinase pathway activation and PASMC phenotype alteration. Our data suggest that decreased NgBR expression in pulmonary hypertension of the newborn contributes to increased PASMC proliferation and oxidative stress, which lead to the pathogenesis of lung injury. PMID:26652754

  15. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension

    PubMed Central

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F.; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G.; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A.; Le, Thanh-Thuy T.; Johnston, Richard A.; Xia, Yang; Eltzschig, Holger K.; Blackburn, Michael R.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2Bf/f-LysMCre) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2Bf/f-LysMCre mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.—Karmouty-Quintana, H., Philip, K., Acero, L. F., Chen, N.-Y., Weng, T., Molina, J. G., Luo, F., Davies, J., Le, N.-B., Bunge, I., Volcik, K. A., Le, T.-T. T., Johnston, R. A., Xia, Y., Eltzschig, H. K., Blackburn, M. R. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. PMID:25318478

  16. Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells.

    PubMed

    Abraham, Nader G; Quan, Shuo; Mieyal, Paul A; Yang, Liming; Burke-Wolin, Theresa; Mingone, Christopher J; Goodman, Alvin I; Nasjletti, Alberto; Wolin, Michael S

    2002-11-01

    Carbon monoxide (CO) stimulates guanylate cyclase (GC) and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels. We transfected rat-lung pulmonary endothelial cells with a retrovirus-mediated human heme oxygenase (hHO)-1 gene. Pulmonary cells that expressed hHO-1 exhibited a fourfold increase in HO activity associated with decreases in the steady-state levels of heme and cGMP without changes in soluble GC (sGC) and endothelial nitric oxide synthase (NOS) proteins or basal nitrite production. Heme elicited significant increases in CO production and intracellular cGMP levels in both pulmonary endothelial and pulmonary hHO-1-expressing cells. N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, significantly decreased cGMP levels in heme-treated pulmonary endothelial cells but not heme-treated hHO-1-expressing cells. In the presence of exogenous heme, CO and cGMP levels in hHO-1-expressing cells exceeded the corresponding levels in pulmonary endothelial cells. Acute exposure of endothelial cells to SnCl2, which is an inducer of HO-1, increased cGMP levels, whereas chronic exposure decreased heme and cGMP levels. These results indicate that prolonged overexpression of HO-1 ultimately decreases sGC activity by limiting the availability of cellular heme. Heme activates sGC and enhances cGMP levels via a mechanism that is largely insensitive to NOS inhibition. PMID:12376366

  17. Foam stabilisation using surfactant exfoliated graphene.

    PubMed

    Sham, Alison Y W; Notley, Shannon M

    2016-05-01

    Liquid-air foams have been stabilised using a suspension of graphene particles at very low particle loadings. The suspension was prepared through the liquid phase exfoliation of graphite in the presence of the non-ionic tri-block surfactant, Pluronic® F108. The graphene particles possess an extremely high aspect ratio, with lateral dimensions of between 0.1 and 1.3 μm as evidenced by TEM imaging. The particles were shown to exhibit a number of other properties known to favour stabilisation of foam structures. Particle surface activity was confirmed through surface tension measurements, suggesting the particles favour adsorption at the air-water interface. The evolution of bubble size distributions over time indicated the presence of particles yielded improvements to foam stability due to a reduction in disproportionation. Foam stability measurements showed a non-linear relationship between foam half-life and graphene concentration, indicative of the rate at which particles adsorb at bubble surfaces. The wettability of the graphene particles was altered upon addition of alkali metal chlorides, with the stability of the foams being enhanced according to the series Na(+)>Li(+)>K(+)>Cs(+). This effect is indicative of the relative hydration capacity of each salt with respect to the surfactant, which is adsorbed along the graphene plane as a result of the exfoliation process. Thus, surfactant exfoliated graphene particles exhibit a number of different features that demonstrate efficient application of high-aspect ratio particles in the customisation and enhancement of foams. PMID:26890385

  18. Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases

    PubMed Central

    Tandra, Varun Sharma; Kotha, Krishna Mohan Reddy; Satyanarayana, Moorthy Gadisetti Venkata; Vadlamani, Kali Varaprasad; Yerravalli, Vyjayanthi

    2015-01-01

    Giant cell tumour (GCT) is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge. PMID:26106496

  19. Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases.

    PubMed

    Tandra, Varun Sharma; Kotha, Krishna Mohan Reddy; Satyanarayana, Moorthy Gadisetti Venkata; Vadlamani, Kali Varaprasad; Yerravalli, Vyjayanthi

    2015-01-01

    Giant cell tumour (GCT) is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge. PMID:26106496

  20. Cyclic-radiation response of murine fibrosarcoma cells grown as pulmonary nodules

    SciTech Connect

    Grdina, D.J.; Hunter, N.

    1982-10-01

    The radiation age response of murine fibrosarcoma (FSa) cells grown as pulmonary nudules in C/sub 3/Hf/Kam mice was determined. FSa cells were irradiated in vivo either with 10 Gy as 14 day-old lung tumors (i.e., artifical micrometastases) following cell separation and synchronization by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine cell-cycle parameters and the relative synchrony of the separated populations, as well as the percent contamination of normal diploid cells in each of the tumor cells populations. Tumor populations containing up to 90% G/sub 1/-, 60% S-, and 75% G/sub 2/+M-phase tumor cells were obtained. Cell clonogenicity, determined using a lung colony assay, ranged from 0.7 to 6% for control FSa cells from the various elutriator fractions. The radiation sensitivity of these separated cell populations varied by a factor of 6, regardless of whether the cells were irradiated as artifical micro or macro-metastases. In each experiment, tumor population most enriched in S-phase cells exhibited the greatest radiation sensitivity. To confirm that these populations were highly enriched in S-phase cells and to demonstrate that they were more radiosensitive than FSa cells in other parts of the cell cycle, the elutriated tumor population were exposed to either suicide labeling by high specific activity tritated thymidine or hydroxyurea. The resultant age response curves were qualitatively similar to those obtained following irradiation and reflected the S-phase sensitivity of FSa cells to these agents.

  1. Iron-induced remodeling in cultured rat pulmonary artery endothelial cells.

    PubMed

    Gorbunov, Nikolai V; Atkins, James L; Gurusamy, Narasimman; Pitt, Bruce R

    2012-02-01

    Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N

  2. Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch.

    PubMed

    Birukov, Konstantin G; Jacobson, Jeffrey R; Flores, Alejandro A; Ye, Shui Q; Birukova, Anna A; Verin, Alexander D; Garcia, Joe G N

    2003-10-01

    Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes vascular barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery endothelial cells (HPAEC) were exposed to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of strain. CS produced rapid (10 min) increases in myosin light chain (MLC) phosphorylation, activation of p38 and extracellular signal-related kinase 1/2 MAP kinases, and actomyosin remodeling. Acute (15 min) and chronic (48 h) CS markedly enhanced thrombin-induced MLC phosphorylation (2.1-fold and 3.2-fold for 15-min CS at 5 and 18% elongation and 2.1-fold and 3.1-fold for 48-h CS at 5 and 18% elongation, respectively). HPAEC preconditioned at 18% CS, but not at 5% CS, exhibited significantly enhanced thrombin-induced reduction in transendothelial electrical resistance but did not affect barrier protective effect of sphingosine-1-phosphate (0.5 microM). Finally, expression profiling analysis revealed a number of genes, including small GTPase rho, apoptosis mediator ZIP kinase, and proteinase activated receptor-2, to be regulated by CS in an amplitude-dependent manner. Thus our study demonstrates a critical role for the magnitude of CS in regulation of agonist-mediated pulmonary endothelial cell permeability and strongly suggests phenotypic regulation of HPAEC barrier properties by CS. PMID:12639843

  3. Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis.

    PubMed

    Sun, Zhaorui; Wang, Cong; Shi, Chaowen; Sun, Fangfang; Xu, Xiaomeng; Qian, Weiping; Nie, Shinan; Han, Xiaodong

    2014-05-01

    Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury. PMID:24573542

  4. Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells

    PubMed Central

    Rafikov, Ruslan; Sun, Xutong; Rafikova, Olga; Louise Meadows, Mary; Desai, Ankit A.; Khalpey, Zain; Yuan, Jason X.-J.; Fineman, Jeffrey R.; Black, Stephen M.

    2015-01-01

    ATP is essential for cellular function and is usually produced through oxidative phosphorylation. However, mitochondrial dysfunction is now being recognized as an important contributing factor in the development cardiovascular diseases, such as pulmonary hypertension (PH). In PH there is a metabolic change from oxidative phosphorylation to mainly glycolysis for energy production. However, the mechanisms underlying this glycolytic switch are only poorly understood. In particular the role of the respiratory Complexes in the mitochondrial dysfunction associated with PH is unresolved and was the focus of our investigations. We report that smooth muscle cells isolated from the pulmonary vessels of rats with PH (PH-PASMC), induced by a single injection of monocrotaline, have attenuated mitochondrial function and enhanced glycolysis. Further, utilizing a novel live cell assay, we were able to demonstrate that the mitochondrial dysfunction in PH-PASMC correlates with deficiencies in the activities of Complexes I–III. Further, we observed that there was an increase in mitochondrial reactive oxygen species generation and mitochondrial membrane potential in the PASMC isolated from rats with PH. We further found that the defect in Complex I activity was due to a loss of Complex I assembly, although the assembly of Complexes II and III were both maintained. Thus, we conclude that loss of Complex I assembly may be involved in the switch of energy metabolism in smooth muscle cells to glycolysis and that maintaining Complex I activity may be a potential therapeutic target for the treatment of PH. PMID:26298201

  5. Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas.

    PubMed

    Masai, Kyohei; Tsuta, Koji; Kawago, Mitsumasa; Tatsumori, Takahiro; Kinno, Tomoaki; Taniyama, Tomoko; Yoshida, Akihiko; Asamura, Hisao; Tsuda, Hitoshi

    2013-07-01

    Recent clinical trials have revealed that accurate histologic typing of non-small cell lung cancer is essential. Until now, squamous cell carcinoma (SQC) and adenocarcinoma (ADC) markers have not been thoroughly analyzed for pulmonary neuroendocrine carcinomas (NECs). We analyzed the expression of 8 markers [p63, cytokeratin (CK) 5/6, SOX2, CK7, desmocollin 3, thyroid transcription factor-1 (8G7G3/1 and SPT24), and napsin A] in 224 NECs. SOX2 (76.2%) had the greatest expression for NECs. CK5/6 (1.4%), desmocollin 3 (0.5%), and napsin A (0%) were expressed less or not at all in NECs. Although our investigated markers have been reported useful for differentiating between SQC and ADC, some of them were also present in a portion of pulmonary NECs. In our study, CK5/6 and desmocollin 3 were highly specific markers for SQC, and napsin A was highly specific for ADC. These markers are recommended for diagnosis of poorly differentiated non-small cell lung cancer. PMID:23060301

  6. Pulmonary Langerhans Cell Histiocytosis with Lytic Bone Involvement in an Adult Smoker: Regression following Smoking Cessation.

    PubMed

    Routy, B; Hoang, J; Gruber, J

    2015-01-01

    Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and dissemination of histiocytes. These in turn may cause symptoms ranging from isolated, infiltrative lesions to severe multisystem disease. Pulmonary Langerhans cell histiocytosis (PLCH) presents as a localized polyclonal proliferation of Langerhans cells in the lungs causing bilateral cysts and fibrosis. In adults, this rare condition is considered a reactive process associated with cigarette smoking. Recently, clonal proliferation has been reported with the presence of BRAF V600E oncogenic mutation in a subset of PLCH patients. Spontaneous resolution was described; however, based on case series, smoking cessation remains the most effective way to achieve complete remission and prevent long term complications related to tobacco. Herein, we report the case of an adult woman with biopsy-proven PLCH presenting with thoracic (T8) vertebral bone destruction. Both the lung and the bone diseases regressed following smoking cessation, representing a rare case of synchronous disseminated PCLH with bone localization. This observation underscores the contribution of cigarette smoking as a systemic trigger of both pulmonary and extrapulmonary bone lesions. A review of similar cases in the literature is also presented. PMID:25789184

  7. Pulmonary Langerhans Cell Histiocytosis with Lytic Bone Involvement in an Adult Smoker: Regression following Smoking Cessation

    PubMed Central

    Routy, B.; Hoang, J.; Gruber, J.

    2015-01-01

    Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and dissemination of histiocytes. These in turn may cause symptoms ranging from isolated, infiltrative lesions to severe multisystem disease. Pulmonary Langerhans cell histiocytosis (PLCH) presents as a localized polyclonal proliferation of Langerhans cells in the lungs causing bilateral cysts and fibrosis. In adults, this rare condition is considered a reactive process associated with cigarette smoking. Recently, clonal proliferation has been reported with the presence of BRAF V600E oncogenic mutation in a subset of PLCH patients. Spontaneous resolution was described; however, based on case series, smoking cessation remains the most effective way to achieve complete remission and prevent long term complications related to tobacco. Herein, we report the case of an adult woman with biopsy-proven PLCH presenting with thoracic (T8) vertebral bone destruction. Both the lung and the bone diseases regressed following smoking cessation, representing a rare case of synchronous disseminated PCLH with bone localization. This observation underscores the contribution of cigarette smoking as a systemic trigger of both pulmonary and extrapulmonary bone lesions. A review of similar cases in the literature is also presented. PMID:25789184

  8. Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells.

    PubMed

    Rafikov, Ruslan; Sun, Xutong; Rafikova, Olga; Meadows, Mary Louise; Desai, Ankit A; Khalpey, Zain; Yuan, Jason X-J; Fineman, Jeffrey R; Black, Stephen M

    2015-12-01

    ATP is essential for cellular function and is usually produced through oxidative phosphorylation. However, mitochondrial dysfunction is now being recognized as an important contributing factor in the development cardiovascular diseases, such as pulmonary hypertension (PH). In PH there is a metabolic change from oxidative phosphorylation to mainly glycolysis for energy production. However, the mechanisms underlying this glycolytic switch are only poorly understood. In particular the role of the respiratory Complexes in the mitochondrial dysfunction associated with PH is unresolved and was the focus of our investigations. We report that smooth muscle cells isolated from the pulmonary vessels of rats with PH (PH-PASMC), induced by a single injection of monocrotaline, have attenuated mitochondrial function and enhanced glycolysis. Further, utilizing a novel live cell assay, we were able to demonstrate that the mitochondrial dysfunction in PH-PASMC correlates with deficiencies in the activities of Complexes I-III. Further, we observed that there was an increase in mitochondrial reactive oxygen species generation and mitochondrial membrane potential in the PASMC isolated from rats with PH. We further found that the defect in Complex I activity was due to a loss of Complex I assembly, although the assembly of Complexes II and III were both maintained. Thus, we conclude that loss of Complex I assembly may be involved in the switch of energy metabolism in smooth muscle cells to glycolysis and that maintaining Complex I activity may be a potential therapeutic target for the treatment of PH. PMID:26298201

  9. Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury

    PubMed Central

    Mitra, Srabani

    2015-01-01

    Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC) apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1) induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control) nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury. PMID:26710067

  10. Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation.

    PubMed

    Rajavelu, Priya; Chen, Gang; Xu, Yan; Kitzmiller, Joseph A; Korfhagen, Thomas R; Whitsett, Jeffrey A

    2015-05-01

    Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen. PMID:25866971

  11. A Protective Role For Club Cell Secretory Protein-16 (CC16) In The Development of Chronic Obstructive Pulmonary Disease (COPD)

    PubMed Central

    Laucho-Contreras, Maria E.; Polverino, Francesca; Gupta, Kushagra; Taylor, Katherine L.; Kelly, Emer; Pinto-Plata, Victor; Divo, Miguel; Afshaq, Naveed; Petersen, Hans; Stripp, Barry; Pilon, Aprile L.; Tesfaigzi, Yohannes; Celli, Bartolome R.; Owen, Caroline A.

    2015-01-01

    Rationale Club cell secretory protein-16 (CC16) is the major secreted product of airway Club cells, but its role in the pathogenesis of COPD is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD mice model. Methods Airway CC16 expression was measured in COPD patients, smokers without COPD, and non-smokers. We exposed wild-type (WT) and CC16-/- mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway MUC5AC expression, small airway remodeling, and pulmonary function. Results Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16-/- mice had greater CS-induced emphysema, airway remodeling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NFκB) activation in CC16-/- lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. Conclusions CC16 protects lungs from CS-induced injury by reducing lung NFκB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD. PMID:25700379

  12. The Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Damayanti, Triya; Yunus, Faisal

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is a chronic and progressive inflammatory disease of the airways and lungs that results in limitations of continuous airflow and is caused by exposure to noxious gasses and particles. A major cause of morbidity and mortality in adults, COPD is a complex disease pathologically mediated by many inflammatory pathways. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are the key inflammatory cells involved in COPD. Recently, the non-coding small RNA, micro-RNA, have also been intensively investigated and evidence suggest that it plays a role in the pathogenesis of COPD. Here, we discuss the accumulated evidence that has since revealed the role of each inflammatory cell and their involvement in the immunopathogenesis of COPD. Mechanisms of steroid resistance in COPD will also be briefly discussed. PMID:26770229

  13. Therapeutic Potential of Mesenchymal Stem Cells for the Treatment of Airway Remodeling in Pulmonary Diseases.

    PubMed

    Nejad-Moghaddam, Amir; Panahi, Yunes; Abdollahpour Alitappeh, Meghdad; Borna, Hojat; Shokrgozar, Mohammad Ali; Ghanei, Mostafa

    2015-12-01

    According to significant improvements in the tissue engineering field over the past several years, lung tissue cells have recently attracted more attention due to the high prevalence and diversity in related diseases. However, selection of an appropriate cell type, screening of suitable conditions for growth and proliferation, as well as subsequent implantation into the body to repair and regenerate damaged tissues are considered as important issues in this context. It should also be noted that most studies have been described in animal models, but not in humans. Because of the high regenerative capacity, predominant immunomodulatory feature, and inhibition of T-lymphocyte proliferation, mesenchymal stem cells (MSCs) may play an important role in the reconstruction of damaged tissues including bronchioles in pulmonary diseases. Interestingly, clinical trial studies demonstrated that MSCs have the significant potential to treat a wide variety of diseases including acute myocardial infarction (AMI), liver cirrhosis, crohn's disease, and graft-versus-host disease (GVHD). PMID:26725553

  14. Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells.

    PubMed

    Ko, Eun A; Burg, Elyssa D; Platoshyn, Oleksandr; Msefya, Joseph; Firth, Amy L; Yuan, Jason X-J

    2007-09-01

    Mice are useful animal models to study pathogenic mechanisms involved in pulmonary vascular disease. Altered expression and function of voltage-gated K(+) (K(V)) channels in pulmonary artery smooth muscle cells (PASMCs) have been implicated in the development of pulmonary arterial hypertension. K(V) currents (I(K(V))) in mouse PASMCs have not been comprehensively characterized. The main focus of this study was to determine the biophysical and pharmacological properties of I(K(V)) in freshly dissociated mouse PASMCs with the patch-clamp technique. Three distinct whole cell I(K(V)) were identified based on the kinetics of activation and inactivation: rapidly activating and noninactivating currents (in 58% of the cells tested), rapidly activating and slowly inactivating currents (23%), and slowly activating and noninactivating currents (17%). Of the cells that demonstrated the rapidly activating noninactivating current, 69% showed I(K(V)) inhibition with 4-aminopyridine (4-AP), while 31% were unaffected. Whole cell I(K(V)) were very sensitive to tetraethylammonium (TEA), as 1 mM TEA decreased the current amplitude by 32% while it took 10 mM 4-AP to decrease I(K(V)) by a similar amount (37%). Contribution of Ca(2+)-activated K(+) (K(Ca)) channels to whole cell I(K(V)) was minimal, as neither pharmacological inhibition with charybdotoxin or iberiotoxin nor perfusion with Ca(2+)-free solution had an effect on the whole cell I(K(V)). Steady-state activation and inactivation curves revealed a window K(+) current between -40 and -10 mV with a peak at -31.5 mV. Single-channel recordings revealed large-, intermediate-, and small-amplitude currents, with an averaged slope conductance of 119.4 +/- 2.7, 79.8 +/- 2.8, 46.0 +/- 2.2, and 23.6 +/- 0.6 pS, respectively. These studies provide detailed electrophysiological and pharmacological profiles of the native K(V) currents in mouse PASMCs. PMID:17581857

  15. O-GlcNAc Transferase Directs Cell Proliferation in Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Barnes, Jarrod W.; Tian, Liping; Heresi, Gustavo A.; Farver, Carol F.; Asosingh, Kewal; Comhair, Suzy A. A.; Aulak, Kulwant S.; Dweik, Raed A.

    2015-01-01

    Background Idiopathic Pulmonary arterial Hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH. Methods and Results Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway (HBP). We measured the levels of O-linked N-acetylglucosamine modification (O-GlcNAc), O-GlcNAc transferase (OGT), and O-GlcNAc hydrolase (OGA) in control and IPAH cells and tissues. Our data suggests that the activation of the HBP directly increased OGT levels and activity triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-GlcNAc levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1 (HCF-1). Conclusions Our data demonstrate that HBP flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of HCF-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH. PMID:25663381

  16. Circulating Myeloid-Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension

    PubMed Central

    Nguyen, Cecilia M.; Belchenko, Dmitry D.; Colvin, Kelley L.; Takatsuki, Shinichi; Ivy, D. Dunbar; Stenmark, Kurt R.

    2012-01-01

    Background: Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in the lungs of humans and animals with PH, and we hypothesized that they would be increased in the blood of patients with PH compared with control subjects. Methods: Twenty-six children with PH and 10 undergoing cardiac catheterization for arrhythmia ablation were studied. Five milliliters of fresh blood were analyzed using flow cytometry. Results were confirmed using magnetic bead sorting and immunofluorescence, while quantitative polymerase chain reaction and intracellular urea concentration assays were used as measures of MDSC arginase-1 activation. Results: Flow cytometry demonstrated enrichment of circulating MDSCs among patients with PH (n = 26; mean, 0.271 × 106 cells/mL ± 0.17; 1.86% of CD45+ population ± 1.51) compared with control subjects (n = 10; mean, 0.176 × 106 cells/mL ± 0.05; 0.57% of CD45+ population ± 0.29; P < .05). Higher numbers of circulating MDSCs correlated to increasing mean pulmonary artery pressure (r = 0.510, P < .05). Among patients with PH, female patients had a twofold increase in MDSCs compared with male patients. Immunofluorescence analysis confirmed the results of flow cytometry. Quantitative reverse transcription polymerase chain reaction assay results for arginase-1 and measurement of intracellular urea concentration revealed increased activity of MDSCs from patients with PH compared with control subjects. Conclusions: Circulating activated MDSCs are significantly increased in children with PH compared with control subjects. Further investigation of these cells is warranted, and we speculate that they might play significant immunomodulatory roles in the disease pathogenesis of PH. PMID:21940769

  17. Doppler-Defined Pulmonary Hypertension in Sickle Cell Anemia in Kurdistan, Iraq.

    PubMed

    Al-Allawi, Nasir; Mohammad, Ameen M; Jamal, Shakir

    2016-01-01

    To determine the frequency, clinical and laboratory associations of pulmonary hypertension in Iraqi Kurds with sickle cell anemia, a total of ninety four such patients attending a major hemoglobinopathy center in Iraqi Kurdistan were enrolled. All patients were re-evaluated clinically and had their blood counts, HbF, serum ferritin, LDH, renal and liver function assessed. Transthoracic Doppler echocardiography with measurement of tricuspid valve regurgitant jet velocity (TRV) was performed. A TRV in excess of 2.8 m/s was considered for the purposes of this study as indicative of pulmonary hypertension (PH). The prevalence of TRV in excess of 2.8m/s was 10.6%. By univariate analysis: significantly higher reticulocyte count, more frequent blood transfusions and pain episodes were encountered in the PH group as compared to the non-PH group (p = 0.001, 0.045 and 0.02 respectively). Moreover, PH patients had significantly higher mean right atrial area, left atrial size, E wave/A wave ratio and ejection fraction by echocardiography (p = 0.027, 0.037, <0.001 and 0.008 respectively). Except for reticulocyte count none of the other parameters remained significant by multivariate analysis (p = 0.024). In conclusion the current study revealed that pulmonary hypertension is rather frequent among Iraqi Kurds with sickle cell anemia, and identified reticulocyte count as an independently associated parameter with PH in this population. Future prospective studies including right heart catheterization and appropriate medical intervention are warranted. PMID:27583566

  18. Microwave Assisted 2D Materials Exfoliation

    NASA Astrophysics Data System (ADS)

    Wang, Yanbin

    Two-dimensional materials have emerged as extremely important materials with applications ranging from energy and environmental science to electronics and biology. Here we report our discovery of a universal, ultrafast, green, solvo-thermal technology for producing excellent-quality, few-layered nanosheets in liquid phase from well-known 2D materials such as such hexagonal boron nitride (h-BN), graphite, and MoS2. We start by mixing the uniform bulk-layered material with a common organic solvent that matches its surface energy to reduce the van der Waals attractive interactions between the layers; next, the solutions are heated in a commercial microwave oven to overcome the energy barrier between bulk and few-layers states. We discovered the minutes-long rapid exfoliation process is highly temperature dependent, which requires precise thermal management to obtain high-quality inks. We hypothesize a possible mechanism of this proposed solvo-thermal process; our theory confirms the basis of this novel technique for exfoliation of high-quality, layered 2D materials by using an as yet unknown role of the solvent.

  19. Exfoliation of montmorillonite in protein solutions.

    PubMed

    Kolman, Krzysztof; Steffen, Werner; Bugla-Płoskońska, Gabriela; Skwara, Aleksandra; Pigłowski, Jacek; Butt, Hans-Jürgen; Kiersnowski, Adam

    2012-05-15

    In the study we demonstrate a method to obtain stable, exfoliated montmorillonite-protein complexes by adsorption of the proteins extracted from hen-egg albumen. Analysis of the process by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed that the complexes are formed by sequential adsorption of ovotransferrin, ovalbumins, ovomucoid and lysozyme on the surface of the silicate. Structural studies performed by X-ray diffraction (XRD) and transmission electron microscopy (TEM) indicated that the adsorption of ovotransferrin and albumins is accompanied by disintegration of clay stacks into discrete platelets. Further analysis by dynamic light scattering (DLS) revealed that at protein to silicate weight ratios exceeding 20, the synergistic adsorption of albumen components leads to reaggregation of silicate platelets into disordered, microgel-like particles. By means of DLS it was found that exfoliation predominantly leads to formation of particles with average hydrodynamic radii (R(h)) of 0.19 μm while their aggregation causes formation of particles having R(h) in of approx. 0.5 μm and larger. PMID:22405581

  20. A method to measure mechanical properties of pulmonary epithelial cell layers.

    PubMed

    Dassow, Constanze; Armbruster, Caroline; Friedrich, Christian; Smudde, Eva; Guttmann, Josef; Schumann, Stefan

    2013-10-01

    The lung has a huge inner alveolar surface composed of epithelial cell layers. The knowledge about mechanical properties of lung epithelia is helpful to understand the complex lung mechanics and biomechanical interactions. Methods have been developed to determine mechanical indices (e.g., tissue elasticity) which are both very complex and in need of costly equipment. Therefore, in this study, a mechanostimulator is presented to dynamically stimulate lung epithelial cell monolayers in order to determine their mechanical properties based on a simple mathematical model. First, the method was evaluated by comparison to classical tensile testing using silicone membranes as substitute for biological tissue. Second, human pulmonary epithelial cells (A549 cell line) were grown on flexible silicone membranes and stretched at a defined magnitude. Equal secant moduli were determined in the mechanostimulator and in a conventional tension testing machine (0.49 ± 0.05 MPa and 0.51 ± 0.03 MPa, respectively). The elasticity of the cell monolayer could be calculated by the volume-pressure relationship resulting from inflation of the membrane-cell construct. The secant modulus of the A549 cell layer was calculated as 0.04 ± 0.008 MPa. These findings suggest that the mechanostimulator may represent an adequate device to determine mechanical properties of cell layers. PMID:23564730

  1. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease.

    PubMed

    Fujii, Satoko; Hara, Hiromichi; Araya, Jun; Takasaka, Naoki; Kojima, Jun; Ito, Saburo; Minagawa, Shunsuke; Yumino, Yoko; Ishikawa, Takeo; Numata, Takanori; Kawaishi, Makoto; Hirano, Jun; Odaka, Makoto; Morikawa, Toshiaki; Nishimura, Stephen; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

    2012-08-01

    Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD. PMID:22934255

  2. Effect of vitamin D3 on chemokine levels and regulatory T-cells in pulmonary tuberculosis.

    PubMed

    Harishankar, M; Anbalagan, S; Selvaraj, P

    2016-05-01

    1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] the active form of vitamin D3 acts as an immunomodulator in various immune cells. The present study is aimed to study the effect of 1,25(OH)2D3 on chemokine levels and regulatory T-cells in 51 healthy controls (HCs) and 50 pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells were cultured with culture filtrate antigen (CFA) of Mycobacterium tuberculosis in the presence or absence of 1,25(OH)2D3 at 10(-7)M concentration for 72h and the percentage positive regulatory T-cell subsets were studied using flow cytometry. The chemokine levels were estimated in the culture supernatants by ELISA. 1,25(OH)2D3 significantly upregulated the frequency of regulatory T-cell subsets while suppressed the production of chemokine levels in CFA stimulated cultures of HCs and PTB patients (p<0.05). Correlation analysis revealed a significant negative correlation between CD4+Foxp3+ regulatory T-cells and MCP-1, MIP-1β and IP-10 in CFA stimulated with 1,25(OH)2D3 treated cells (p<0.05). The results suggested that 1,25(OH)2D3 upregulated regulatory T-cells and act as anti-inflammatory by downregulating chemokine levels which could be beneficial to protect the host from inflammation and tissue damage during infection. PMID:26927615

  3. Prominin-1/CD133 expression as potential tissue-resident vascular endothelial progenitor cells in the pulmonary circulation.

    PubMed

    Sekine, Ayumi; Nishiwaki, Tetsu; Nishimura, Rintaro; Kawasaki, Takeshi; Urushibara, Takashi; Suda, Rika; Suzuki, Toshio; Takayanagi, Shin; Terada, Jiro; Sakao, Seiichiro; Tada, Yuji; Iwama, Atsushi; Tatsumi, Koichiro

    2016-06-01

    Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues. PMID:27059286

  4. Iptakalim influences the proliferation and apoptosis of human pulmonary artery smooth muscle cells

    PubMed Central

    LI, QINGLIN; YAN, XIAOPEI; KONG, HUI; XIE, WEIPING; WANG, HONG

    2016-01-01

    The aim of the present study was to determine the effect of an ATP-sensitive K+ (KATP) channel opener iptakalim (IPT) on the proliferation and apoptosis of human pulmonary artery smooth muscle cells (HPASMCs), and examine the potential value of IPT to hypoxic pulmonary hypertension (HPH) at a cellular level. HPASMCs were divided into the control, ET-1, ET-1+IPT and ET-1+IPT+glibenclamide (GLI) groups. GLI was administered 30 min prior to ET-1 and IPT. The 4 groups were incubated with corresponding reagents for 24 h. Cell viability was evaluated using a CCK-8 assay, cell proliferation by 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, and cell apoptosis via the expression of apoptosis-related proteins, i.e., Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) using western blotting. We incubated HPASMCs with varying concentrations of ET-1 for 24, 48 and 72 h, and found that cell survival rate was increased in a dose-dependent manner (P<0.05) rather than in a time-dependent manner (P>0.05). After co-incubation of HPASMCs with varying concentrations of IPT and ET-1 for 24 h, the cell survival rate was decreased in a dose-dependent manner. The cell survival rate in the IPT+ET-1 group was significantly lower than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1 group were higher than those in the control group, and the expression of Bax/Bcl-2 was lower than the control group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT group were lower than those in the ET-1 group, and the expression of Bax/Bcl-2 was higher than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT+GLI group were higher than those in the ET-1+IPT group, and the expression of Bax/Bcl-2 was lower than that in the ET-1+IPT group (P<0.05). In conclusion, IPT inhibited ET-1-induced HPASMC proliferation and promoted cell apoptosis. Thus, it may play an

  5. Iptakalim influences the proliferation and apoptosis of human pulmonary artery smooth muscle cells.

    PubMed

    Li, Qinglin; Yan, Xiaopei; Kong, Hui; Xie, Weiping; Wang, Hong

    2016-07-01

    The aim of the present study was to determine the effect of an ATP-sensitive K+ (KATP) channel opener iptakalim (IPT) on the proliferation and apoptosis of human pulmonary artery smooth muscle cells (HPASMCs), and examine the potential value of IPT to hypoxic pulmonary hyper-tension (HPH) at a cellular level. HPASMCs were divided into the control, ET-1, ET-1+IPT and ET-1+IPT+glibenclamide (GLI) groups. GLI was administered 30 min prior to ET-1 and IPT. The 4 groups were incubated with corresponding reagents for 24 h. Cell viability was evaluated using a CCK-8 assay, cell proliferation by 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and cell apoptosis via the expression of apoptosis-related proteins, i.e., Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) using western blotting. We incubated HPASMCs with varying concentrations of ET-1 for 24, 48 and 72 h, and found that cell survival rate was increased in a dose-dependent manner (P<0.05) rather than in a time-dependent manner (P>0.05). After co-incubation of HPASMCs with varying concentrations of IPT and ET-1 for 24 h, the cell survival rate was decreased in a dose-dependent manner. The cell survival rate in the IPT+ET-1 group was significantly lower than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1 group were higher than those in the control group, and the expression of Bax/Bcl-2 was lower than the control group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT group were lower than those in the ET-1 group, and the expression of Bax/Bcl-2 was higher than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT+GLI group were higher than those in the ET-1+IPT group, and the expression of Bax/Bcl-2 was lower than that in the ET-1+IPT group (P<0.05). In conclusion, IPT inhibited ET-1‑induced HPASMC proliferation and promoted cell apoptosis. Thus, it may

  6. A solitary pulmonary ground-glass nodule in adult systemic langerhans' cell histiocytosis.

    PubMed

    Zhou, Ying; Li, Yunyuan; Fan, Li; Liu, Shiyuan

    2015-01-01

    During a thoracic computed tomography (CT) scan, a 36-year-old male was diagnosed with a solitary oval pulmonary mixed ground-glass nodule in the right upper lobe of the lung. The edge of the nodule was well-defined, and its largest axial size was approximately 1.1 × 0.9 cm(2). This nodule was slightly lobulated, but not obviously speculated. Solid components, micro-cystic lucency shadow, small high-density rings and tiny vascular branches were all visible in the nodule. During hospitalization, a technetium 99 m methylene diphosphonate (Tc-99 m MDP) bone scan was performed, which showed a skeletal foci with abnormal uptake in the left iliac. A pulmonary lobectomy of the right upper lobe of the lung by video-assisted thoracoscopy was performed. In post-operative pathological photomicrographs, proliferative Langerhans' cells, eosinophils and lymphocytes were found. Immunohistochemistry showed that the expression of S-100 protein, CD1a, and CD68 antigen all stained positive. Since Langerhans' cell histiocytosis (LCH) that is also associated with isolated mixed ground-glass nodules is relatively rare, such a multi-systemic LCH case as identified herein, is reported. PMID:26722574

  7. A solitary pulmonary ground-glass nodule in adult systemic langerhans’ cell histiocytosis

    PubMed Central

    Zhou, Ying; Li, Yunyuan; Fan, Li; Liu, Shiyuan

    2015-01-01

    During a thoracic computed tomography (CT) scan, a 36-year-old male was diagnosed with a solitary oval pulmonary mixed ground-glass nodule in the right upper lobe of the lung. The edge of the nodule was well-defined, and its largest axial size was approximately 1.1×0.9 cm2. This nodule was slightly lobulated, but not obviously speculated. Solid components, micro-cystic lucency shadow, small high-density rings and tiny vascular branches were all visible in the nodule. During hospitalization, a technetium 99 m methylene diphosphonate (Tc-99 m MDP) bone scan was performed, which showed a skeletal foci with abnormal uptake in the left iliac. A pulmonary lobectomy of the right upper lobe of the lung by video-assisted thoracoscopy was performed. In post-operative pathological photomicrographs, proliferative Langerhans’ cells, eosinophils and lymphocytes were found. Immunohistochemistry showed that the expression of S-100 protein, CD1a, and CD68 antigen all stained positive. Since Langerhans’ cell histiocytosis (LCH) that is also associated with isolated mixed ground-glass nodules is relatively rare, such a multi-systemic LCH case as identified herein, is reported. PMID:26722574

  8. p53/PUMA expression in human pulmonary fibroblasts mediates cell activation and migration in silicosis

    PubMed Central

    Wang, Wei; Liu, Haijun; Dai, Xiaoniu; Fang, Shencun; Wang, Xingang; Zhang, Yingming; Yao, Honghong; Zhang, Xilong; Chao, Jie

    2015-01-01

    Phagocytosis of SiO2 into the lung causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Clinical evidence has indicated that the activation of alveolar macrophages by SiO2 produces rapid and sustained inflammation characterized by the generation of monocyte chemotactic protein 1, which, in turn, induces fibrosis. However, the details of events downstream of monocyte chemotactic protein 1 activity in pulmonary fibroblasts remain unclear. Here, to elucidate the role of p53 in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Experiments using primary cultured adult human pulmonary fibroblasts led to the following results: 1) SiO2 treatment resulted in a rapid and sustained increase in p53 and PUMA protein levels; 2) the MAPK and PI3K pathways were involved in the SiO2-induced alteration of p53 and PUMA expression; and 3) RNA interference targeting p53 and PUMA prevented the SiO2-induced increases in fibroblast activation and migration. Our study elucidated a link between SiO2-induced p53/PUMA expression in fibroblasts and cell migration, thereby providing novel insight into the potential use of p53/PUMA in the development of novel therapeutic strategies for silicosis treatment. PMID:26576741

  9. Primary Pulmonary Diffuse Large B-Cell Lymphoma on FDG PET/CT-MRI and DWI

    PubMed Central

    Xu, Huiting; Xu, Kai; Wang, Ru; Liu, Xiaohua

    2015-01-01

    Abstract Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) directly arising from lung tissue is extremely rare. It may usually be misdiagnosed as inflammation including pulmonary tuberculosis, even lung cancer, because its clinical symptoms and signs are often nonspecific. The final diagnosis usually depends on lung biopsy. Herein, we report a case of PPDLBCL and review of diagnosis of this disease, particularly in radiology. A 44-year-old man presented with cough, sputum, and intermittent chest pain for 4 weeks. Multiple radiological examinations showed an irregular mass in the right upper lobe with ground-glass opacities around it and air-filled bronchi in the consolidation. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (MRI) detected positive FDG uptake, and diffusion-weighted imaging indicated abnormal hyperintension in the lesion. Inflammation was suspected, but malignance cannot be excluded. Finally, ultrasound-guided fine-needle aspiration cytology was performed for histological examination and definitive diagnosis yielded lymphomatous cells infiltration in the right upper lobe. This report emphasizes the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, staging, and management of lymphomas. PMID:26200643

  10. Cationic Surface Modification of PLG Nanoparticles Offers Sustained Gene Delivery to Pulmonary Epithelial Cells

    PubMed Central

    BAOUM, ABDULGADER; DHILLON, NAVNEET; BUCH, SHILPA; BERKLAND, CORY

    2010-01-01

    Biodegradable polymeric nanoparticles are currently being explored as a nonviral gene delivery system; however, many obstacles impede the translation of these nanomaterials. For example, nanoparticles delivered systemically are inherently prone to adsorbing serum proteins and agglomerating as a result of their large surface/volume ratio. What is desired is a simple procedure to prepare nanoparticles that may be delivered locally and exhibit minimal toxicity while improving entry into cells for effectively delivering DNA. The objective of this study was to optimize the formulation of poly(D,L-lactide-co-glycolide) (PLG) nanoparticles for gene delivery performance to a model of the pulmonary epithelium. Using a simple solvent diffusion technique, the chemistry of the particle surface was varied by using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (~200 nm) efficiently encapsulated plasmids encoding for luciferase (80–90%) and slowly released the same for 2 weeks. In A549 alveolar lung epithelial cells, high levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least 2 weeks. In contrast, PEI gene expression ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. PMID:19911425

  11. Human pulmonary artery endothelial cells in the model of mucopolysaccharidosis VI present a prohypertensive phenotype

    PubMed Central

    Golda, Adam; Jurecka, Agnieszka; Gajda, Karolina; Tylki-Szymańska, Anna; Lalik, Anna

    2015-01-01

    Background Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB). Pulmonary hypertension (PH) occurs in MPS VI patients and is a marker of bad prognosis. Malfunction of endothelium, which regulates vascular tonus and stimulates angiogenesis, can contribute to the occurrence of PH in MPS VI. Aim The aim of the study was to establish a human MPS VI cellular model of pulmonary artery endothelial cells (HPAECs) and evaluate how it affects factors that may trigger PH such as proliferation, apoptosis, expression of endothelial nitric oxide synthase (eNOS), natriuretic peptide type C (NPPC), and vascular endothelial growth factor A (VEGFA). Results Increasing concentrations of dermatan sulfate (DS) reduce the viability of the cells in both ARSB deficiency and controls, but hardly influence apoptosis. The expression of eNOS in HPAECs is reduced up to two thirds in the presence of DS. NPPC shows a biphasic expression reaction with an increase at 50 μg/mL DS and reduction at 0 and 100 μg/mL DS. The expression of VEGFA decreases with increasing DS concentrations and absence of elastin, and increases with increasing DS in the presence of elastin. Conclusion Our data suggest that MPS VI endothelium presents a prohypertensive phenotype due to the reduction of endothelium's proliferation ability and expression of vasorelaxing factors. PMID:26937388

  12. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension.

    PubMed

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A; Le, Thanh-Thuy T; Johnston, Richard A; Xia, Yang; Eltzschig, Holger K; Blackburn, Michael R

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH. PMID:25318478

  13. Quantitative risk stratification of oral leukoplakia with exfoliative cytology.

    PubMed

    Liu, Yao; Li, Jianying; Liu, Xiaoyong; Liu, Xudong; Khawar, Waqaar; Zhang, Xinyan; Wang, Fan; Chen, Xiaoxin; Sun, Zheng

    2015-01-01

    Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma (OSCC). Test outcome is reported as "negative", "atypical" (defined as abnormal epithelial changes of uncertain diagnostic significance), and "positive" (defined as definitive cellular evidence of epithelial dysplasia or carcinoma). The major challenge is how to properly manage the "atypical" patients in order to diagnose OSCC early and prevent OSCC. In this study, we collected exfoliative cytology data, histopathology data, and clinical data of normal subjects (n=102), oral leukoplakia (OLK) patients (n=82), and OSCC patients (n=93), and developed a data analysis procedure for quantitative risk stratification of OLK patients. This procedure involving a step called expert-guided data transformation and reconstruction (EdTAR) which allows automatic data processing and reconstruction and reveals informative signals for subsequent risk stratification. Modern machine learning techniques were utilized to build statistical prediction models on the reconstructed data. Among the several models tested using resampling methods for parameter pruning and performance evaluation, Support Vector Machine (SVM) was found to be optimal with a high sensitivity (median>0.98) and specificity (median>0.99). With the SVM model, we constructed an oral cancer risk index (OCRI) which may potentially guide clinical follow-up of OLK patients. One OLK patient with an initial OCRI of 0.88 developed OSCC after 40 months of follow-up. In conclusion, we have developed a statistical method for qualitative risk stratification of OLK patients. This method may potentially improve cost-effectiveness of clinical follow-up of OLK patients, and help design clinical chemoprevention trial for high-risk populations. PMID:25978541

  14. Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis.

    PubMed

    Uhal, Bruce D; Dang, MyTrang; Dang, Vinh; Llatos, Roger; Cano, Esteban; Abdul-Hafez, Amal; Markey, Jonathan; Piasecki, Christopher C; Molina-Molina, Maria

    2013-07-01

    Alveolar epithelial type II cells, a major source of angiotensin-converting enzyme (ACE)-2 in the adult lung, are normally quiescent but actively proliferate in lung fibrosis and downregulate this protective enzyme. It was, therefore, hypothesised that ACE-2 expression might be related to cell cycle progression. To test this hypothesis, ACE-2 mRNA levels, protein levels and enzymatic activity were examined in fibrotic human lungs and in the alveolar epithelial cell lines A549 and MLE-12 studied at postconfluent (quiescent) versus subconfluent (proliferating) densities. ACE-2 mRNA, immunoreactive protein and enzymatic activity were all high in quiescent cells, but were severely downregulated or absent in actively proliferating cells. Upregulation of the enzyme in cells that were progressing to quiescence was completely inhibited by the transcription blocker actinomycin D or by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). In lung biopsy specimens obtained from patients with idiopathic pulmonary fibrosis, immunoreactive enzyme was absent in alveolar epithelia that were positive for proliferation markers, but was robustly expressed in alveolar epithelia devoid of proliferation markers. These data explain the loss of ACE-2 in lung fibrosis and demonstrate cell cycle-dependent regulation of this protective enzyme by a JNK-mediated transcriptional mechanism. PMID:23100504

  15. Effects of treatment with a combination of cardiac rehabilitation and bosentan in patients with pulmonary Langerhans cell histiocytosis associated with pulmonary hypertension.

    PubMed

    Fukuda, Yusuke; Miura, Shin-ichiro; Fujimi, Kanta; Yano, Masaya; Nishikawa, Hiroaki; Yanagisawa, Jun; Hiratsuka, Masafumi; Shiraishi, Takeshi; Iwasaki, Akinori; Saku, Keijiro

    2014-12-01

    Pulmonary hypertension (PH), which is classified as group 5 in the clinical classification of PH, is sometimes a complication of Pulmonary langerhans cell histiocytosis (PLCH), and is associated with high mortality. A 36-year-old woman had suffered from severe dyspnea 9 years previously and was diagnosed with PLCH and was on a waiting list for a lung transplant. Right heart failure had been observed and the mean pulmonary artery pressure was over 40 mmHg. The patient was diagnosed as PLCH with PH. After combined treatment with exercise rehabilitation and bosentan for 6 months, the cardiothoracic ratio, brain natriuretic peptide, and bodyweight were significantly decreased (cardiothoracic ratio from 43 to 38%, brain natriuretic peptide from 284 to10 pg/ml and bodyweight from 63 to 58 kg). Six-minute walk test also improved from 214 to 275 meters and the SF36 score for screening of depressive and anxiety disorders was improved. This is the report demonstrating the efficacy and safety of cardiac rehabilitation in combination with bosentan in a single patient with PLCH associated with PH. PMID:23897898

  16. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells.

    PubMed

    Murakami, Takashi; Maki, Wusi; Cardones, Adela R; Fang, Hui; Tun Kyi, Adrian; Nestle, Frank O; Hwang, Sam T

    2002-12-15

    The chemokine receptors CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR) 4 have been implicated in cancer metastasis. To evaluate whether CXCR4 is sufficient to increase tumor metastasis in an organ-specific manner, we transduced murine B16 melanoma cells with CXCR4 (CXCR4-B16) and followed the metastatic fate of the transduced cells in both i.v. and s.c. inoculation models of metastasis. CXCR4-B16 cells demonstrated marked increases (>10-fold) in pulmonary metastasis compared with vector (pLNCX2)-B16 after i.v. and s.c. inoculation of tumor cells. The increase in metastasis could be completely inhibited by T22, a small peptide antagonist of CXCR4. As early as 24 and 48 h after i.v. injection, CXCR4-B16 cells were significantly increased in the lung compared with control B16 cells by 5- and 10-fold (P < 0.05), respectively. CXCR4-B16 cells adhered better to both dermal and pulmonary microvascular endothelial cells relative to control B16 cells. Moreover, CXCL12 promoted the growth of CXCR4-B16 cells in vitro. Whereas expression of CXCR4 in B16 cells dramatically enhanced pulmonary metastasis, metastasis to the lymph nodes, liver, and kidney was rare. Immunohistochemical staining of both primary human cutaneous melanoma and pulmonary metastases revealed CXCR4 expression. Thus, CXCR4 plays a potentially important role in promoting organ-selective metastasis, possibly by stimulating tumor adhesion to microvascular endothelial cells and by enhancing the growth of tumor cells under stress. PMID:12499276

  17. MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts.

    PubMed

    Liu, Haijun; Dai, Xiaoniu; Cheng, Yusi; Fang, Shencun; Zhang, Yingming; Wang, Xingang; Zhang, Wei; Liao, Hong; Yao, Honghong; Chao, Jie

    2016-01-15

    Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2). Phagocytosis of SiO2 in the lungs initiates an inflammatory cascade that results in fibroblast proliferation and migration followed by fibrosis. According to previous data from our laboratory, monocyte chemotactic protein-1 (MCP-1) plays a critical role in fibroblast proliferation and migration in conventional two-dimensional (2D) monolayer cultures. The present study aimed to explore the downstream cascade of MCP-1 in both 2D and three-dimensional (3D) cell culture models of silicosis. Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following: 1) SiO2 treatment induces expression of MCP-1-induced protein (MCPIP1) in a time- and dose-dependent manner in both 2D and 3D cultures; 2) the MAPK and phosphatidylinositol-3-kinase (PI3K)/Akt pathways are involved in SiO2-induced MCPIP1 expression; and 3) MCPIP1 induction mediates the SiO2-induced increase in cell migration in both 2D and 3D cultures. The effect of MCP-1 in silicosis occurs mainly through MCPIP1, which, in turn, mediates the observed SiO2-induced increase in pulmonary fibroblast migration. However, the time frame for MCPIP1 induction differed between 2D and 3D cultures, indicating that, compared with conventional 2D cell culture systems, 3D culture may be useful for analyses of fibroblast physiology under conditions that more closely resemble in vivo environments. Our study determined the link between fibroblast-derived MCPIP1 and SiO2-induced cell migration, and this finding provides novel evidence of the potential of MCPIP1 in the development of novel therapeutic strategies for silicosis. PMID:26608530

  18. miR-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension

    PubMed Central

    Stevens, Hannah; Lu, Ruifang; Caudrillier, Axelle; McBride, Martin; McClure, John D; Grant, Jenny; Thomas, Matthew; Frid, Maria; Stenmark, Kurt; White, Kevin; Seto, Anita G.; Morrell, Nicholas W.; Bradshaw, Angela C; MacLean, Margaret R.; Baker, Andrew H.

    2015-01-01

    Rationale The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143−/− and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions miR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology. PMID:26311719

  19. T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease

    PubMed Central

    Lambers, C; Hacker, S; Posch, M; Hoetzenecker, K; Pollreisz, A; Lichtenauer, M; Klepetko, W; Jan Ankersmit, H

    2009-01-01

    Pathogenetic mechanisms leading to chronic obstructive pulmonary disease (COPD) remain poorly understood. Because clonogenic T cells (CD4+CD28null) were shown to be increased in autoimmune diseases we hypothesized that CD4+CD28null T cells play a role in COPD. Here we describe that enhanced presence of CD4+CD28null cells is associated with impaired lung function. Sixty-four patients and controls were included. T cell phenotype was analysed using flow cytometry. Enzyme-linked immunosorbent assays were utilized to determine cytokines. Statistical evaluations were performed using non-parametric group comparisons and correlations. A logistic regression model was used to determine predictive values of CD4+CD28null in the diagnosis of COPD. Populations of CD4+ T cells lacking surface co-stimulatory CD28 were enlarged significantly in evaluated patients when compared with controls. Natural killer (NK)-like T cell receptors (CD94, 158) and intracellular perforin, granzyme B were increased in CD4+CD28null cells. Cytokine production after triggering of peripheral blood mononuclear cells (PBMCs) was elevated in patients at early disease stages. Receiver operating characteristic curve plotting revealed that presence of CD4+CD28null T cells has a diagnostic value. These CD4+CD28null T cells show increased expression of NK-like T cell receptors (CD94, 158) and intracellular perforin and granzyme B. Furthermore, triggering of PBMCs obtained from patients with mild COPD led to increased interferon-γ and tumour necrosis factor-α production in vitro compared with controls. Our finding of increased CD4+CD28null T cells in COPD indicates that chronic antigen exposure, e.g. through contents of smoke, leads to loss of CD28 and up-regulation of NK cell receptors expression on T cells in susceptible patients. PMID:19220836

  20. Relation between time spent outdoors and exfoliation glaucoma or exfoliation glaucoma suspect

    PubMed Central

    Kang, Jae Hee; Wiggs, Janey L.; Pasquale, Louis R.

    2014-01-01

    Purpose To evaluate the relation between time spent outdoors at various life periods and risk of exfoliation glaucoma or exfoliation glaucoma suspect. Design Retrospective cohort study in the United States. Methods Participants (49,033 women in the Nurses Health Study and 20,066 men in the Health Professionals Follow-up Study) were 60+ years old, free of glaucoma and cataract, reported eye exams and completed questions about time spent outdoors in direct sunlight at mid-day at 3 life periods: high school to age 24 years, age 25-35 years, and age 36-59 years (asked in 2006 in women and 2008 in men). Participants were followed biennially with mailed questionnaires from 1980 (women) / 1986 (men) to 2010. Incident cases (223 women and 38 men) were confirmed with medical records. Cohort-specific multivariable-adjusted rate ratios from Cox proportional hazards models were estimated and pooled with meta-analysis. Results Although no association was observed with greater time spent outdoors in the ages of 25-35 or ages 36-59 years, the pooled multivariable-adjusted rate ratios for ≥11 hours per week spent outdoors in high school to age 24 years compared with ≤5 hours per week was 2.00 (95% confidence interval=1.30, 3.08; p for linear trend=0.001). In women, this association was stronger in those who resided in the southern geographic tier in young adulthood (p for interaction = 0.07). Conclusions Greater time spent outdoors in young adulthood was associated with risk of exfoliation glaucoma or exfoliation glaucoma suspect, supporting an etiologic role of early exposures to climatic factors. PMID:24857689

  1. Calpain-2 activates Akt via TGF-β1-mTORC2 pathway in pulmonary artery smooth muscle cells.

    PubMed

    Abeyrathna, Prasanna; Kovacs, Laszlo; Han, Weihong; Su, Yunchao

    2016-07-01

    Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are the downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibitions of calpain-2 by using calpain inhibitor MDL28170 and calpain-2 small interfering RNA attenuated Akt phosphorylations at serine-473 (S473) and threonine-308 (T308), as well as collagen synthesis and cell proliferation of PASMCs induced by PDGF. Overexpression of calpain-2 in PASMCs induced dramatic increases in Akt phosphorylations at S473 and T308. Moreover, knockout of calpain attenuated Akt phosphorylations at S473 and T308 in smooth muscle of pulmonary arterioles of mice with chronic hypoxic pulmonary hypertension. The cell-permeable-specific transforming growth factor (TGF)-β receptor inhibitor SB431542 attenuated Akt phosphorylations at both S473 and T308 induced by PDGF and by overexpressed calpain-2 in PASMCs. Furthermore, SB-431452 and knocking down activin receptor-like kinase-5 significantly reduced PDGF-induced collagen synthesis and cell proliferation of PASMCs. Nevertheless, neutralizing extracellular TGF-β1 using a cell-impermeable TGF-β1 neutralizing antibody did not affect PDGF-induced Akt phosphorylations at S473 and T308. Furthermore, inhibition of mammalian target of rapamycin complex 2 (mTORC2) by knocking down its component protein Rictor prevented Akt phosphorylations at S473 and T308 induced by PDGF and by overexpressed calpain-2. These data provide first evidence supporting that calpain-2 upregulates PDGF-induced Akt phosphorylation in pulmonary vascular remodeling via an intracrine TGF-β1/mTORC2 mechanism. PMID:27099352

  2. Pulmonary function and symptoms of Nigerian workers exposed to carbon black in dry cell battery and tire factories

    SciTech Connect

    Oleru, U.G.; Elegbeleye, O.O.; Enu, C.C.; Olumide, Y.M.

    1983-02-01

    The pulmonary function and symptoms of 125 workers exposed to carbon black in dry cell battery and tire manufacturing plants were investigated. There was no significant difference in the pulmonary function of the subjects in the two plants. There was good agreement in the symptoms reported in the two different factories: cough with phlegm production, tiredness, chest pain, catarrh, headache, and skin irritation. The symptoms also corroborate those reported in the few studies on the pulmonary effects of carbon black. The suspended particulate levels in the dry cell battery plant ranged from 25 to 34 mg/m/sup 3/ and the subjects with the highest probable exposure level had the most impaired pulmonary function. The pulmonary function of the exposed subjects was significantly lower than that of a control, nonindustrially exposed population. The drop in the lung function from the expected value per year of age was relatively constant for all the study subgroups but the drop per year of duration of employment was more severe in the earlier years of employment. This study has underscored the need for occupational health regulations in the industries of developing countries.

  3. Axonal Degeneration in Dental Pulp Precedes Human Primary Teeth Exfoliation.

    PubMed

    Suzuki, K; Lovera, M; Schmachtenberg, O; Couve, E

    2015-10-01

    The dental pulp in human primary teeth is densely innervated by a plethora of nerve endings at the coronal pulp-dentin interface. This study analyzed how the physiological root resorption (PRR) process affects dental pulp innervation before exfoliation of primary teeth. Forty-four primary canine teeth, classified into 3 defined PRR stages (early, middle, and advanced) were fixed and demineralized. Longitudinal cryosections of each tooth were stained for immunohistochemical and quantitative analysis of dental pulp nerve fibers and associated components with confocal and electron microscopy. During PRR, axonal degeneration was prominent and progressive in a Wallerian-like scheme, comprising nerve fiber bundles and nerve endings within the coronal and root pulp. Neurofilament fragmentation increased significantly during PRR progression and was accompanied by myelin degradation and a progressive loss of myelinated axons. Myelin sheath degradation involved activation of autophagic activity by Schwann cells to remove myelin debris. These cells expressed a sequence of responses comprising dedifferentiation, proliferative activity, GAP-43 overexpression, and Büngner band formation. During the advanced PRR stage, increased immune cell recruitment within the dental pulp and major histocompatibility complex (MHC) class II upregulation by Schwann cells characterized an inflammatory condition associated with the denervation process in preexfoliative primary teeth. The ensuing loss of dental pulp axons is likely to be responsible for the progressive reduction of sensory function of the dental pulp during preexfoliative stages. PMID:26149320

  4. Surfactant mediated liquid phase exfoliation of graphene

    NASA Astrophysics Data System (ADS)

    Narayan, Rekha; Kim, Sang Ouk

    2015-10-01

    Commercialization of graphene based applications inevitably requires cost effective mass production. From the early days of research on graphene, direct liquid phase exfoliation (LPE) of graphite has been considered as the most promising strategy to produce high-quality mono or few-layer graphene sheets in solvent dispersion forms. Substantial success has been achieved thus far in the LPE of graphene employing numerous solvent systems and suitable surfactants. This invited review article principally showcase the recent research progress as well as shortcomings of surfactant assisted LPE of graphene. In particular, a comprehensive assessment of the quality and yield of the graphene sheets produced by different categories of the surfactants are summarized. Future direction of LPE methods is also proposed for the eventual success of commercial applications.

  5. Ferromagnetism in exfoliated tungsten disulfide nanosheets

    PubMed Central

    2013-01-01

    Two-dimensional-layered transition metal dichalcogenides nanosheets have attracted tremendous attention for their promising applications in spintronics because the atomic-thick nanosheets can not only enhance the intrinsic properties of their bulk counterparts, but also give birth to new promising properties. In this paper, ultrathin tungsten disulfide (WS2) nanosheets were gotten by liquid exfoliation route from its bulk form using dimethylformamide (DMF). Compared to the antiferromagnetism bulk WS2, ultrathin WS2 nanosheets show intrinsic room-temperature ferromagnetism (FM) with the maximized saturation magnetization of 0.004 emu/g at 10 K, where the appearance of FM in the nanosheets is partly due to the presence of zigzag edges in the magnetic ground state at the grain boundaries. PMID:24134699

  6. Exfoliative cytology of buccal squames: A quantitative cytomorphometric analysis of patients with diabetes

    PubMed Central

    Sankhla, Bharat; Sharma, Abhishek; Shetty, Raju Singam; Bolla, Sheetal Chowdary; Gantha, Naga Sribala; Reddy, Prasun

    2014-01-01

    Background: Diabetes is a third leading cause of mortality and morbidity in the world. Diabetes is one of the most common endocrine metabolic disorders and its prevalence has been increasing worldwide. Oral exfoliative cytology may be a more appropriate adjunctive diagnostic tool in conditions like diabetes mellitus, where the invasive techniques lose viability. Aims: The purpose of this study is to analyze the cytomorphometric changes in the exfoliated cells of the oral mucosa, as an adjunct to the diagnosis of diabetes. Materials and Methods: Smears were taken from the buccal mucosa of 30 diabetes patients (study group) and 30 healthy individuals (control group). All the smears were stained with rapid Papanicolaou stain (PAP). In the PAP smears, the nuclear area (NA), cytoplasmic area (CA), and cytoplasmic-to-nuclear ratio (CNR) were evaluated for 50 cells in each smear, using the Image Analysis Software (Magnus Pro™) and research microscope (Lawrence and Mayo™). Results: The results showed that the mean NA was significantly higher (P < 0.001) in the study group, whereas, the mean CA did not exhibit a statistically significant difference (P > 0.001). The mean CNR was significantly lower in the study group (P < 0.001). Interpretation and Conclusion: The results associated with the clinical observations suggest that diabetes can produce morphological and functional alterations in the oral epithelial cells, detectable by microscopic and cytomorphometric analysis using exfoliative cytology, which can be used in the diagnosis of the disease. PMID:25374837

  7. Pulmonary alveolar proteinosis with myeloproliferative syndrome with myelodysplasia: bronchoalveolar lavage reduces white blood cell count.

    PubMed

    Pollack, Seth M; Gutierrez, Guillermo; Ascensao, Joao

    2006-08-01

    Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by surfactant component accumulation in the alveolar space. Primary PAP is likely an autoimmune disorder caused by antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). When an underlying disease causes PAP, this is called secondary PAP. Hematologic malignancies are an important cause of secondary PAP. As the pathogenesis of primary PAP has become more fully understood, improvements in diagnostic and therapeutic approaches have followed. However, when PAP is secondary to an underlying hematologic malignancy, much remains unclear. Here we describe for the first time a patient with hybrid myelodysplastic syndrome/myeloproliferative syndrome and PAP who had a marked decrease in her white blood cell count following a transbronchial biopsy accompanied by bronchoalveolar lavage (BAL). Similar significant decreases in WBC count accompanied clinical improvement following two unilateral BALs. Given that patients with pulmonary alveolar proteinosis frequently have elevated GM-CSF in bronchoalveolar fluid, this observation provides a unique vantage point to understand the pathophysiology of secondary PAP. PMID:16906593

  8. Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease.

    PubMed

    Pashankar, Farzana D; Carbonella, Judith; Bazzy-Asaad, Alia; Friedman, Alan

    2009-03-01

    Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sbeta(0) thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) > or =2.5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19-31 months). Patients with initial TRV > or = 3 or TRV > or = 2.5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow-up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram (P = 0.01), lower haemoglobin (P = 0.003) and lower oxygen saturation (P = 0.03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40.16 to 29.26 (P = 0.017) after 3-6 months and to 23.6 mmHg (P = 0.002) after 9-12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea. PMID:19055665

  9. Identification of Functional Voltage-gated Na+ Channels in Cultured Human Pulmonary Artery Smooth Muscle Cells

    PubMed Central

    Sison, Tiffany; Yuan, Jason X.-J.

    2005-01-01

    Electrical excitability, which plays an important role in excitation-contraction coupling in the pulmonary vasculature, is regulated by transmembrane ion flux in pulmonary artery smooth muscle cells (PASMC). This study aimed to characterize the electrophysiological properties and molecular identities of voltage-gated Na+ channels in cultured human PASMC. We recorded tetrodotoxin-sensitive and rapidly inactivating Na+ currents with properties similar to those described in cardiac myocytes. Using RT-PCR, we detected transcripts of seven Na+ channel α genes (SCN2A, 3A, 4A, 7A, 8A, 9A, and 11A), and two β subunit genes (SCN1B and 2B). Our results demonstrate that human PASMC express TTX-sensitive voltage-gated Na+ channels. Their physiological functions remain unresolved, although our data suggest that Na+ channel activity does not directly influence membrane potential, intracellular Ca2+ release, or proliferation in normal human PASMC. Whether their expression and/or activity are heightened in the pathological state is discussed. PMID:16052353

  10. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease.

    PubMed

    Detterich, Jon A; Kato, Roberta M; Rabai, Miklos; Meiselman, Herbert J; Coates, Thomas D; Wood, John C

    2015-08-01

    Tricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia. PMID:26036801

  11. Pulmonary edema

    MedlinePlus

    ... congestion; Lung water; Pulmonary congestion; Heart failure - pulmonary edema ... Pulmonary edema is often caused by congestive heart failure . When the heart is not able to pump efficiently, blood ...

  12. Flow Cytometric Analysis of Protective T-Cell Response Against Pulmonary Coccidioides Infection.

    PubMed

    Hung, Chiung-Yu; Wozniak, Karen L; Cole, Garry T

    2016-01-01

    The incidence of systemic fungal infections has increased throughout the world, spurring much interest in developing effective vaccines. Coccidioidomycosis, also known as San Joaquin Valley fever, is a potentially life-threatening respiratory mycosis. A vaccine against Coccidioides infection would contribute significantly to the well-being of the approx. 30 million residents in the Southwestern USA as well as the multitude of travelers who annually visit the endemic regions. We have applied a live, attenuated vaccine (∆T) to explore the nature of vaccine immunity in mice after intranasal challenge with a potentially lethal dose of Coccidioides spores. Coccidioides spores are airborne and highly infectious for mammalian hosts and classified as a biosafety level 3 agent. T cells are critical in the development of protective immunity against a variety of microorganisms as well as the development of autoimmune disease and allergic responses. Profiles of cytokines detected in lung homogenates of ∆T-vaccinated mice were indicative of a mixed Th1, Th2, and Th17 immune response. We have developed an intracellular cytokine staining and flow cytometric (ICS) technique to measure activated CD4(+) and CD8(+) T cells and IFN-γ-, IL-4-, IL-5-, and IL-17A-producing T cells in the lungs of mice that are challenged with a potentially lethal dose of Coccidioides spores. The numbers of pulmonary Th1 and Th17 cells during the first 2 weeks post-challenge showed a progressive increase in vaccinated mice and corresponded with reduction of fungal burden. In this protocol, we describe the methodology for culture and isolation of the live, attenuated ΔT spores of Coccidioides used to vaccinate mice, preparation of pulmonary cells, and staining protocol for cell surface markers and intracellular cytokines. This is the most reliable and robust procedure to measure frequencies and numbers of each selected T-cell subsets in lungs of vaccinated versus control mice and can be readily

  13. Phospholipase D signaling in serotonin-induced mitogenesis of pulmonary artery smooth muscle cells.

    PubMed

    Liu, Y; Fanburg, B L

    2008-09-01

    We have previously reported the participation of mitogen-activated protein, Rho, and phosphoinositide-3 (PI3) kinases in separate pathways in serotonin (5-HT)-induced proliferation of pulmonary artery smooth muscle cells (SMCs). In this study, we investigated the possible participation of phospholipase D (PLD) and phosphatidic acid (PA) in this growth process. 5-HT stimulated a time-dependent increase in [(3)H]phosphatidylbutanol and PA generation. Exposure of SMCs to 1-butanol or overexpression of an inactive mutant of human PLD1R898R blocked 5-HT-induced proliferation. Furthermore, 1-butanol inhibited 5-HT activation of S6K1 and S6 protein, downstream effectors of mammalian target of rapamycin (mTOR), by 80 and 72%, respectively, and partially blocked activation of extracellular signal-regulated kinase (ERK) by 30% but had no effect on other associated signaling pathways. Exogenous PA caused cellular proliferation and revitalized cyclin D1 expression by 5-HT of the 1-butanol-treated cells. PA also reproduced activations by 5-HT of mTOR, S6K1, and ERK. Transfection with inactive human PLD1 reduced 5-HT-induced activation of S6K1 by approximately 50%. Inhibition of 5-HT receptor 2A (R 2A) with ketaserin blocked PLD activation by 5-HT. Inhibition with PI3-kinase inhibitor failed to block either activation of PLD by 5-HT or PA-dependent S6K1 phosphorylation. Taken together, these results indicate that ligation of the 5-HTR 2A by 5-HT initiates PLD activation in SMCs, and that its product, PA, is an early signaling molecule in 5-HT-induced pulmonary artery SMC proliferation. Signaling by PA produces its downstream effects primarily through the mTOR/S6K1 pathway and to a lesser extent through the ERK pathway. Hydrolysis of cell membrane lipid may be important in vascular effects of 5-HT. PMID:18621911

  14. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

    PubMed

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  15. A case of primary pulmonary diffuse large B-cell lymphoma diagnosed by transbronchial biopsy.

    PubMed

    Yoshino, Naoyuki; Hirata, Tomomi; Takeuchi, Chie; Usuda, Jitsuo; Hosone, Masaru

    2015-01-01

    A 76-year-old man took a chest X-ray for his medical checkup and an abnormal shadow was detected in the right lower lung field. For more detailed examination, he was referred to our hospital. Chest computed tomography showed a 20-mm nodule with relatively regular margins in the right lower lobe. A compact proliferation of circular to polygonal cells with a high nucleus-cytoplasm ratio was evident in a transbronchial lung biopsy. Based on pathological findings, a mature large B-cell lymphoma was diagnosed. Thoracoscopic right lower lobectomy and mediastinal lymphadenectomy were performed. The post-surgical pathological examination showed that the tumor consisted of diffuse to compact proliferation of medium to large atypical lymphocyte-like cells. Immunohistochemical staining yielded positive results for B-cell lineage markers. Five months after surgical resection, neither local recurrence nor accumulation in remote organs was observed on gallium scintigraphy. The diagnosis of primary pulmonary diffuse large B-cell lymphoma was established. PMID:25912218

  16. Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells

    PubMed Central

    Dassah, MaryAnn; Almeida, Dena; Hahn, Rebecca; Bonaldo, Paolo; Worgall, Stefan; Hajjar, Katherine A.

    2014-01-01

    ABSTRACT The annexins are an evolutionarily conserved family of phospholipid-binding proteins of largely unknown function. We observed that the AnxA2−/− lung basement membrane specifically lacks collagen VI (COL6), and postulated that ANXA2 directs bronchial epithelial cell secretion of COL6, an unusually large multimeric protein. COL6 serves to anchor cells to basement membranes and, unlike other collagens, undergoes multimerization prior to secretion. Here, we show that AnxA2−/− mice have reduced exercise tolerance with impaired lung tissue elasticity, which was phenocopied in Col6a1−/− mice. In vitro, AnxA2−/− fibroblasts retained COL6 within intracellular vesicles and adhered poorly to their matrix unless ANXA2 expression was restored. In vivo, AnxA2−/− bronchial epithelial cells underwent apoptosis and disadhesion. Immunoprecipitation and immunoelectron microscopy revealed that ANXA2 associates with COL6 and the SNARE proteins SNAP-23 and VAMP2 at secretory vesicle membranes of bronchial epithelial cells, and that absence of ANXA2 leads to retention of COL6 in a late-Golgi, VAMP2-positive compartment. These results define a new role for ANXA2 in the COL6 secretion pathway, and further show that this pathway establishes cell–matrix interactions that underlie normal pulmonary function and epithelial cell survival. PMID:24357721

  17. Adenosine-5'-triphosphate release by Mannheimia haemolytica, lipopolysaccharide, and interleukin-1 stimulated bovine pulmonary epithelial cells.

    PubMed

    Craddick, Michael; Patel, Rakhi; Lower, Amanda; Highlander, Sarah; Ackermann, Mark; McClenahan, David

    2012-09-15

    Mannheimia haemolytica, one of the agents associated with bovine respiratory disease complex, can cause severe lung pathology including the leakage of vascular products into the airways and alveoli. Previous work by this laboratory has demonstrated that bovine lung endothelial and epithelial cells undergo dramatic permeability increases when exposed to adenosine-5'-triphosphate (ATP). Therefore, we wanted to determine if ATP levels were elevated in bronchoalveolar lavage (BAL) samples from calves experimentally infected with M. haemolytica. In addition, cultured bovine pulmonary epithelial (BPE) cells were stimulated with heat-killed and live M. haemolytica bacteria, lipopolysaccharide (LPS), lipoteichoic acid (LTA), interleukin-1 (IL-1), and zymosan activated plasma (ZAP) to determine whether they might release extracellular ATP during in vitro infection. Calves experimentally exposed to M. haemolytica had an approximately 2-fold higher level of ATP in their BAL samples compared to control. BPE cells exposed to increasing numbers of heat-killed or live M. haemolytica had significantly increased levels of ATP release as compared to time-matched controls. Finally, BPE cells treated with several concentrations of LPS and IL-1 had increases in ATP release as compared to time-matched controls. This increase appeared to be a result of active ATP secretion by the cells, as cell viability was similar between treated and non-treated cells. Neither ZAP nor LTA induced any ATP release by the cells. In conclusion, ATP levels are elevated in lung secretions from calves infected with M. haemolytica. In addition, lung epithelial cells can actively release ATP when exposed to heat-killed or live M. haemolytica, LPS or IL-1. PMID:22771196

  18. Impaired function of regulatory T-cells in patients with chronic obstructive pulmonary disease (COPD).

    PubMed

    Tan, Dino B A; Fernandez, Sonia; Price, Patricia; French, Martyn A; Thompson, Philip J; Moodley, Yuben P

    2014-12-01

    Anti-inflammatory pathways affecting chronic obstructive pulmonary disease (COPD) are poorly understood. Regulatory T-cells (Tregs) are important negative regulators of T-cell activity and hence were investigated in COPD patients in this study. We hypothesised that functional defects in Tregs may promote increased inflammation contributing to the pathogenesis of COPD. Peripheral blood mononuclear cells (PBMC) were isolated from patients with stable COPD and age-matched non-smoking controls. Treg-mediated suppression of memory non-Treg (Foxp3(-)CD45RO(+)) CD4(+) T-cell activation was analysed by comparing PBMC responses to staphylococcal enterotoxin-B (SEB) pre- and post-depletion of Tregs (CD25(+)CD127(low)CD4(+) T-cells) by fluorescence-activated cell sorting (FACS). Activation of T-cells was assessed by HLA-DR expression. Levels of secreted cytokines were measured by ELISA. Depletion of Tregs increased SEB-induced activation of Foxp3(-)CD45RO(+) CD4(+) T-cells in samples from 15/15 healthy controls (demonstrating Treg-mediated suppression) and 9/14 COPD patients (Fisher's test, p=0.017). A screen of clinical data associated a failure of Treg-mediated suppression in the remaining five COPD patients with a higher body mass index (BMI) (33-38 kg/m(2)) compared to patients with unimpaired Treg function (20-32 kg/m(2)). In conclusion, we demonstrate impaired Treg-mediated suppression of CD4(+) T-cell activation in a subset of COPD patients, all of whom had high BMI. Obesity and/or perturbed homeostasis of Treg subsets may explain this defect and therefore contribute to increased inflammation observed in COPD. PMID:25097153

  19. Evaluation of Nanoclay Exfoliation Strategies for Thermoset Polyimide Nanocomposite Systems

    NASA Technical Reports Server (NTRS)

    Ginter, Michael J.; Jana, Sadhan C.; Miller, Sandi G.

    2007-01-01

    Prior works show exfoliated layered silicate reinforcement improves polymer composite properties. However, achieving full clay exfoliation in high performance thermoset polyimides remains a challenge. This study explores a new method of clay exfoliation, which includes clay intercalation by lower molecular weight PMR monomer under conditions of low and high shear and sonication, clay treatments by aliphatic and aromatic surfactants, and clay dispersion in primary, higher molecular weight PMR resin. Clay spacing, thermal, and mechanical properties were evaluated and compared with the best results available in literature for PMR polyimide systems.

  20. Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease

    PubMed Central

    Wallace, Kori L.

    2010-01-01

    We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1−/− mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation–induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation. PMID:20798237

  1. Fluticasone propionate and pentamidine isethionate reduce airway hyperreactivity, pulmonary eosinophilia and pulmonary dendritic cell response in a guinea pig model of asthma.

    PubMed

    Lawrence, T E; Millecchia, L L; Fedan, J S

    1998-01-01

    In this study, we examined the effects of fluticasone propionate (FP) and pentamidine isethionate (PI) on antigen-induced lung inflammation and airway hyperreactivity in guinea pigs. Male guinea pigs were sensitized on days 0 and 14 with 10 micrograms of ovalbumin (OVA) plus 1 mg of Al(OH)3. On day 21, animals were challenged with a 2% OVA aerosol inhalation until they developed pulmonary obstruction. Animals were treated with aerosol inhalation of FP (2 ml of 0.5 mg/ml, five consecutive doses at 12-hr intervals with the last dose given 6 hr before OVA challenge) or PI (30 mg/ml for 30 min 1 hr before OVA challenge), and control animals received no drug before OVA challenge. Airway reactivity to methacholine (MCh) was assessed before sensitization and 18 hr after OVA challenge. At 18 hr after challenge, histological sections of trachea and lung were examined for eosinophil, dendritic cell (DC) and macrophage cell densities in the airways. In control animals, OVA evoked airway hyperreactivity to MCh in conjunction with pulmonary eosinophilia and increases in DC prevalence in the trachea and bronchi. Treatment with FP or PI abolished the OVA-induced hyperresponsiveness and significantly reduced the OVA-induced increases in eosinophils and DCs in the airways. FP and PI had no effect on saline-treated animals. Our study indicates that both inhaled FP and inhaled PI reduce antigen-induced airway hyperreactivity and pulmonary inflammation in guinea pigs. The results also suggest that the DC is a target of the anti-inflammatory effects of these drugs in the airways. PMID:9435182

  2. Invasive Pulmonary Aspergillosis in a Haematopoietic Stem Cell Transplant Recipient with Sickle Cell Disease: a Successful Treatment

    PubMed Central

    Paciaroni, Katia; De Angelis, Gioia; Gallucci, Cristiano; Alfieri, Cecilia; Ribersani, Michela; Roveda, Andrea; Isgrò, Antonella; Marziali, Marco; Aloi, Ivan Pietro; Inserra, Alessandro; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2015-01-01

    Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated. PMID:25574365

  3. Invasive pulmonary aspergillosis in a haematopoietic stem cell transplant recipient with sickle cell disease: a successful treatment.

    PubMed

    Paciaroni, Katia; De Angelis, Gioia; Gallucci, Cristiano; Alfieri, Cecilia; Ribersani, Michela; Roveda, Andrea; Isgrò, Antonella; Marziali, Marco; Aloi, Ivan Pietro; Inserra, Alessandro; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2015-01-01

    Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated. PMID:25574365

  4. Hamster-adapted Sin Nombre virus causes disseminated infection and efficiently replicates in pulmonary endothelial cells without signs of disease.

    PubMed

    Safronetz, David; Prescott, Joseph; Haddock, Elaine; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki

    2013-04-01

    To date, a laboratory animal model for the study of Sin Nombre virus (SNV) infection or associated disease has not been described. Unlike infection with Andes virus, which causes lethal hantavirus pulmonary syndrome (HPS)-like disease in hamsters, SNV infection is short-lived, with no viremia and little dissemination. Here we investigated the effect of passaging SNV in hamsters. We found that a host-adapted SNV achieves prolonged and disseminated infection in hamsters, including efficient replication in pulmonary endothelial cells, albeit without signs of disease. PMID:23388711

  5. Unusual Development of Pulmonary Tumor Embolism from Controlled Liver Metastases of Transitional Cell Carcinoma: An Autopsy Case.

    PubMed

    Kitayama, Hiromitsu; Yokota, Taro; Kondo, Tomohiro; Sugiyama, Junko; Hirayama, Michiaki; Oyamada, Yumiko; Tsuji, Yasushi

    2016-01-01

    Clinicians generally suspect pulmonary tumor embolism (PTE) with uncontrolled carcinomas which often spread to lungs. We, however, experienced an autopsy case of diffuse microscopic PTE despite controlled liver metastases of transitional cell carcinoma (TCC). A 66-year-old man with progressing respiratory symptoms showed almost normal chest findings on computed tomography. Although liver metastases were successfully shrunk by chemotherapy, the patient died from aggressive respiratory failure. An autopsy revealed small pulmonary vessels showing diffuse tumor emboli. TCC can cause PTE even if liver metastases are controlled. We must therefore be aware that PTE can manifest as respiratory symptoms without any computed tomography findings. PMID:27580549

  6. GIANT CELL TUMOR IN THE PROXIMAL PHALANX WITH PULMONARY METASTASIS: CASE REPORT AND LITERATURE REVIEW

    PubMed Central

    de Medeiros, Frederico Carvalho; de Medeiros, Fernando Carvalho; de Campos Carvalho Lopes, Izabella; de Medeiros, Guilherme Carvalho; de Medeiros, Eduardo Carvalho

    2015-01-01

    This is a case report on a giant cell tumor (GCT) in the proximal phalanx of the third finger of the left hand, with pulmonary metastasis. The patient presented pain in the finger without any previous history of trauma. Clinical examination, radiographic imaging and magnetic resonance imaging were carried out. A histological evaluation was carried out from an incisional biopsy, taking the hypothesis of GCT. The patient underwent amputation of the finger and the diagnosis was confirmed by means of microscopy on the specimen. The patient was followed up because of the risk of lung metastasis, which was shown by radiographic examination and computed tomography on the chest, and thoracotomy was performed. Since then, there has been an improvement in the symptoms that had been reported preoperatively, and no local recurrence or new metastasis has been found. PMID:27027012

  7. Pulmonary Langerhans Cell Histiocytosis and Diabetes Insipidus in a Young Smoker

    PubMed Central

    Earlam, K.; Souza, C. A.; Glikstein, R.; Gomes, M. M.; Pakhalé, S.

    2016-01-01

    Langerhans cell histiocytosis is characterized by the abnormal nodular proliferation of histiocytes in various organ systems. Pulmonary involvement seen in young adults is nearly always seen in the context of past or current cigarette smoking. Although it tends to be a single-system disease, extrapulmonary manifestations involving the skin, bone, and hypothalamic-pituitary-axis are possible. High resolution CT (HRCT) of the thorax findings includes centrilobular nodules and cysts that are bizarre in shape, variable in size, and thin-walled. Often the diagnosis can be made based on the appropriate clinical presentation and typical imaging findings. Treatment includes smoking cessation and the potential use of glucocorticoids or cytotoxic agents depending on the severity of disease and multisystem involvement.

  8. Rare interstitial lung disease: Pulmonary Langerhans Cell Histiocytosis in a young non smoking Indian female.

    PubMed

    Fernandes, Lalita; Vadala, Rohit; Mesquita, Anthony Menezes; Vaideeswar, Pradeep

    2015-01-01

    Adult Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare interstitial lung disease which occurs almost exclusively in smokers. A marked male predominance was initially reported, but recent studies show both men and women are equally affected due to the increasing smoking habits in women. The natural history is variable with 25% of patients having asymptomatic disease while 10-20% progress rapidly to respiratory insufficiency and death. The diagnosis is not easily recognized by clinicians or pathologists. Awareness of the clinical presentation and classical HRCT findings helps in early diagnosis and management of this disease. We report a rare case of severe PLCH in a young non smoking female with a short history who progressed rapidly to respiratory failure and died. PMID:25857566

  9. Pulmonary embolus

    MedlinePlus

    ... blood clot; Blood clot - lung; Embolus; Tumor embolus; Embolism - pulmonary; DVT-pulmonary embolism; Thrombosis - pulmonary embolism ... x-ray CT angiogram of the chest Pulmonary ventilation/perfusion scan, also called a V/Q scan ...

  10. Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study.

    PubMed Central

    Masani, F

    1986-01-01

    The myocardial layer of the pulmonary vein of adult rats was examined by electron microscopy. Among ordinary myocardial cells resembling those of the atrial myocardium, clear cells with structural features similar to those of sinus node cells were identified. They were distributed in the intrapulmonary, preterminal portion of the pulmonary vein. They appeared singly or in small groups among the ordinary myocardial cells. Their cytoplasm was characterised by a paucity of myofilaments, irregular disposition of myofilament bundles, small and oval mitochondria, absence of atrial specific granules and a wide cytoplasmic matrix between intracellular organelles. The intercalated discs of node-like cells were composed of small junctional specialisations. Nerve fibres containing small and large vesicles with and without dense cores were juxtaposed to the node-like cells over an intercellular space of more than 200 nm. Taking into consideration physiological data, the possibility is discussed that the node-like cells may have a potential pacemaking activity and represent an ectopic pacemaker centre in the pulmonary vein. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:3429299

  11. Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells.

    PubMed

    Zhang, Shaojie; Patel, Ananddeep; Moorthy, Bhagavatula; Shivanna, Binoy

    2015-09-01

    Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants that is characterized by alveolar simplification and decreased lung angiogenesis. Hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD in premature infants. Adrenomedullin (AM) is an endogenous peptide with potent angiogenic, anti-oxidant, and anti-inflammatory properties. Whether AM regulates hyperoxic injury in fetal primary human lung cells is unknown. Therefore, we tested the hypothesis that AM-deficient fetal primary human pulmonary microvascular endothelial cells (HPMEC) will have increased oxidative stress, inflammation, and cytotoxicity compared to AM-sufficient HPMEC upon exposure to hyperoxia. Adrenomedullin gene (Adm) was knocked down in HPMEC by siRNA-mediated transfection and the resultant AM-sufficient and -deficient cells were evaluated for hyperoxia-induced oxidative stress, inflammation, cytotoxicity, and Akt activation. AM-deficient HPMEC had significantly increased hyperoxia-induced reactive oxygen species (ROS) generation and cytotoxicity compared to AM-sufficient HPMEC. Additionally, AM-deficient cell culture supernatants had increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, AM deficiency was associated with an abrogated Akt activation upon exposure to hyperoxia. These findings support the hypothesis that AM deficiency potentiates hyperoxic injury in primary human fetal HPMEC via mechanisms entailing Akt activation. PMID:26196743

  12. Regulation of Cell Cycle Regulators by SIRT1 Contributes to Resveratrol-Mediated Prevention of Pulmonary Arterial Hypertension

    PubMed Central

    Zhou, Shuang; Li, Meng-Tao; Jia, Yu-Yan; Liu, Jin-Jing; Wang, Qian; Tian, Zhuang; Liu, Yong-Tai; Chen, Hou-Zao; Liu, De-Pei; Zeng, Xiao-Feng

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in rheumatic diseases. Vascular remodeling due to the proliferation of pulmonary arterial smooth muscle cells (PASMCs) is central to the development of PAH. To date, it is still unclear if Silence Information Regulator 1 (SIRT1) regulates cell cycle regulators in the proliferation of PASMCs and contributes to prevention of PAH by resveratrol. In this study, we found that a significant decrease of SIRT1 expression levels in platelet-derived growth factor BB (PDGF-BB) treated human PASMCs (HPASMCs) and in monocrotaline (MCT) induced PAH rat. Overexpression of SIRT1 induced G1 phase arrest and increased p21 expression but decreased cyclin D1 expression in PDGF-BB treated HPASMCs. Moreover, resveratrol attenuated pulmonary arterial remodeling, decreased pulmonary arterial pressure, and upregulated SIRT1 and p21 expression but downregulated cyclin D1 expression in MCT induced PAH rat. Notably, knockdown of SIRT1 eliminated the regulation of resveratrol on p21 and cyclin D1 expression in PDGF-BB treated HPASMCs. These results demonstrated that SIRT1 mediated the regulation of resveratrol on the expression of cell cycle regulatory molecules. It suggests that SIRT1 exerts a protective role in PAH associated with rheumatic diseases and can be a potential treatment target. PMID:26273643

  13. Nitric oxide decreases the sensitivity of pulmonary endothelial cells to LPS-induced apoptosis in a zinc-dependent fashion.

    PubMed

    Tang, Zi-Lue; Wasserloos, Karla J; Liu, Xianghong; Stitt, Molly S; Reynolds, Ian J; Pitt, Bruce R; St Croix, Claudette M

    2002-01-01

    We hypothesized that: (a) S-nitrosylation of metallothionein (MT) is a component of pulmonary endothelial cell nitric oxide (NO) signaling that is associated with an increase in labile zinc; and (b) NO mediated increases in labile zinc in turn reduce the sensitivity of pulmonary endothelium to LPS-induced apoptosis. We used microspectrofluorometric techniques to show that exposing mouse lung endothelial cells (MLEC) to the NO-donor, S-nitrosocysteine, resulted in a 45% increase in fluorescence of the Zn2+-specific fluorophore, Zinquin, that was rapidly reversed by exposure to the Zn2+ chelator, NNN'N'-tetrakis-(2-pyridylmethyl)ethylenediamine; TPEN). The absence of a NO-mediated increase in labile Zn2+ in MLEC from MT-I and -II knockout mice inferred a critical role for MT in the regulation of Zn2+ homeostasis by NO. Furthermore, we found that prior exposure of cultured endothelial cells from sheep pulmonary artery (SPAEC), to the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP) reduced their sensitivity to lipopolysaccharide (LPS) induced apoptosis. The anti-apoptotic effects of NO were significantly inhibited by Zn2+ chelation with low doses of TPEN (10 microM). Collectively, these data suggest that S-nitrosylation of MT is associated with an increase in labile (TPEN chelatable) zinc and NO-mediated MT dependent zinc release is associated with reduced sensitivity to LPS-induced apoptosis in pulmonary endothelium. PMID:12162436

  14. Bilateral Pulmonary Embolism in an Adolescent with Sickle Cell Disease and a Recent Total Hip Arthroplasty: a Case Report and Review of the Literature

    PubMed Central

    Burnham, Jeremy M; Broussard, Marlene; Milbrandt, Todd

    2014-01-01

    Pulmonary embolism is a life-threatening but treatable condition. Factors such as hypercoagulability and recent lower extremity surgery are associated with a higher incidence of thrombus formation and pulmonary embolism. Patients with sickle cell disease have a baseline hypercoaguable state and are at a greater risk forming deep vein thrombosis and pulmonary embolism than the general population. This increased risk is rarely cited in the literature. We describe a sickle cell patient two-weeks status-post total hip arthroplasty who presented with bilateral pulmonary embolism complaining of chest and shoulder pain. We highlight the need to include pulmonary embolism in the differential diagnosis of all sickle cell patients complaining of chest pain. PMID:25328468

  15. Functional characterisation of human pulmonary monocyte-like cells in lipopolysaccharide-mediated acute lung inflammation

    PubMed Central

    2014-01-01

    Background We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR+CD14++CD16+cells) and inducible PMLC (iPMLC, HLA-DR+CD14++CD16- cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We have carried out the first functional evaluation of PMLC subpopulations in the inflamed lung, following the isolation of these cells, and other lineages, from BAL fluid using novel and complex protocols. Methods iPMLC, rPMLC, alveolar macrophages (AM), neutrophils, and regulatory T cells were quantified in BAL fluid of healthy subjects at 9 hours post-LPS inhalation (n = 15). Cell surface antigen expression by iPMLC, rPMLC and AM and the ability of each lineage to proliferate and to undergo phagocytosis were investigated using flow cytometry. Basal cytokine production by iPMLC compared to AM following their isolation from BAL fluid and the responsiveness of both cell types following in vitro treatment with the synthetic corticosteroid dexamethasone were assessed. Results rPMLC have a significantly increased expression of mature macrophage markers and of the proliferation antigen Ki67, compared to iPMLC. Our cytokine data revealed a pro-inflammatory, corticosteroid-resistant phenotype of iPMLC in this model. Conclusions These data emphasise the presence of functionally distinct subpopulations of the monocyte/macrophage lineage in the human lung in experimental acute lung inflammation. PMID:24684897

  16. Molecular Resolution in situ Imaging of Spontaneous Graphene Exfoliation.

    PubMed

    Elbourne, Aaron; McLean, Ben; Voïtchovsky, Kislon; Warr, Gregory G; Atkin, Rob

    2016-08-18

    All reported methods of graphene exfoliation require external energy input, most commonly from sonication,1 shaking,2 or stirring.3 The reverse process-aggregation of single or few layer graphene sheets-occurs spontaneously in most solvents. This makes producing, and especially storing, graphene in economic quantities challenging,4,5 which is a significant barrier to widespread commercialization. This study reveals ionic liquids (ILs) can spontaneously exfoliate graphene from graphite at room temperature. The process is thermally activated and follows an Arrhenius-type behavior, resulting in thermodynamically stable IL/graphene suspensions. Using atomic force microscopy, the kinetics of the exfoliation could be followed in situ and with subnanometer resolution, showing that both the size and the charge of the constituent IL ions play a key role. Our results provide a general molecular mechanism underpinning spontaneous graphene exfoliation at room temperature in electrically conducting ILs, paving the way for their adoption in graphene-based technology. PMID:27463824

  17. Adhesive tape exfoliation: Why it works for graphene

    NASA Astrophysics Data System (ADS)

    Bohr, Jakob

    2015-03-01

    Single-crystal graphite can be cleaved by the use of an adhesive tape. This was also the initial route for obtaining graphene, a one-layer thick graphite slab. In this letter a few simple and fun considerations are presented in an attempt to shed some light on why this procedure is successful. In particular on the nature of the surprisingly small number of repetitive steps that are needed in order to obtain a single-layer slab. Two frameworks for exfoliation are investigated: parallel exfoliation involving repetitive simultaneous cleaving, the other, serial exfoliation, which involves the repetitive cleaving of a single chunk of graphite. For both cases, parallel and serial exfoliation, it is investigated how many generations of cleavages are needed. An approximate model with the probability distribution expressed as a simple closed form is presented and compared with the simulations.

  18. Graphene Made by Mechanical Exfoliation of Graphite Intercalation Compound

    NASA Astrophysics Data System (ADS)

    Fukada, Seiya; Shintani, Yumi; Shimomura, Midori; Tahara, Fumiya; Yagi, Ryuta

    2012-08-01

    We report a method of making few-layer graphene flakes by mechanically exfoliating SbCl5-graphite intercalation compounds (GICs). The number of layers of exfoliated graphene flakes had a particular distribution relevant to the stage structure of the GICs. The carrier doping of the few-layer graphene flakes was about two orders of magnitude smaller than that expected from the stoichiometry of the GICs. The measured electric mobility was comparable to that made from pristine graphite.

  19. Identification of first exfoliative toxin in Staphylococcus pseudintermedius.

    PubMed

    Futagawa-Saito, Keiko; Makino, Shinichiroh; Sunaga, Fujiko; Kato, Yukio; Sakurai-Komada, Naomi; Ba-Thein, William; Fukuyasu, Tsuguaki

    2009-12-01

    Staphylococcus aureus, Staphylococcus hyicus, and Staphylococcus chromogenes are known to cause skin infections in human or animals by producing exfoliative toxins (ETs). Staphylococcus pseudintermedius can also cause canine pyoderma, but no exfoliative toxins or similar toxins have been reported. PCR with degenerate primers targeted to the conserved regions in ETA, ETB, and ETD from S. aureus and SHETB from S. hyicus, and subsequent chromosome walking identified a novel gene, designated as exi (exfoliative toxin of pseudintermedius) in S. pseudintermedius. EXI had significant homologies with the exfoliative toxins (43-68% identity), particularly with ETB (67.1%), ETD (67.9%), and SHETB (65.1%). Phylogenetic analysis showed close relation between EXI and ETB with a bootstrap value of 80%. Neonatal mice injected with the crude proteins from the culture supernatant or recombinant EXI showed gross blisters and/or characteristic skin exfoliation. The prevalence of exi assessed by dot-blot hybridization was 23.3% (10/43) in S. pseudintermedius isolates from canine pyoderma. The EXI reported herein is the first exfoliative toxin identified in S. pseudintermedius. PMID:19891731

  20. Hyperoxia enhanced the production of plasminogen activator by cultured pulmonary artery endothelial cells

    SciTech Connect

    Phillips, P.G.; Ryan, T.J.; Birnby, L.; Tsan, M.F. New York State Health Lab., Albany )

    1990-02-26

    Pulmonary artery endothelial cell (EC) monolayers exposed to hyperoxia show increased permeability to albumin and marked alterations in actin filament distribution. The mechanism for these cytoskeletal changes is unknown. The authors now report that cells exposed to hyperoxia (95% O{sub 2}) produce significant quantities of urokinase-type plasminogen activators (u-PA). Zymographic analysis revealed that plasminogen-dependent caseinolytic activity in conditioned media from O{sub 2}-exposed cells was several fold higher than controls, especially at 48 hr. Cell-associated lytic activity was markedly increased at 48 and 72 hr when oxidative effects on the cytoskeleton were most apparent. Amidolytic assays confirmed these findings. (1) Conditioned media, CTA U/ml (mean {+-} SEM): Control 0.73{+-}0.05 vs 48 hr O{sub 2} 2.09{+-}0.50, (2) Cell-associated activity (preparations enriched for adhesion plaques), CTA mU/10{sup 6} cells: Control 0.17{+-}0.06; O{sub 2}: 24 hr 0.18{+-}0.07; 48 hr 0.46{+-}0.08; 72 hr 0.48{+-}0.08; O{sub 2} 48 hr or 72 hr vs Control. Immunocytochemical analysis demonstrated breakdown and restructuring of fibronectin and collagen components of the extracellular matrix at 48 and 72 hours. They conclude that hyperoxia enhanced both PA production and dismantling of matrix by EC. These changes may in part be responsible for some of the actin filament alterations which occur in conjunction with O{sub 2}-induced permeability increases.

  1. Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation.

    PubMed

    Abram, Melanie; Wegmann, Michael; Fokuhl, Verena; Sonar, Sanchaita; Luger, Elke Olga; Kerzel, Sebastian; Radbruch, Andreas; Renz, Harald; Zemlin, Michael

    2009-04-15

    Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-kappaB subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease. PMID:19342646

  2. RNA-seq analysis of transcriptomes in thrombin-treated and control human pulmonary microvascular endothelial cells.

    PubMed

    Cheranova, Dilyara; Gibson, Margaret; Chaudhary, Suman; Zhang, Li Qin; Heruth, Daniel P; Grigoryev, Dmitry N; Ye, Shui Qing

    2013-01-01

    The characterization of gene expression in cells via measurement of mRNA levels is a useful tool in determining how the transcriptional machinery of the cell is affected by external signals (e.g. drug treatment), or how cells differ between a healthy state and a diseased state. With the advent and continuous refinement of next-generation DNA sequencing technology, RNA-sequencing (RNA-seq) has become an increasingly popular method of transcriptome analysis to catalog all species of transcripts, to determine the transcriptional structure of all expressed genes and to quantify the changing expression levels of the total set of transcripts in a given cell, tissue or organism. RNA-seq is gradually replacing DNA microarrays as a preferred method for transcriptome analysis because it has the advantages of profiling a complete transcriptome, providing a digital type datum (copy number of any transcript) and not relying on any known genomic sequence. Here, we present a complete and detailed protocol to apply RNA-seq to profile transcriptomes in human pulmonary microvascular endothelial cells with or without thrombin treatment. This protocol is based on our recent published study entitled "RNA-seq Reveals Novel Transcriptome of Genes and Their Isoforms in Human Pulmonary Microvascular Endothelial Cells Treated with Thrombin," in which we successfully performed the first complete transcriptome analysis of human pulmonary microvascular endothelial cells treated with thrombin using RNA-seq. It yielded unprecedented resources for further experimentation to gain insights into molecular mechanisms underlying thrombin-mediated endothelial dysfunction in the pathogenesis of inflammatory conditions, cancer, diabetes, and coronary heart disease, and provides potential new leads for therapeutic targets to those diseases. The descriptive text of this protocol is divided into four parts. The first part describes the treatment of human pulmonary microvascular endothelial cells with

  3. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis

    PubMed Central

    Gharib, Sina A.; Johnston, Laura K.; Huizar, Isham; Birkland, Timothy P.; Hanson, Josiah; Wang, Ying; Parks, William C.; Manicone, Anne M.

    2014-01-01

    Members of the MMP family function in various processes of innate immunity, particularly in controlling important steps in leukocyte trafficking and activation. MMP28 (epilysin) is a member of this family of proteinases, and we have found that MMP28 is expressed by macrophages and regulates their recruitment to the lung. We hypothesized that MMP28 regulates other key macrophage responses, such as macrophage polarization. Furthermore, we hypothesized that these MMP28-dependent changes in macrophage polarization would alter fibrotic responses in the lung. We examined the gene expression changes in WT and Mmp28−/− BMDMs, stimulated with LPS or IL-4/IL-13 to promote M1 and M2 cells, respectively. We also collected macrophages from the lungs of Pseudomonas aeruginosa-exposed WT and Mmp28−/− mice to evaluate changes in macrophage polarization. Lastly, we evaluated the macrophage polarization phenotypes during bleomycin-induced pulmonary fibrosis in WT and Mmp28−/− mice and assessed mice for differences in weight loss and total collagen levels. We found that MMP28 dampens proinflammatory macrophage function and promots M2 programming. In both in vivo models, we found deficits in M2 polarization in Mmp28−/− mice. In bleomycin-induced lung injury, these changes were associated with reduced fibrosis. MMP28 is an important regulator of macrophage polarization, promoting M2 function. Loss of MMP28 results in reduced M2 polarization and protection from bleomycin-induced fibrosis. These findings highlight a novel role for MMP28 in macrophage biology and pulmonary disease. PMID:23964118

  4. Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth.

    PubMed

    Laube, Mandy; Stolzing, Alexandra; Thome, Ulrich H; Fabian, Claire

    2016-05-01

    Preterm infants frequently suffer from pulmonary complications resulting in significant morbidity and mortality. Physiological and structural lung immaturity impairs perinatal lung transition to air breathing resulting in respiratory distress. Mechanical ventilation and oxygen supplementation ensure sufficient oxygen supply but enhance inflammatory processes which might lead to the establishment of a chronic lung disease called bronchopulmonary dysplasia (BPD). Current therapeutic options to prevent or treat BPD are limited and have salient side effects, highlighting the need for new therapeutic approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in animal models of BPD. This review focuses on MSC-based therapeutic approaches to treat pulmonary complications and critically compares results obtained in BPD models. Thereby bottlenecks in the translational systems are identified that are preventing progress in combating BPD. Notably, current animal models closely resemble the so-called "old" BPD with profound inflammation and injury, whereas clinical improvements shifted disease pathology towards a "new" BPD in which arrest of lung maturation predominates. Future studies need to evaluate the utility of MSC-based therapies in animal models resembling the "new" BPD though promising in vitro evidence suggests that MSCs do possess the potential to stimulate lung maturation. Furthermore, we address the mode-of-action of MSC-based therapies with regard to lung development and inflammation/fibrosis. Their therapeutic efficacy is mainly attributed to an enhancement of regeneration and immunomodulation due to paracrine effects. In addition, we discuss current improvement strategies by genetic modifications or precondition of MSCs to enhance their therapeutic efficacy which could also prove beneficial for BPD therapies. PMID:26928452

  5. BioGraphene: Direct Exfoliation of Graphite in a Kitchen Blender for Enzymology Applications.

    PubMed

    Kumar, C V; Pattammattel, A

    2016-01-01

    A high yielding method for the aqueous exfoliation of graphite crystals to produce high quality graphene nanosheets in a kitchen blender is described here. Bovine serum albumin (BSA), β-lactoglobulin, ovalbumin, lysozyme, and hemoglobin as well as calf serum were used for the exfoliation of graphene. Among these, BSA gave the maximum exfoliation efficiency, exceeding 4mgmL(-1)h(-1) of graphene. Quality of graphene produced was examined by Raman spectroscopy, which indicated 3-5 layer graphene of very high quality and very low levels of defects. Transmission electron microscopy indicated an average size of ~0.5μm flakes. The graphene/BSA dispersions were stable over pH 3.0-11, and at 5°C or 50°C, for more than 2 months. Current approach gave higher rates of BSA/graphene (BioGraphene) in better yields than other methods. Calf serum, when used in place of BSA, also gave high yields of good quality BioGraphene and these preparations may be of direct use for cell culture studies. A simple example of BioGraphene preparation is described that can be adapted in most laboratories, and graphene-adsorbed glucose oxidase is nearly as active as the free enzyme. Current approach may facilitate large-scale production of graphene in most laboratories around the world and it may open new opportunities for biological applications of graphene. PMID:27112402

  6. Swelling, intercalation, and exfoliation behavior of layered ruthenate derived from layered potassium ruthenate

    SciTech Connect

    Fukuda, Katsutoshi; Kato, Hisato; Sato, Jun; Sugimoto, Wataru; Takasu, Yoshio

    2009-11-15

    The intercalation chemistry of a layered protonic ruthenate, H{sub 0.2}RuO{sub 2.1}.nH{sub 2}O, derived from a layered potassium ruthenate was studied in detail. Three phases with different hydration states were isolated, H{sub 0.2}RuO{sub 2.1}.nH{sub 2}O (n={approx}0, 0.5, 0.9), and its reactivity with tetrabutylammonium ions (TBA{sup +}) was considered. The layered protonic ruthenate mono-hydrate readily reacted with TBA{sup +}, affording direct intercalation of bulky tetrabutylammonium ions into the interlayer gallery. Fine-tuning the reaction conditions allowed exfoliation of the layered ruthenate into elementary nanosheets and thereby a simplified one-step exfoliation was achieved. Microscopic observation by atomic force microscopy and transmission electron microscopy clearly showed the formation of unilamellar sheets with very high two-dimensional anisotropy, a thickness of only 1.3+-0.1 nm. The nanosheets were characterized by two-dimensional crystallites with the oblique cell of a=0.5610(8) nm, b=0.5121(6) nm and gamma=109.4(2){sup o} on the basis of in-plane diffraction analysis. - Graphical abstract: Layered protonic ruthenate derived from a potassium form was directly reacted with bulky tetrabutylammonium ions to trigger exfoliation into nanosheets as long as it is highly hydrated.

  7. Translocation of left inferior lobe pulmonary artery to the pulmonary artery trunk for central type non-small cell lung cancers

    PubMed Central

    Sun, Yifeng; Yang, Yang; Chen, Yong; Pan, Xufeng; Yang, Yu; Gao, Wen

    2016-01-01

    Background The purpose of this study was to report on a technique for translocation of the left inferior lobar pulmonary artery (PA) to the PA trunk associated with bronchial sleeve resection of the left superior lobe in the treatment of bronchogenic cancer. Methods The clinical data of four non-small-cell lung cancer (NSCLC) patients with translocation of the left inferior lobar PA to the PA trunk associated with bronchial sleeve resection of the left superior lobe was retrospectively reviewed between June 13, 2014 and June 8, 2015. A reconstruction of the left pulmonary arteries was performed by translocating the left inferior lobar PA to the PA trunk with end-to-side anastomosis, sleeve resection of bronchus, and systemic lymphadenectomy. Results Histology confirmed squamous carcinoma in these four cases. Stage pT3N2M0-IIIA was confirmed in 2 cases, pT3N1M0-IIIA in 1 case, and pT3N0M0-IIB in 1 case. No perioperative deaths or complications were observed. Four patients underwent postoperative chemotherapies, and the end of follow-ups date was Oct. 21, 2015. Conclusions Translocation of the left inferior lobar PA to the PA trunk is practicable as a lung-sparing procedure, despite being technically challenging. PMID:27162655

  8. Inhibitory effect of Bailing capsule on hypoxia-induced proliferation of rat pulmonary arterial smooth muscle cells

    PubMed Central

    Li, Xiaohui; Peng, Kejun; Zhou, Yutian; Deng, Fengmei; Ma, Jiao

    2016-01-01

    Objectives: To investigated the effects of Bailing capsule on hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). Methods: This prospective study was performed at the Central Laboratory, Chengdu Medical College, Chengdu, China between April 2012 and November 2014. Ten healthy adult male Wistar rats were administrated with gastric perfusion of Bailing capsule to obtain serum containing the tested drugs. Proliferation of pulmonary arterial smooth muscle cells proliferation was measured using cell counting kit-8 assay. Production of reactive oxygen species (ROS) in rat PASMCs was determined through a fluorometric assay, whereas production of endothelin-1 (ET-1) was detected by ELISA and quantitative real-time PCR (qRT-PCR). Expression of proliferating cell nuclear antigen (PCNA), c-fos, and c-jun in PASMCs was also determined using immunohistochemistry staining and qRT-PCR. Results: We observed that the medicated serum obviously inhibited hypoxia-induced cell proliferation in a concentration-dependent manner. Moreover, the medicated serum significantly reduced hypoxia-induced production of ROS and ET-1, as well as expression of PCNA, c-fos, and c-jun, in PASMCs. Conclusion: Results demonstrated that Bailing capsule can inhibit hypoxia-induced PASMC proliferation possibly by suppressing ET-1 and ROS production and by inhibiting expression of PCNA, c-fos, and c-jun. These results suggest that Bailing possess antiproliferative property, which is probably one of the underlying mechanisms of Bailing capsule for the clinical treatment of chronic obstructive pulmonary disease. PMID:27146611

  9. IL-27 enhances innate immunity of human pulmonary fibroblasts and epithelial cells through upregulation of TLR4 expression.

    PubMed

    Su, Yufeng; Yao, Hua; Wang, Hong; Xu, Fang; Li, Dagen; Li, Dairong; Zhang, Xuemei; Yin, Yibing; Cao, Ju

    2016-01-15

    Lung tissue cells play an active role in the pathogenesis of pulmonary inflammatory diseases by releasing a variety of cytokines and chemokines. However, how lung tissue cells respond to microbial stimuli during pulmonary infections remains unclear. In this study, we found that patients with community-acquired pneumonia displayed increased IL-27 levels in bronchoalveolar lavage fluid and serum. We subsequently examined the immunopathological mechanisms for the activation of primary human lung fibroblasts and bronchial epithelial cells by IL-27. We demonstrated that IL-27 priming enhanced LPS-induced production of IL-6 and IL-8 from lung fibroblasts and bronchial epithelia cells via upregulating Toll-like receptor-4 (TLR4) expression. IL-27 upregulated TLR4 expression in lung fibroblasts through activation of Janus-activated kinase (JAK) and Jun NH2-terminal kinase (JNK) signaling pathways, and inhibition of the JAK pathway could partially decrease IL-27-induced TLR4 expression, while inhibition of JNK pathway could completely suppress IL-27-induced TLR4 expression. Our data suggest that IL-27 modulates innate immunity of lung tissue cells through upregulating TLR4 expression during pulmonary infections. PMID:26608531

  10. Therapeutic expansion of CD4+FoxP3+ regulatory T cells limits allergic airway inflammation during pulmonary fungal infection.

    PubMed

    Schulze, Bianca; Piehler, Daniel; Eschke, Maria; Heyen, Laura; Protschka, Martina; Köhler, Gabriele; Alber, Gottfried

    2016-06-01

    Allergic asthma can be frequently caused and exacerbated by sensitization to ubiquitous fungal allergens associated with pulmonary mucus production, airway hyperresponsiveness and bronchial constriction, resulting in a complex disease that is often difficult to treat. Fungal infections are frequently complicated by the development of a type 2 immune response that prevents successful elimination of the fungal pathogen. Furthermore, production of type 2 cytokines triggers allergic airway inflammation. Following intranasal infection of BALB/c mice with the fungusCryptococcus neoformans, we recently described a more pronounced type 2 immune response in the absence of regulatory T (Treg) cells. To determine whether Treg cell expansion is able to suppress type 2-related fungal allergic inflammation, we increased Treg cell numbers during pulmonaryC. neoformansinfection by administration of an interleukin (IL)-2/anti-IL-2 complex. Expansion of Treg cells resulted in reduced immunoglobulin E production and decreased allergic airway inflammation including reduced production of pulmonary mucus and type 2 cytokines as well as production of immunosuppressive cytokines such as IL-10 and transforming growth factor-β1. From our data we conclude that Treg cells and/or their suppressive mediators represent potential targets for therapeutic intervention during allergic fungal airway disease. PMID:27001975

  11. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines

    PubMed Central

    Wallace, Kori L.; Marshall, Melissa A.; Ramos, Susan I.; Lannigan, Joanne A.; Field, Joshua J.; Strieter, Robert M.

    2009-01-01

    Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69+, interferon-γ+ [IFN-γ+]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-γ, IFN-γ–inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN-γ and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1−/− mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN-γ and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease. PMID:19433855

  12. Preferential metabolism of N-nitrosodiethylamine by two cell lines derived from human pulmonary adenocarcinomas

    SciTech Connect

    Falzon, M.; McMahon, J.B.; Gazdar, A.F.; Schuller, H.M.

    1986-01-01

    Diethylnitrosamine (DEN), in common with other nitrosamines, is a carcinogenic agent which produces tumors in a wide variety of tissues in experimental animals. The pulmonary Clara cell is a major target of N-nitrosamine-induced carcinogenesis in hamsters and rats. DEN is believed to require metabolic activation to elicit its carcinogenic effects. The metabolism of (/sup 14/C)DEN was studied in two cell lines derived from human lung adenocarcinomas and two cell lines derived from human small cell lung cancers by monitoring /sup 14/CO/sub 2/ production and covalent binding of radiolabel from (/sup 14/C)DEN to the cell protein and DNA fractions. (/sup 14/C)DEN was metabolized by adenocarcinoma-derived NCI-H322 (with Clara cell features) and NCI-H358 (with features of alveolar type II cells) but not by NCI-H69 and NCI-H128 (derived from small cell carcinoma). Metabolism was markedly inhibited by heat denaturation of the cell protein. (/sup 14/C)DEN metabolism by NCI-H322 was greatly decreased when the incubation was carried out under anaerobic conditions and in the presence of a carbon monoxide enriched atmosphere. These results suggested the involvement of the cytochrome P-450-dependent monooxygenase enzyme system. Metabolism by NCI-H358 was also decreased in the absence of oxygen or presence of carbon monoxide although the effects were relatively small compared with the results with NCI-H322. On the other hand, aspirin or indomethacin, which are inhibitors of the fatty acid cyclooxygenase component of prostaglandin endoperoxide synthetase, preferentially inhibited (/sup 14/C)DEN metabolism by NIC-H358. There were little or no effects of these inhibitors on the metabolism of DEN in NCI-H322. The data suggest that DEN metabolism in different lung cell types may be carried out by different enzyme systems which in turn may contribute to the selective effect of DEN in the lung.

  13. Glucocorticoids regulate surfactant protein synthesis in a pulmonary adenocarcinoma cell line

    SciTech Connect

    O'Reilly, M.A.; Gazdar, A.F.; Clark, J.C.; Pilot-Matias, T.J.; Wert, S.E.; Hull, W.M.; Whitsett, J.A. )

    1989-12-01

    Synthesis of pulmonary surfactant proteins SP-A, SP-B, and SP-C was demonstrated in a cell line derived from a human adenocarcinoma of the lung. The cells contained numerous lamellar inclusion bodies and formed organized groups of cells containing well-developed junctional complexes and apical microvillous membranes. Synthesis of SP-A was detected in the cells by enzyme-linked immunoabsorbent assay and by immunoprecipitation of (35S)methionine-labeled protein. SP-A was identified as an Mr 31,000-36,000 polypeptide containing asparagine-linked carbohydrate. Northern blot analysis detected SP-A mRNA of 2.2 kb. Dexamethasone (1-10 nM) enhanced the relative abundance of SP-A mRNA. Despite stimulation of SP-A mRNA, intracellular SP-A content was unaltered or inhibited by dexamethasone. SP-B and SP-C mRNAs and synthesis of the SP-B and SP-C precursors were markedly induced by dexamethasone. ProSP-B was synthesized and secreted primarily as an Mr 42,000-46,000 polypeptide. Proteolysis of the proSP-B resulted in the generation of endoglycosidase F-sensitive Mr = 19,000-21,000 and 25,000-27,000 peptides, which were detected both intra- and extracellularly. SP-C proprotein of Mr = 22,000 and smaller SP-C fragments were detected intracellularly but were not detected in the media. Mature forms of SP-B (Mr = 8,000) and SP-C (Mr = 4,000) were not detected. Glucocorticoids directly enhance the relative synthesis and mRNA of the surfactant proteins SP-A, SP-B, and SP-C. Discrepancies among SP-A mRNA, its de novo synthesis, and cell content suggest that glucocorticoid may alter both pre- and posttranslational factors modulating SP-A expression.

  14. Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

    PubMed Central

    Ueno, Keigo; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-01-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  15. Dendritic cell-based immunization ameliorates pulmonary infection with highly virulent Cryptococcus gattii.

    PubMed

    Ueno, Keigo; Kinjo, Yuki; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-04-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  16. Influence of Rho kinase inhibitor Fasudil on late endothelial progenitor cells in peripheral blood of COPD patients with pulmonary artery hypertension.

    PubMed

    Liu, Pei; Zhang, Hongmei; Tang, Yijun; Sheng, Chunfeng; Liu, Jianxin; Zeng, Yanjun

    2014-02-01

    The objective of our work was to investigate the influence of Fasudil, a Rho inhibitor on the number and function of the late endothelial progenitor cells in peripheral blood of chronic obstructive pulmonary diseases (COPD) patients with pulmonary artery hypertension. Eighty COPD patients with pulmonary artery hypertension were selected and divided into two groups: the treatment group and the control group, which had 40 patients respectively. The control group received routine treatment, including oxygen uptake, anti-infection and phlegm dissolving. The treatment group received the Fasudil in addition to the routine treatment. The changes on the number and function of the late endothelial progenitor cells in peripheral blood of the patients before and after the treatment were compared between the two groups. The changes on the pulmonary artery pressure were also compared. The number of the late endothelial progenitor cells in peripheral blood of the treatment group increased and the function was enhanced. The pulmonary artery pressure was reduced. The difference before and after the treatment and with the control group was statistically significant (p<0.05). The changes on the number and function of the late endothelial progenitor cells in peripheral blood and the pulmonary artery pressure before and after the treatment of the control group were not statistically significant (p>0.05). The Rho-kinase inhibitor Fasudil increased the number and enhanced the function of the late endothelial progenitor cells in peripheral blood of COPD patients with pulmonary artery hypertension. PMID:24579970

  17. NO Hyperpolarizes Pulmonary Artery Smooth Muscle Cells and Decreases the Intracellular Ca2+ Concentration by Activating Voltage-Gated K+ Channels

    NASA Astrophysics Data System (ADS)

    Yuan, Xiao-Jian; Tod, Mary L.; Rubin, Lewis J.; Blaustein, Mordecai P.

    1996-09-01

    NO causes pulmonary vasodilation in patients with pulmonary hypertension. In pulmonary arterial smooth muscle cells, the activity of voltage-gated K+ (KV) channels controls resting membrane potential. In turn, membrane potential is an important regulator of the intracellular free calcium concentration ([Ca2+]i) and pulmonary vascular tone. We used patch clamp methods to determine whether the NO-induced pulmonary vasodilation is mediated by activation of KV channels. Quantitative fluorescence microscopy was employed to test the effect of NO on the depolarization-induced rise in [Ca2+]i. Blockade of KV channels by 4-aminopyridine (5 mM) depolarized pulmonary artery myocytes to threshold for initiation of Ca2+ action potentials, and thereby increased [Ca2+]i. NO (≈ 3 μ M) and the NO-generating compound sodium nitroprusside (5-10 μ M) opened KV channels in rat pulmonary artery smooth muscle cells. The enhanced K+ currents then hyperpolarized the cells, and blocked Ca2+-dependent action potentials, thereby preventing the evoked increases in [Ca2+]i. Nitroprusside also increased the probability of KV channel opening in excised, outside-out membrane patches. This raises the possibility that NO may act either directly on the channel protein or on a closely associated molecule rather than via soluble guanylate cyclase. In isolated pulmonary arteries, 4-aminopyridine significantly inhibited NO-induced relaxation. We conclude that NO promotes the opening of KV channels in pulmonary arterial smooth muscle cells. The resulting membrane hyperpolarization, which lowers [Ca2+]i, is apparently one of the mechanisms by which NO induces pulmonary vasodilation.

  18. Type 2 diabetes mellitus is associated with altered CD8+ T and natural killer cell function in pulmonary tuberculosis

    PubMed Central

    Kumar, Nathella P; Sridhar, Rathinam; Nair, Dina; Banurekha, Vaithilingam V; Nutman, Thomas B; Babu, Subash

    2015-01-01

    Type 2 diabetes mellitus (DM) is associated with expanded frequencies of mycobacterial antigen-specific CD4+ T helper type 1 (Th1) and Th17 cells in individuals with active pulmonary tuberculosis (TB). No data are available on the role of CD8+ T and natural killer (NK) cells in TB with coincident DM. To identify the role of CD8+ T and NK cells in pulmonary TB with diabetes, we examined mycobacteria-specific immune responses in the whole blood of individuals with TB and DM (TB-DM) and compared them with those without DM (TB-NDM). We found that TB-DM is characterized by elevated frequencies of mycobacterial antigen-stimulated CD8+ T cells expressing type 1 [interferon-γ and interleukin-2 (IL-2)] and type 17 (IL-17F) cytokines. We also found that TB-DM is characterized by expanded frequencies of TB antigen-stimulated NK cells expressing type 1 (tumour necrosis factor-α) and type 17 (IL-17A and IL-17F) cytokines. In contrast, CD8+ T cells were associated with significantly diminished expression of the cytotoxic markers perforin, granzyme B and CD107a both at baseline and following antigen or anti-CD3 stimulation, while NK cells were associated with significantly decreased antigen-stimulated expression of CD107a only. This was not associated with alterations in CD8+ T-cell or NK cell numbers or subset distribution. Therefore, our data suggest that pulmonary TB complicated with type 2 DM is associated with an altered repertoire of cytokine-producing and cytotoxic molecule-expressing CD8+ T and NK cells, possibly contributing to increased pathology. PMID:25363329

  19. P. falciparum isolate-specific distinct patterns of induced apoptosis in pulmonary and brain endothelial cells.

    PubMed

    N'Dilimabaka, Nadine; Taoufiq, Zacharie; Zougbédé, Sergine; Bonnefoy, Serge; Lorthiois, Audrey; Couraud, Pierre Oliver; Rebollo, Angelita; Snounou, Georges; Mazier, Dominique; Moreno Sabater, Alicia

    2014-01-01

    The factors implicated in the transition from uncomplicated to severe clinical malaria such as pulmonary oedema and cerebral malaria remain unclear. It is known that alterations in vascular integrity due to endothelial cell (EC) activation and death occur during severe malaria. In this study, we assessed the ability of different P. falciparum clinical isolates to induce apoptosis in ECs derived from human lung and brain. We observed that induction of EC apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the cell, though it was not correlated to the ability of the parasite to cytoadhere. Moreover, the extent of induced apoptosis in the two EC types varied with the isolate. Analysis of parasite genes transcript led us to propose that the activation of different pathways, such as Plasmodium apoptosis-linked pathogenicity factors (PALPF), PALPF-2, PALPF-5 and PF11_0521, could be implied in EC death. These observations provide an experimental framework to decipher the molecular mechanism implicated in the genesis of severe malaria. PMID:24686750

  20. P. falciparum Isolate-Specific Distinct Patterns of Induced Apoptosis in Pulmonary and Brain Endothelial Cells

    PubMed Central

    N'Dilimabaka, Nadine; Bonnefoy, Serge; Lorthiois, Audrey; Couraud, Pierre Oliver; Rebollo, Angelita; Snounou, Georges; Mazier, Dominique; Moreno Sabater, Alicia

    2014-01-01

    The factors implicated in the transition from uncomplicated to severe clinical malaria such as pulmonary oedema and cerebral malaria remain unclear. It is known that alterations in vascular integrity due to endothelial cell (EC) activation and death occur during severe malaria. In this study, we assessed the ability of different P. falciparum clinical isolates to induce apoptosis in ECs derived from human lung and brain. We observed that induction of EC apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the cell, though it was not correlated to the ability of the parasite to cytoadhere. Moreover, the extent of induced apoptosis in the two EC types varied with the isolate. Analysis of parasite genes transcript led us to propose that the activation of different pathways, such as Plasmodium apoptosis–linked pathogenicity factors (PALPF), PALPF-2, PALPF-5 and PF11_0521, could be implied in EC death. These observations provide an experimental framework to decipher the molecular mechanism implicated in the genesis of severe malaria. PMID:24686750

  1. Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease

    PubMed Central

    Yuditskaya, Susan; Tumblin, Ashaunta; Hoehn, Gerard T.; Wang, Guanghui; Drake, Steven K.; Xu, Xiuli; Ying, Saixia; Chi, Amy H.; Remaley, Alan T.; Shen, Rong-Fong; Munson, Peter J.; Suffredini, Anthony F.

    2009-01-01

    Pulmonary arterial hypertension (PAH) is emerging as a major complication and independent risk factor for death among adults with sickle cell disease (SCD). Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS), we searched for biomarkers of PAH in plasma specimens from 27 homozygous sickle cell anemia (HbSS) patients with PAH and 28 without PAH. In PAH patients, analysis consistently showed lower abundance of a 28.1-kDa peak (P < .001), identified by high-resolution mass spectrometry as the oxidant-scavenging protein apolipoprotein A-I (apoA-I), which correlated with clinical assays of apoA-I (r = .58, P < .001) and high-density lipoprotein (HDL) levels (r = .50, P = .001). Consistent with endothelial dysfunction that may mediate this effect in PAH, HbSS patients with lower apoA-I levels also displayed impaired vasodilatory responses to acetylcholine (mean ± SEM, 189% ± 34% [n = 13] vs 339% ± 51% [n = 13], P < .001). As a group, patients with SCD demonstrated significantly lower apoA-I levels than African-American control subjects. The PAH cohort was further characterized by high levels of apolipoproteins A-II and B and serum amyloid A, and low levels of haptoglobin dimers and plasminogen. These results imply a relationship of apolipoproteins to the development of PAH vasculopathy in SCD, potentially involving an unexpected mechanistic parallel to atherosclerosis, another proliferative vasculopathy. PMID:19023114

  2. Force control of endothelium permeability in mechanically stressed pulmonary micro-vascular endothelial cells.

    PubMed

    Wang, Bin; Caluch, Adam; Fodil, Redouane; Féréol, Sophie; Zadigue, Patricia; Pelle, Gabriel; Louis, Bruno; Isabey, Daniel

    2012-01-01

    Mechanical factors play a key role in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) as contributing to alveolo-capillary barrier dysfunction. This study aims at elucidating the role of the cytoskeleton (CSK) and cell-matrix adhesion system in the stressed endothelium and more precisely in the loss of integrity of the endothelial barrier. We purposely develop a cellular model made of a monolayer of confluent Human Pulmonary Microvascular Endothelial Cells (HPMVECs) whose cytoskeleton (CSK) is directly exposed to sustained cyclic mechanical stress for 1 and 2 h. We used RGD-coated ferromagnetic beads and measured permeability before and after stress application. We find that endothelial permeability increases in the stressed endothelium, hence reflecting a loss of integrity. Structural and mechanical results suggest that this endothelial barrier alteration would be due to physically-founded discrepancies in latero-basal reinforcement of adhesion sites in response to the global increase in CSK stiffness or centripetal intracellular forces. Basal reinforcement of adhesion is presently evidenced by the marked redistribution of αvβ3 integrin with cluster formation in the stressed endothelium. PMID:22766716

  3. Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling

    PubMed Central

    Chow, Kelsey; Fessel, Joshua P.; KaoriIhida-Stansbury; Schmidt, Eric P.; Gaskill, Christa; Alvarez, Diego; Graham, Brian; Harrison, David G.; Wagner, David H.; Nozik-Grayck, Eva; West, James D.; Klemm, Dwight J.; Majka, Susan M.

    2013-01-01

    Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of lung mesenchymal stem cells (MSCs) in these processes. We tested the hypothesis that dysfunctional lung MSCs directly participate in remodeling of the microcirculation. We employed a genetic model to deplete extracellular superoxide dismutase (EC-SOD) in lung MSCs coupled with lineage tracing analysis. We crossed floxpsod3 and mT/mG reporter mice to a strain expressing Cre recombinase under the control of the ABCG2 promoter. We demonstrated In vivo that depletion of EC-SOD in lung MSCs resulted in their contribution to microvascular remodeling in the smooth muscle actin positive layer. We further characterized lung MSCs to be multipotent vascular precursors, capable of myofibroblast, endothelial and pericyte differentiation in vitro. EC-SOD deficiency in cultured lung MSCs accelerated proliferation and apoptosis, restricted colony-forming ability, multilineage differentiation potential and promoted the transition to a contractile phenotype. Further studies correlated cell dysfunction to alterations in canonical Wnt/β-catenin signaling, which were more evident under conditions of oxidative stress. Our data establish that lung MSCs are a multipotent vascular precursor population, a population which has the capacity to participate in vascular remodeling and their function is likely regulated in part by the Wnt/β-catenin signaling pathway. These studies highlight an important role for microenviromental regulation of multipotent MSC function as well as their potential to contribute to tissue remodeling. PMID:23662173

  4. Primary pulmonary T-cell lymphoma mimicking pneumonia: A case report and literature review

    PubMed Central

    YANG, LINGYI; FENG, WEI; CHEN, CHENG; ZHANG, XIUQIN; ZHU, YEHAN; LEI, WEI; HUANG, JIAN-AN

    2016-01-01

    Primary pulmonary T-cell lymphoma is an extremely rare neoplasm. The present study describes the case of an elderly male patient who was admitted to hospital with initial symptoms including a fever, coughing and dyspnea. A chest computed tomography scan detected pneumonia-like features, including multiple variable nodules, ground-glass opacities, patchy infiltration and subpleural consolidation, which progressed rapidly. No mediastinal or hilar adenopathy was noted. The patient was initially diagnosed with severe pneumonia; however, the patient developed severe respiratory failure and extensive progression in radiographic manifestation despite receiving a combination treatment of broad-spectrum antibiotics and antifungal agents. Negative results were obtained for anti-nuclear antibodies and anti-neutrophil cytoplasmic antibody assays, which eliminated the possibility that the patient was affected by a connective tissue disease. A bronchoscopy with transbronchial lung biopsy was not performed on account of intolerance. A histological examination, which was performed using specimens obtained via video-assisted thoracoscopic surgery, allowed the final diagnosis of T-cell lymphoma to be confirmed. Unfortunately, the patient succumbed to respiratory failure and a probable thoracic hemorrhage prior to the initiation of chemotherapy. PMID:27347063

  5. First Line of Defense: Innate Cell-Mediated Control of Pulmonary Aspergillosis

    PubMed Central

    Espinosa, Vanessa; Rivera, Amariliz

    2016-01-01

    Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis. PMID:26973640

  6. Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival

    SciTech Connect

    Borst, Gerben R.; Jaeger, Katrien de; Belderbos, Jose; Burgers, Sjaak A.; Lebesque, Joos V. . E-mail: j.lebesque@nki.nl

    2005-07-01

    Purpose: To evaluate the changes in pulmonary function after high-dose radiotherapy (RT) for non-small-cell lung cancer in patients with a long-term disease-free survival. Methods and Materials: Pulmonary function was measured in 34 patients with inoperable non-small-cell lung cancer before RT and at 3 and 18 months of follow-up. Thirteen of these patients had a pulmonary function test (PFT) 36 months after RT. The pulmonary function parameters (forced expiratory volume in 1 s [FEV{sub 1}], diffusion capacity [T{sub lcoc}], forced vital capacity, and alveolar volume) were expressed as a percentage of normal values. Changes were expressed as relative to the pre-RT value. We evaluated the impact of chronic obstructive pulmonary disease, radiation pneumonitis, mean lung dose, and PFT results before RT on the changes in pulmonary function. Results: At 3, 18, and 36 months, a significant decrease was observed for the T{sub lcoc} (9.5%, 14.6%, and 22.0%, respectively) and the alveolar volume (5.8%, 6.6%, and 15.8%, respectively). The decrease in FEV{sub 1} was significant at 18 and 36 months (8.8% and 13.4%, respectively). No recovery of any of the parameters was observed. Chronic obstructive pulmonary disease was an important risk factor for larger PFT decreases. FEV{sub 1} and T{sub lcoc} decreases were dependent on the mean lung dose. Conclusion: A significant decrease in pulmonary function was observed 3 months after RT. No recovery in pulmonary function was seen at 18 and 36 months after RT. The decrease in pulmonary function was dependent on the mean lung dose, and patients with chronic obstructive pulmonary disease had larger reductions in the PFTs.

  7. 8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway

    SciTech Connect

    Ma, Jun; Zhang, Lei; Li, Shanshan; Liu, Shulin; Ma, Cui; Li, Weiyang; Falck, J.R.; Manthati, Vijay L.; Reddy, D. Sudarshan; Medhora, Meetha; Jacobs, Elizabeth R.; Zhu, Daling

    2010-08-15

    Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) catalyzed by cytochrome P450 (CYP), have many essential biologic roles in the cardiovascular system including inhibition of apoptosis in cardiomyocytes. In the present study, we tested the potential of 8,9-EET and derivatives to protect pulmonary artery smooth muscle cells (PASMCs) from starvation induced apoptosis. We found 8,9-epoxy-eicos-11(Z)-enoic acid (8,9-EET analog (214)), but not 8,9-EET, increased cell viability, decreased activation of caspase-3 and caspase-9, and decreased TUNEL-positive cells or nuclear condensation induced by serum deprivation (SD) in PASMCs. These effects were reversed after blocking the Rho-kinase (ROCK) pathway with Y-27632 or HA-1077. Therefore, 8,9-EET analog (214) protects PASMC from serum deprivation-induced apoptosis, mediated at least in part via the ROCK pathway. Serum deprivation of PASMCs resulted in mitochondrial membrane depolarization, decreased expression of Bcl-2 and enhanced expression of Bax, all effects were reversed by 8,9-EET analog (214) in a ROCK dependent manner. Because 8,9-EET and not the 8,9-EET analog (214) protects pulmonary artery endothelial cells (PAECs), these observations suggest the potential to differentially promote apoptosis or survival with 8,9-EET or analogs in pulmonary arteries.

  8. Albumin leak across human pulmonary microvascular vs. umbilical vein endothelial cells under septic conditions.

    PubMed

    Shelton, Jennifer L; Wang, Lefeng; Cepinskas, Gediminas; Sandig, Martin; Inculet, Richard; McCormack, David G; Mehta, Sanjay

    2006-01-01

    Human pulmonary microvascular endothelial cell (HPMVEC) injury is central to the pathophysiology of human lung injury. However, septic HPMVEC barrier dysfunction and the contribution of neutrophils have not been directly addressed in vitro. Instead, human EC responses are often extrapolated from studies of human umbilical vein EC (HUVEC). We hypothesized that HUVEC was not a good model for investigating HPMVEC barrier function under septic conditions. HPMVEC was isolated from lung tissue resected from lung cancer patients using magnetic bead-bound anti-PECAM-1 antibody. In confluent monolayers in 3-mum cell-culture inserts, we assessed trans-EC Evans-Blue (EB)-conjugated albumin leak under basal, unstimulated conditions and following stimulation with either lipopolysaccharide or a mixture of equal concentrations of TNF-alpha, IL-1beta and IFN-gamma (cytomix). Basal EB-albumin leak was significantly lower across HPMVEC than HUVEC (0.64 +/- 0.06% vs. 1.13 +/- 0.10%, respectively, P < 0.001). Lipopolysaccharide and cytomix increased leak across both HPMVEC and HUVEC in a dose-dependent manner, with a similar increase relative to basal leak in both cell types. The presence of neutrophils markedly and dose-dependently enhanced cytomix-induced EB-albumin leak across HPMVEC (P < 0.01), but had no effect on EB-albumin leak across HUVEC. Both cytomix and lipopolysaccharide-induced albumin leak was not associated with a loss of cell viability. In conclusion, HPMVEC barrier dysfunction under septic conditions is dramatically enhanced by neutrophil presence, and HUVEC is not a suitable model for studying HPMVEC septic barrier responses. The direct study of HPMVEC septic responses will lead to a better understanding of human lung injury. PMID:16376951

  9. ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis

    PubMed Central

    Baldan, Angel; Gonen, Ayelet; Choung, Christina; Que, Xuchu; Marquart, Tyler J.; Hernandez, Irene; Bjorkhem, Ingemar; Ford, David A.; Witztum, Joseph L.; Tarling, Elizabeth J.

    2014-01-01

    Many metabolic diseases, including atherosclerosis, type 2 diabetes, pulmonary alveolar proteinosis (PAP), and obesity, have a chronic inflammatory component involving both innate and adaptive immunity. Mice lacking the ATP binding cassette (ABC) transporter ABCG1 develop chronic inflammation in the lungs, associated with lipid accumulation (cholesterol, cholesterol ester, and phospholipid) and cholesterol crystal deposition, characteristic of atherosclerotic lesions and PAP. Here we demonstrate that specific lipids, likely oxidized (Ox) phospholipids and/or sterols, elicit a lung-specific immune response in Abcg1−/− mice. Loss of ABCG1 results in increased levels of specific oxysterols, phosphatidylcholines and oxidized phospholipids, including 1-palmitoyl-2-(5’-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), in the lungs. Further, we identify a niche-specific increase in natural antibody (NAb)-secreting B-1 B cells in response to this lipid accumulation that is paralleled by increased titers of IgM, IgA and IgG against oxidation specific epitopes such as those on OxLDL and malondialdehyde-modified LDL (MDA-LDL). Finally we identify a cytokine/chemokine signature reflective of increased B cell activation, antibody secretion and homing. Collectively, these data demonstrate that the accumulation of lipids in Abcg1−/− mice induces the specific expansion and localization of B-1 B cells, which secrete NAbs that may help protect against the development of atherosclerosis. Indeed, despite chronic lipid accumulation and inflammation, hyperlipidemic mice lacking ABCG1 develop smaller atherosclerotic lesions compared to controls. These data also suggest that Abcg1−/− mice may represent a new model in which to study the protective functions of B-1 B cells/NAbs, and suggest novel targets for pharmacologic intervention and treatment of disease. PMID:25339664

  10. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  11. Determination of sex by exfoliative cytology using acridine orange confocal microscopy: A short study

    PubMed Central

    Reddy, D Shyam Prasad; Sherlin, Herald J; Ramani, Pratibha; Prakash, P Ajay

    2012-01-01

    Context: Establishing individuality is an imperative aspect in any investigation procedure. Sometimes, in identifying an individual, it becomes necessary to determine the sex of that particular individual. Combining rapidity with reliability, an innovative idea has been put forward using a confocal microscope in exfoliative cytology. In the present study, we have determined the sex of the individual from buccal mucosal scrapings. The exfoliative cells were observed for Barr bodies under a confocal microscope, and the percentage of Barr-body-positive cells was determined. Aims: The main objective of this study is to assess confocal microscopy for the determination of sex by observing Barr bodies in the exfoliative cells of both men and women. Settings and Design: Samples of buccal mucosa smears were made followed by acridine orange staining. The stained slides were observed under a confocal microscope and the data obtained was subjected for statistical analysis, especially for mean and standard deviation. Materials and Methods: Samples of buccal mucosa smears from 20 men and 20 women were obtained by scraping with flat wooden sticks (exfoliative cytology). The smears were fixed in 100% alcohol for 15 min, followed by acridine orange (AO) staining as described by Von Bertalanffy et al. Smears stained with AO were examined under a confocal microscope and the percentage of Barr-body-positive cells was determined. Statistical Analysis Used: Data obtained was subjected for statistical analysis, especially for mean and standard deviation. Results: Two non-overlapping ranges for the percentage of Barr-body-positive cells have been obtained for men and women. It was observed that in the male samples, the percentage of Barr-body-positive cells ranged from 0-3%. In the female samples, the percentage of Barr-body-positive cells ranged from 18-72%, and all the females showed the presence of Barr bodies. Conclusion: The study showed that the presence of Barr body in buccal

  12. Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Mediated Redox Signaling and Vascular Remodeling by 16α-Hydroxyestrone in Human Pulmonary Artery Cells: Implications in Pulmonary Arterial Hypertension.

    PubMed

    Hood, Katie Y; Montezano, Augusto C; Harvey, Adam P; Nilsen, Margaret; MacLean, Margaret R; Touyz, Rhian M

    2016-09-01

    Estrogen and oxidative stress have been implicated in pulmonary arterial hypertension (PAH). Mechanisms linking these systems are elusive. We hypothesized that estrogen metabolite, 16α-hydroxyestrone (16αOHE1), stimulates nicotinamide adenine dinucleotide phosphate oxidase (Nox)-induced reactive oxygen species (ROS) generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMCs) and that in PAH aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of estrogen-Nox-dependent processes was studied in female Nox1(-/-) and Nox4(-/-) mice with PAH. PASMCs from control subjects (control hPASMCs) and PAH patients (PAH-hPASMCs) were exposed to estrogen and 16αOHE1 in the presence/absence of inhibitors of Nox, cytochrome P450 1B1, and estrogen receptors. Estrogen, through estrogen receptor-α, increased Nox-derived ROS and redox-sensitive growth in hPASMCs, with greater effects in PAH-hPASMCs versus control hPASMCs. Estrogen effects were inhibited by cytochrome P450 1B1 blockade. 16αOHE1 stimulated transient ROS production in hPASMCs, with sustained responses in PAH-hPASMCs. Basal expression of Nox1/Nox4 was potentiated in PAH-hPASMCs. In hPASMCs, 16αOHE1 increased Nox1 expression, stimulated irreversible oxidation of protein tyrosine phosphatases, decreased nuclear factor erythroid-related factor 2 activity and expression of nuclear factor erythroid-related factor 2-regulated antioxidant genes, and promoted proliferation. This was further amplified in PAH-hPASMCs. Nox1(-/-) but not Nox4(-/-) mice were protected against PAH and vascular remodeling. Our findings demonstrate that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth primarily through Nox1. Supporting this, in vivo studies exhibited protection against pulmonary hypertension and remodeling in Nox1(-/-) mice. This study provides new insights through Nox1/ROS and nuclear factor erythroid-related factor 2 whereby 16αOHE1 influences

  13. Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors

    PubMed Central

    Rossi, Lorena; Martignano, Filippo; Gallà, Valentina; Maugeri, Antonio; Schepisi, Giuseppe

    2016-01-01

    Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID:27471579

  14. Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors.

    PubMed

    Rossi, Lorena; Martignano, Filippo; Gallà, Valentina; Maugeri, Antonio; Schepisi, Giuseppe

    2016-04-15

    Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID:27471579

  15. EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity

    PubMed Central

    Darrah, Rebecca; McKone, Edward; O'Connor, Clare; Rodgers, Christine; Genatossio, Alan; McNamara, Sharon; Gibson, Ronald; Stuart Elborn, J.; Ennis, Madeleine; Gallagher, Charles G.; Kalsheker, Noor; Aitken, Moira; Wiese, Dawn; Dunn, John; Smith, Paul; Pace, Rhonda; Londono, Douglas; Goddard, Katrina A. B.; Knowles, Michael R.

    2010-01-01

    Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) patients, even among patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Endothelin, a proinflammatory peptide and smooth muscle agonist, is increased in CF airways, potentially contributing to the pulmonary phenotype. Four cohorts of CF patients were screened for variants in endothelin pathway genes to determine whether any of these variants associated with pulmonary function. An initial cohort of 808 CF patients homozygous for the common CF mutation, ΔF508, showed significant association for polymorphisms in the endothelin receptor A gene, EDNRA (P = 0.04), but not in the related endothelin genes (EDN1, EDN2, EDN3, or EDNRB) or NOS1, NOS2A, or NOS3. Variants within EDNRA were examined in three additional cohorts of CF patients, 238 patients from Seattle, WA, 303 from Ireland and the U.K., and 228 from Cleveland, OH, for a total of 1,577 CF patients. The three additional groups each demonstrated a significant association between EDNRA 3′-untranslated region (UTR) variant rs5335 and pulmonary function (P = 0.002). At the molecular level, single nucleotide primer extension assays suggest that the effect of the variants is quantitative. EDNRA mRNA levels from cultured primary tracheal smooth muscle cells are greater for the allele that appears to be deleterious to lung function than for the protective allele, suggesting a mechanism by which increased receptor function is harmful to the CF airway. Finally, cell proliferation studies using human airway smooth muscle cells demonstrated that cells homozygous for the deleterious allele proliferate at a faster rate than those homozygous for the protective allele. PMID:20028935

  16. Omeprazole does not Potentiate Acute Oxygen Toxicity in Fetal Human Pulmonary Microvascular Endothelial Cells Exposed to Hyperoxia

    PubMed Central

    Patel, Ananddeep; Zhang, Shaojie; Moorthy, Bhagavatula; Shivanna, Binoy

    2015-01-01

    Hyperoxia contributes to the pathogenesis of broncho-pulmonary dysplasia (BPD), which is a developmental lung disease of premature infants that is characterized by an interruption of lung alveolar and pulmonary vascular development. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. Earlier we observed that OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury in adult mice and oxygen toxicity in adult human lung cells. However, our later studies in newborn mice demonstrated that OM potentiates hyperoxia-induced developmental lung injury. Whether OM exerts a similar toxicity in primary human fetal lung cells is unknown. Hence, we tested the hypothesis that OM potentiates hyperoxia-induced cytotoxicity and ROS generation in the human fetal lung derived primary human pulmonary microvascular endothelial cells (HPMEC). OM activated AhR as evident by a dose-dependent increase in cytochrome P450 (CYP) 1A1 mRNA levels in OM-treated cells. Furthermore, OM at a concentration of 100 μM (OM 100) increased NADP(H) quinone oxidoreductase 1 (NQO1) expression. Surprisingly, hyperoxia decreased rather than increase the NQO1 protein levels in OM 100-treated cells. Exposure to hyperoxia increased cytotoxicity and hydrogen peroxide (H2O2) levels. Interestingly, OM 100-treated cells exposed to air had increased H2O2 levels. However, hyperoxia did not further augment H2O2 levels in OM 100-treated cells. Additionally, hyperoxia-mediated oxygen toxicity was similar in both vehicle- and OM-treated cells. These findings contradict our hypothesis and support the hypothesis that OM does not potentiate acute hyperoxic injury in HPMEC in vitro. PMID:26779382

  17. Multimodal 4D imaging of cell-pathogen interactions in the lungs provides new insights into pulmonary infections

    NASA Astrophysics Data System (ADS)

    Fiole, Daniel; Douady, Julien; Cleret, Aurélie; Garraud, Kévin; Mathieu, Jacques; Quesnel-Hellmann, Anne; Tournier, Jean-Nicolas

    2011-07-01

    Lung efficiency as gas exchanger organ is based on the delicate balance of its associated mucosal immune system between inflammation and sterility. In this study, we developed a dynamic imaging protocol using confocal and twophoton excitation fluorescence (2PEF) on freshly harvested infected lungs. This modus operandi allowed the collection of important information about CX3CR1+ pulmonary cells. This major immune cell subset turned out to be distributed in an anisotropic way in the lungs: subpleural, parenchymal and bronchial CX3CR1+ cells have then been described. The way parenchymal CX3CR1+ cells react against LPS activation has been considered using Matlab software, demonstrating a dramatic increase of average cell speed. Then, interactions between Bacillus anthracis spores and CX3CR1+ dendritic cells have been investigated, providing not only evidences of CX3CR1+ cells involvement in pathogen uptake but also details about the capture mechanisms.

  18. Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension.

    PubMed

    Sada, Yoshiharu; Dohi, Yoshihiro; Uga, Sayuri; Higashi, Akifumi; Kinoshita, Hiroki; Kihara, Yasuki

    2016-08-01

    Regulatory T cells (Tregs) have been reported to play a pivotal role in the vascular remodeling of pulmonary arterial hypertension (PAH). Recent studies have revealed that Tregs are heterogeneous and can be characterized by three phenotypically and functionally different subsets. In this study, we investigated the roles of Treg subsets in the pathogenesis of PAH in eight patients with PAH and 14 healthy controls. Tregs and their subsets in peripheral blood samples were analyzed by flow cytometry. Treg subsets were defined as CD4(+)CD45RA(+)FoxP3(low) resting Tregs (rTregs), CD4(+)CD45RA(-)FoxP3(high) activated Tregs (aTregs), and CD4(+)CD45RA(-)FoxP3(low) non-suppressive Tregs (non-Tregs). The proportion of Tregs among CD4(+) T cells was significantly higher in PAH patients than in controls (6.54 ± 1.10 vs. 3.81 ± 0.28 %, p < 0.05). Of the three subsets, the proportion of non-Tregs was significantly elevated in PAH patients compared with controls (4.06 ± 0.40 vs. 2.79 ± 0.14 %, p < 0.01), whereas those of rTregs and aTregs were not different between the two groups. Moreover, the expression levels of cytotoxic T lymphocyte antigen 4, a functional cell surface molecule, in aTregs (p < 0.05) and non-Tregs (p < 0.05) were significantly higher in PAH patients compared with controls. These results suggested the non-Treg subset was expanded and functionally activated in peripheral lymphocytes obtained from IPAH patients. We hypothesize that immunoreactions involving the specific activation of the non-Treg subset might play a role in the vascular remodeling of PAH. PMID:26319442

  19. Cell adhesion antagonists: therapeutic potential in asthma and chronic obstructive pulmonary disease.

    PubMed

    Woodside, Darren G; Vanderslice, Peter

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the beta1 and beta2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin alphaIIbbeta3 (e.g. abciximab), integrin alphaLbeta2 (efalizumab), and integrin alpha4beta1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin alpha4beta1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming. PMID:18345706

  20. Non-oxidative, controlled exfoliation of graphite in aqueous medium.

    PubMed

    Srivastava, Pawan Kumar; Yadav, Premlata; Ghosh, Subhasis

    2016-08-25

    We present a simple, non-oxidative and controlled method to synthesize graphene monolayers by exfoliation in water from different solid carbon sources, such as highly ordered pyrolytic graphite and low density graphite. Any water based method is highly desirable due to several attractive features, such as environmental friendliness, low cost and wide compatibility with other water based processes. We show that thin graphene layers can be exfoliated controllably and reproducibly by varying different parameters during exfoliation in aqueous medium. It has been possible to obtain high quality graphene monolayers with a yield of ∼2.45 wt%, which can be increased up to 16.6 wt% by recycling the sediments. Field effect transistors based on exfoliated graphene monolayers have shown n-type doping and a high carrier mobility of 4500 cm(2) V(-1) s(-1) at room temperature and ∼20 000 cm(2) V(-1) s(-1) at low temperature. Density functional calculations corroborate the infrared spectroscopic results and also indicate that the charge transfer preferentially occurs from water molecules to the graphene sheets resulting in n-type doping. We anticipate that exfoliation of high quality graphene layers in aqueous medium would open up a pathway for various graphene based electronic and biological applications. PMID:27523721

  1. Pulmonary Langerhans Cell Histiocytosis in an Adult Male Presenting with Central Diabetes Insipidus and Diabetes Mellitus: A Case Report

    PubMed Central

    Choi, Yeun Seoung; Lim, Jung Soo; Kwon, Woocheol; Jung, Soon-Hee; Park, Il Hwan; Lee, Myoung Kyu; Lee, Won Yeon; Yong, Suk Joong; Lee, Seok Jeong; Jung, Ye-Ryung; Choi, Jiwon; Choi, Ji Sun; Jeong, Joon Taek; Yoo, Jin Sae

    2015-01-01

    Pulmonary Langerhans cell histiocytosis is an uncommon diffuse cystic lung disease in adults. In rare cases, it can involve extrapulmonary organs and lead to endocrine abnormalities such as central diabetes insipidus. A 42-year-old man presented with polyphagia and polydipsia, as well as a dry cough and dyspnea on exertion. Magnetic resonance imaging of the hypothalamic-pituitary system failed to show the posterior pituitary, which is a typical finding in patients with central diabetes insipidus. This condition was confirmed by a water deprivation test, and the patient was also found to have type 2 diabetes mellitus. Computed tomographic scanning of the lungs revealed multiple, irregularly shaped cystic lesions and small nodules bilaterally, with sparing of the costophrenic angles. Lung biopsy through video-assisted thoracoscopic surgery revealed pulmonary Langerhans cell histiocytosis. On a follow-up visit, only 1 year after the patient had quit smoking, clinical and radiological improvement was significant. Here, we report an uncommon case of pulmonary Langerhans cell histiocytosis that simultaneously presented with diabetes insipidus and diabetes mellitus. PMID:26508947

  2. Pulmonary Langerhans Cell Histiocytosis in an Adult Male Presenting with Central Diabetes Insipidus and Diabetes Mellitus: A Case Report.

    PubMed

    Choi, Yeun Seoung; Lim, Jung Soo; Kwon, Woocheol; Jung, Soon-Hee; Park, Il Hwan; Lee, Myoung Kyu; Lee, Won Yeon; Yong, Suk Joong; Lee, Seok Jeong; Jung, Ye-Ryung; Choi, Jiwon; Choi, Ji Sun; Jeong, Joon Taek; Yoo, Jin Sae; Kim, Sang-Ha

    2015-10-01

    Pulmonary Langerhans cell histiocytosis is an uncommon diffuse cystic lung disease in adults. In rare cases, it can involve extrapulmonary organs and lead to endocrine abnormalities such as central diabetes insipidus. A 42-year-old man presented with polyphagia and polydipsia, as well as a dry cough and dyspnea on exertion. Magnetic resonance imaging of the hypothalamic-pituitary system failed to show the posterior pituitary, which is a typical finding in patients with central diabetes insipidus. This condition was confirmed by a water deprivation test, and the patient was also found to have type 2 diabetes mellitus. Computed tomographic scanning of the lungs revealed multiple, irregularly shaped cystic lesions and small nodules bilaterally, with sparing of the costophrenic angles. Lung biopsy through video-assisted thoracoscopic surgery revealed pulmonary Langerhans cell histiocytosis. On a follow-up visit, only 1 year after the patient had quit smoking, clinical and radiological improvement was significant. Here, we report an uncommon case of pulmonary Langerhans cell histiocytosis that simultaneously presented with diabetes insipidus and diabetes mellitus. PMID:26508947

  3. Infant formula alters surfactant protein A (SP-A) and SP-B expression in pulmonary epithelial cells.

    PubMed

    Chen, Maurice G; Atkins, Constance L; Bruce, Shirley R; Khan, Amir M; Liu, Yuying; Alcorn, Joseph L

    2011-09-01

    Surfactant proteins A (SP-A) and SP-B are critical in the ability of pulmonary surfactant to reduce alveolar surface tension and provide innate immunity. Aspiration of infant milk formula can lead to lung dysfunction, but direct effects of aspirated formula on surfactant protein expression in pulmonary cells have not been described. The hypothesis that infant formula alters surfactant protein homeostasis was tested in vitro by assessing surfactant protein gene expression in cultured pulmonary epithelial cell lines expressing SP-A and SP-B that were transiently exposed (6 hr) to infant formula. Steady-state levels of SP-A protein and mRNA and SP-B mRNA in human bronchiolar (NCI-H441) and mouse alveolar (MLE15) epithelial cells were reduced in a dose-dependent manner 18 hr after exposure to infant formula. SP-A mRNA levels remained reduced 42 hr after exposure, but SP-B mRNA levels increased 10-fold. Neither soy formula nor non-fat dry milk affected steady-state SP-A and SP-B mRNA levels; suggesting a role of a component of infant formula derived from cow milk. These results indicate that infant formula has a direct, dose-dependent effect to reduce surfactant protein gene expression. Ultimately, milk aspiration may potentially result in a reduced capacity of the lung to defend against environmental insults. PMID:21520433

  4. Quantitative profiling of the in vivo enzymatic activity of ricin reveals disparate depurination of different pulmonary cell types.

    PubMed

    Falach, Reut; Sapoznikov, Anita; Gal, Yoav; Israeli, Ofir; Leitner, Moshe; Seliger, Nehama; Ehrlich, Sharon; Kronman, Chanoch; Sabo, Tamar

    2016-09-01

    The plant-derived toxins ricin and abrin, operate by site-specific depurination of ribosomes, which in turn leads to protein synthesis arrest. The clinical manifestation following pulmonary exposure to these toxins is that of a severe lung inflammation and respiratory insufficiency. Deciphering the pathways mediating between the catalytic activity and the developing lung inflammation, requires a quantitative appreciation of the catalytic activity of the toxins, in-vivo. In the present study, we monitored truncated cDNA molecules which are formed by reverse transcription when a depurinated 28S rRNA serves as template. We found that maximal depurination after intranasal exposure of mice to 2LD50 ricin was reached 48h, where nearly 40% of the ribosomes have been depurinated and that depurination can be halted by post-exposure administration of anti-ricin antibodies. We next demonstrated that the effect of ricin intoxication on different cell types populating the lungs differs greatly, and that outstandingly high levels of damage (80% depurination), were observed in particular for pulmonary epithelial cells. Finally, we found that the magnitude of depurination induced by the related plant-derived toxin abrin, was significantly lower in comparison to ricin, and can be attributed mostly to reduced depurination of pulmonary epithelial cells by abrin. This study provides for the first time vital information regarding the scope and timing of the catalytic performance of ricin and abrin in the lungs of intact animals. PMID:27298272

  5. Asymmetric dimethylarginine inhibits HSP90 activity in Pulmonary Arterial Endothelial Cells: Role of Mitochondrial Dysfunction

    PubMed Central

    Sud, Neetu; Wells, Sandra M.; Wiseman, Dean A.; Wilham, Jason; Black, Stephen M.

    2013-01-01

    Increased ADMA levels have been implicated in the pathogenesis of a number of conditions affecting the cardiovascular system. However, the mechanism(s) by which ADMA exerts its effect has not been adequately elucidated. Thus, the purpose of this study was to determine the effect of increased ADMA on nitric oxide (NO) signaling and to begin to elucidate the mechanism by which ADMA acts. Our initial data demonstrated that that ADMA increased NOS uncoupling both in recombinant human endothelial NO synthase (eNOS) and pulmonary arterial endothelial cells (PAEC). Further, we found that this eNOS uncoupling increased 3-nitrotyrosine levels preferentially in the mitochondria of PAEC due to a redistribution of eNOS from the plasma membrane to the mitochondria. This increase in nitration in the mitochondria was found to induce mitochondrial dysfunction as determined by increased mitochondrial derived reactive oxygen species and decreased generation of ATP. Finally, we found that the decrease in ATP resulted in a reduction in the chaperone activity of HSP90 resulting in a decrease in its interaction with eNOS. In conclusion increased levels of ADMA causes mitochondrial dysfunction and a loss of HSP90 chaperone activity secondary to an uncoupling of eNOS. Mitochondrial dysfunction may be an understudied component of the endothelial dysfunction associated with various cardiovascular disease states. PMID:18385287

  6. Pulmonary Langerhans' cell granulomatosis (histiocytosis X): clinical analysis of 8 cases.

    PubMed

    Callebaut, W; Demedts, M; Verleden, G

    1998-10-01

    A detailed retrospective analysis of 8 cases has been set up to obtain an update of the clinical, radiological, diagnostic and therapeutical aspects of pulmonary Langerhans' cell granulomatosis (PLCG), previously called Histiocytosis X. This disease represents 2.8% of interstitial lung diseases (ILD) in a registration by pneumologists in Flanders. Seventy five% of our patients were active smokers. Cough, dyspnoe and constitutional symptoms were the main presenting symptoms. There was a 37.5% frequency of pneumothorax during the whole disease evolution and all these patients had to be treated with chemical or surgical pleurodesis. Spirometric pattern was variable but CO-transferfactor (TLCO) was significantly impaired in all our patients. Radiologically nodules and/or cystic lesions were found with preserved volumes. Open lung biopsy led to the diagnosis in 6 of the 8 cases. Transbronchial biopsies (TBB) were found to be not sensitive. Systemic staging in our group showed 50% of the patients to have a second focus of organ involvement. Treatment with corticosteroids and possibly immunosuppressives was without clear effect. Since 25% of our patients ultimately became candidate for lung transplantation extrapulmonary staging is prerogative and the high frequency of pleurodesis procedures in the past medical history of our patients has important implications since bilateral pleurodesis is still a contraindication for lung transplantation in some but not all institutions. PMID:9861760

  7. An investigation of the influence of cell topography on epithelial mechanical stresses during pulmonary airway reopening

    NASA Astrophysics Data System (ADS)

    Jacob, A. M.; Gaver, D. P.

    2005-03-01

    The goal of this study is to assess the local mechanical environment of the pulmonary epithelium in a computational model of airway reopening. To this end, the boundary element method (BEM) in conjunction with lubrication theory is implemented to assess the stationary-state behavior of a semi-infinite bubble traveling through a liquid-occluded parallel plate flow chamber lined with epithelial cells. The fluid occlusion is assumed to be Newtonian and inertia is neglected. The interactions between the microgeometry of the model airway's walls and the interfacial kinematics surrounding the bubble's tip result in a complex, spatially and temporally dependent stress distribution. The walls' nonplanar topography magnifies the normal and shear stresses and stress gradients. We find that decreasing the bubble's speed serves to increase the maximum normal stress and stress gradient but decrease the maximum shear stress and stress gradient. Our results give credence to the pressure-gradient-induced epithelial damage theory recently proposed by Bilek et al. [J. Appl. Physiol. 94, 770 (2003)] and Kay et al. [J. Appl. Physiol. 97, 269 (2004)]. We conclude that the amplified pressure gradients found in this study may be even more detrimental to the airway's cellular epithelium during airway reopening.

  8. An investigation of the influence of cell topography on epithelial mechanical stresses during pulmonary airway reopening.

    PubMed

    Jacob, A M; Gaver, D P

    2005-01-01

    The goal of this study is to assess the local mechanical environment of the pulmonary epithelium in a computational model of airway reopening. To this end, the boundary element method (BEM) in conjunction with lubrication theory is implemented to assess the stationary-state behavior of a semi-infinite bubble traveling through a liquid-occluded parallel plate flow chamber lined with epithelial cells. The fluid occlusion is assumed to be Newtonian and inertia is neglected. The interactions between the microgeometry of the model airway's walls and the interfacial kinematics surrounding the bubble's tip result in a complex, spatially and temporally dependent stress distribution. The walls' nonplanar topography magnifies the normal and shear stresses and stress gradients. We find that decreasing the bubble's speed serves to increase the maximum normal stress and stress gradient but decrease the maximum shear stress and stress gradient. Our results give credence to the pressure-gradient-induced epithelial damage theory recently proposed by Bilek et al. [J. Appl. Physiol. 94, 770 (2003)] and Kay et al. [J. Appl. Physiol. 97, 269 (2004)]. We conclude that the amplified pressure gradients found in this study may be even more detrimental to the airway's cellular epithelium during airway reopening. PMID:23745044

  9. An investigation of the influence of cell topography on epithelial mechanical stresses during pulmonary airway reopening

    PubMed Central

    Jacob, A. M.; Gaver, D. P.

    2013-01-01

    The goal of this study is to assess the local mechanical environment of the pulmonary epithelium in a computational model of airway reopening. To this end, the boundary element method (BEM) in conjunction with lubrication theory is implemented to assess the stationary-state behavior of a semi-infinite bubble traveling through a liquid-occluded parallel plate flow chamber lined with epithelial cells. The fluid occlusion is assumed to be Newtonian and inertia is neglected. The interactions between the microgeometry of the model airway’s walls and the interfacial kinematics surrounding the bubble’s tip result in a complex, spatially and temporally dependent stress distribution. The walls’ nonplanar topography magnifies the normal and shear stresses and stress gradients. We find that decreasing the bubble’s speed serves to increase the maximum normal stress and stress gradient but decrease the maximum shear stress and stress gradient. Our results give credence to the pressure-gradient-induced epithelial damage theory recently proposed by Bilek et al. [J. Appl. Physiol. 94, 770 (2003)] and Kay et al. [J. Appl. Physiol. 97, 269 (2004)]. We conclude that the amplified pressure gradients found in this study may be even more detrimental to the airway’s cellular epithelium during airway reopening. PMID:23745044

  10. Regulation of pulmonary surfactant synthesis in fetal rat type II alveolar epithelial cells by microRNA-26a.

    PubMed

    Zhang, Xiao-Qun; Zhang, Pan; Yang, Yang; Qiu, Jie; Kan, Qin; Liang, Hong-Lu; Zhou, Xiao-Yu; Zhou, Xiao-Guang

    2014-09-01

    Pulmonary surfactant, a unique developmentally regulated, phospholipid-rich lipoprotein, is synthesized by the type II epithelial cells (AECII) of the pulmonary alveolus, where it is stored in organelles termed lamellar bodies. The synthesis of pulmonary surfactant is under multifactorial control and is regulated by a number of hormones and factors, including glucocorticoids, prolactin, insulin, growth factors, estrogens, androgens, thyroid hormones, and catecholamines acting through beta-adrenergic receptors, and cAMP. While there is increasing evidence that microRNAs (miRNAs) are involved in the regulation of almost every cellular and physiological process, the potential role of miRNAs in the regulation of pulmonary surfactant synthesis remains unknown. miRNA-26a (miR-26a) has been predicted to target SMAD1, one of the bone morphogenetic protein (BMP) receptor downstream signaling proteins that plays a key role in differentiation of lung epithelial cells during lung development. In this study, we explored the regulation role of miR-26a in the synthesis of pulmonary surfactant. An adenoviral miR-26a overexpression vector was constructed and introduced into primary cultured fetal AECII. GFP fluorescence was observed to determinate the transfection efficiency and miR-26a levels were measured by RT-PCR. MTT was performed to analyze AECII viability. qRT-PCR and Western blotting were used to determine the mRNA and protein level of SMAD1 and surfactant-associated proteins. The results showed that miR-26a in fetal AECII was overexpressed after the transfection, and that the overexpression of miR-26a inhibited pulmonary surfactant synthesis in AECII. There was no significant change in cell proliferation. Our results further showed that overexpression of miR-26a reduced the SMAD1 expression both in mRNA and protein level in fetal AECII. These findings indicate that miR-26a regulates surfactant synthesis in fetal AECII through SMAD1. PMID:24395810

  11. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice.

    PubMed

    Takahashi, Saeko; Nakamura, Hidetoshi; Seki, Makoto; Shiraishi, Yoshiki; Yamamoto, Miyuki; Furuuchi, Momoyo; Nakajima, Takahiro; Tsujimura, Shuko; Shirahata, Toru; Nakamura, Miho; Minematsu, Naoto; Yamasaki, Motohiro; Tateno, Hiroki; Ishizaka, Akitoshi

    2008-05-01

    Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS- group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS- group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS-) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS- group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS- group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions. PMID:18310229

  12. Technetium-99m red blood cell venography of the lower limb in symptomatic pulmonary embolization.

    PubMed

    Lisbona, R; Rush, C; Lepanto, L

    1987-02-01

    Tc-99m RBC venography of the legs was obtained in 42 patients with primary pulmonary symptomatology and a diagnosis of pulmonary embolization. In 31 of these 42 patients (74%), the nuclear venogram revealed the presence of deep vein thrombosis (DVT) and a source of embolization. Of the 31 patients with leg DVT documented by venography, 13 (42%) showed thrombosis confined to the calf. Clinical findings suggested that only 20 of the 31 patients (65%) with DVT could have harboured a source of embolization in the legs. Tc-99m RBC venography is a useful noninvasive test for the global and comprehensive assessment of patients with symptomatic pulmonary embolization. PMID:3829541

  13. An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease

    PubMed Central

    Klings, Elizabeth S.; Machado, Roberto F.; Barst, Robyn J.; Morris, Claudia R.; Mubarak, Kamal K.; Gordeuk, Victor R.; Kato, Gregory J.; Ataga, Kenneth I.; Gibbs, J. Simon; Castro, Oswaldo; Rosenzweig, Erika B.; Sood, Namita; Hsu, Lewis; Wilson, Kevin C.; Telen, Marilyn J.; DeCastro, Laura M.; Krishnamurti, Lakshmanan; Steinberg, Martin H.; Badesch, David B.; Gladwin, Mark T.

    2014-01-01

    Background: In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. Methods: A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. Results: Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. Conclusions: Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating. PMID:24628312

  14. Pulmonary Rehabilitation

    MedlinePlus

    ... Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a link to NHLBI to someone by ... people who have COPD (chronic obstructive pulmonary disease), sarcoidosis (sar-koy-DOE-sis), idiopathic pulmonary fibrosis , or ...

  15. Pulmonary embolus

    MedlinePlus

    ... Blood clot - lung; Embolus; Tumor embolus; Embolism - pulmonary; DVT-pulmonary embolism; Thrombosis - pulmonary embolism ... area). This type of clot is called a deep vein thrombosis (DVT) . The blood clot breaks off and travels ...

  16. Quantitative intravital two-photon excitation microscopy reveals absence of pulmonary vaso-occlusion in unchallenged Sickle Cell Disease mice

    PubMed Central

    Bennewitz, Margaret F.; Watkins, Simon C.; Sundd, Prithu

    2015-01-01

    Sickle cell disease (SCD) is a genetic disorder that leads to red blood cell (RBC) sickling, hemolysis and the upregulation of adhesion molecules on sickle RBCs. Chronic hemolysis in SCD results in a hyper-inflammatory state characterized by activation of circulating leukocytes, platelets and endothelial cells even in the absence of a crisis. A crisis in SCD is often triggered by an inflammatory stimulus and can lead to the acute chest syndrome (ACS), which is a type of lung injury and a leading cause of mortality among SCD patients. Although it is believed that pulmonary vaso-occlusion could be the phenomenon contributing to the development of ACS, the role of vaso-occlusion in ACS remains elusive. Intravital imaging of the cremaster microcirculation in SCD mice has been instrumental in establishing the role of neutrophil-RBC-endothelium interactions in systemic vaso-occlusion; however, such studies, although warranted, have never been done in the pulmonary microcirculation of SCD mice. Here, we show that two-photon excitation fluorescence microscopy can be used to perform quantitative analysis of neutrophil and RBC trafficking in the pulmonary microcirculation of SCD mice. We provide the experimental approach that enables microscopic observations under physiological conditions and use it to show that RBC and neutrophil trafficking is comparable in SCD and control mice in the absence of an inflammatory stimulus. The intravital imaging scheme proposed in this study can be useful in elucidating the cellular and molecular mechanism of pulmonary vaso-occlusion in SCD mice following an inflammatory stimulus. PMID:25995970

  17. PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation.

    PubMed

    Sysol, Justin R; Natarajan, Viswanathan; Machado, Roberto F

    2016-06-01

    Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease for which there is currently no curative treatment available. Pathologic changes in this disease involve remodeling of the pulmonary vasculature, including marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Recently, the bioactive lipid sphingosine-1-phosphate (S1P) and its activating kinase, sphingosine kinase 1 (SphK1), have been shown to be upregulated in PAH and promote PASMC proliferation. The mechanisms regulating the transcriptional upregulation of SphK1 in PASMCs are unknown. In this study, we investigated the role of platelet-derived growth factor (PDGF), a PAH-relevant stimuli associated with enhanced PASMC proliferation, on SphK1 expression regulation. In human PASMCs (hPASMCs), PDGF significantly increased SphK1 mRNA and protein expression and induced cell proliferation. Selective inhibition of SphK1 attenuated PDGF-induced hPASMC proliferation. In silico promoter analysis for SphK1 identified several binding sites for early growth response protein 1 (Egr-1), a PDGF-associated transcription factor. Luciferase assays demonstrated that PDGF activates the SphK1 promoter in hPASMCs, and truncation of the 5'-promoter reduced PDGF-induced SphK1 expression. Stimulation of hPASMCs with PDGF induced Egr-1 protein expression, and direct binding of Egr-1 to the SphK1 promoter was confirmed by chromatin immunoprecipitation analysis. Inhibition of ERK signaling prevented induction of Egr-1 by PDGF. Silencing of Egr-1 attenuated PDGF-induced SphK1 expression and hPASMC proliferation. These studies demonstrate that SphK1 is regulated by PDGF in hPASMCs via the transcription factor Egr-1, promoting cell proliferation. This novel mechanism of SphK1 regulation may be a therapeutic target in pulmonary vascular remodeling in PAH. PMID:27099350

  18. The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension.

    PubMed

    Yang, Minxia; Deng, Chaosheng; Wu, Dawen; Zhong, Zhanghua; Lv, Xiaoting; Huang, Zhihua; Lian, Ningfang; Liu, Kaixiong; Zhang, Qiaoxian

    2016-07-01

    Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls (P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different (P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation-coagulation-thrombosis cycle. PMID:26667361

  19. Pulmonary response to inhaled antigen: neuroimmune interactions promote the recruitment of dendritic cells to the lung and the cellular immune response to inhaled antigen.

    PubMed Central

    Kradin, R.; MacLean, J.; Duckett, S.; Schneeberger, E. E.; Waeber, C.; Pinto, C.

    1997-01-01

    Dendritic cells (DCs) play a critical role in capturing and presenting inhaled antigens to T lymphocytes. We report that pulmonary DCs in the Lewis rat are normally located in the lung in immediate proximity to nerve fibers that contain immunoreactive substance P (SP). Functionally, pulmonary DCs bound 125I-SP and displayed increased motility in vitro in response to graded concentrations of SP. However, SP had no effect on the accessory cell activities of DCs. To examine the role of neural influences on the pulmonary immune response to inhaled antigen, Lewis rats were pretreated with capsaicin (CAP), which damages small nerves and depletes neuropeptide stores, and then challenged intratracheally (i.t.) with hen egg lysozyme (HEL). The number and antigen-presenting cell activities of pulmonary DCs in the CAP-treated rats were comparable to those of controls up to day 14. T lymphocytes harvested from the regional lymph nodes draining the lung were effectively sensitized to HEL in both groups. However, when CAP-treated rats sensitized to HEL i.t. at day 0 were rechallenged with HEL i.t. at day 14, the lungs showed decreased numbers of OX-6+ DCs and diminished pulmonary lymphoid infiltrates compared with controls. We suggest that CAP interferes with a neural-mediated response that contributes to the accumulation of inflammatory cells during the efferent limb of the pulmonary-cell-mediated immune response in vivo. Images Figure 1 Figure 2 Figure 5 Figure 6 PMID:9137097

  20. Thermal Exfoliation of Natural Cellulosic Material for Graphene Synthesis

    NASA Astrophysics Data System (ADS)

    Ray, Ajoy Kumar; Chatterjee, Somenath; Singh, Jitendra Kumar; Bapari, Himangshu

    2015-01-01

    Hibiscus flower petals have been used as a cheap natural resource precursor for cost-effective synthesis of high quality graphene by thermal exfoliation process. In order to compare the quality of graphene obtained from the flower petals directly with the flower petals pretreated with nickel(II) chloride, Raman spectroscopic technique has been used as the structural probe. The role of temperature and the effect of nickel on thermal exfoliation process have been examined. It has been observed that graphene obtained via nickel incorporation is of better quality because NI2+ ions that get dispersed in the layered-structured cellulose at elevated temperatures get reduced to the metallic state, which in turn push the graphitic layers during thermal exfoliation to produce good quality graphene. In contrast, no such driving force is present in cellulose and hemi-cellulose of flower petals that contain lignin.

  1. Calcium-activated chloride channels in bovine pulmonary artery endothelial cells.

    PubMed Central

    Nilius, B; Prenen, J; Szücs, G; Wei, L; Tanzi, F; Voets, T; Droogmans, G

    1997-01-01

    1. We characterized Ca(2+)-activated Cl- currents in calf pulmonary artery endothelial (CPAE) cells by using a combined patch clamp and fura-2 microfluorescence technique to simultaneously measure ionic currents and the intracellular Ca2+ concentration, [Ca2+]i. 2. Various procedures that increased [Ca2+]i, such as stimulation with ATP or ionomycin, or loading the cells with Ca2+ via the patch pipette, activated a strongly outwardly rectifying current with a reversal potential close to the Cl- equilibrium potential. Changing the extracellular Cl- concentration shifted this reversal potential as predicted for a Cl- current. Buffering Ca2+ rises with BAPTA prevented ATP from activating the current. 3. Ca(2+)-activated Cl- currents could be distinguished from volume-activated Cl- currents, which were sometimes coactivated in the same cell. The latter showed much less outward rectification, their activation was voltage independent, and they could be inhibited by exposing the cells to hypertonic solutions. 4. The permeability ratio for the Ca(2+)-activated conductance of the anions iodide:chloride: gluconate was 1.71 +/- 0.06:1:0.39 +/- 0.03 (n = 12). 5. This Ca(2+)-activated Cl- current, ICl, Ca, inactivated rapidly at negative potentials and activated slowly at positive potentials. Outward tail currents were slowly decaying, while inward tail currents decayed much faster. 6. 4,4'-Diisothiocyanatostilbene-2,2'-disulphonic-acid (DIDS) and niflumic acid inhibited Icl,Ca in a voltage-dependent manner, i.e. they exerted a more potent block at positive potentials. The block by N-phenylanthracilic acid (NPA), 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and tamoxifen was voltage independent. Niflumic acid and tamoxifen were the most potent blockers. 7. The single-channel conductance was 7.9 +/- 0.7 pS (n = 15) at 300 mM extracellular Cl-. The channel open probability was high at positive potentials, but very small at negative potentials. 8. It is concluded that [Ca2+]i

  2. Cell- and isoform-specific increases in arginase expression in acute silica-induced pulmonary inflammation.

    PubMed

    Poljakovic, Mirjana; Porter, Dale W; Millecchia, Lyndell; Kepka-Lenhart, Diane; Beighley, Christopher; Wolfarth, Michael G; Castranova, Vincent; Morris, Sidney M

    2007-01-15

    Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase were elucidated in lungs of Sprague-Dawley rats 24 h following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time polymerase chain reaction (PCR), and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced two- and three-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100 g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no inducible nitric oxide synthase (iNOS) immunoreactivity was detected. In silica-treated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica. PMID:17365572

  3. Cell- and Isoform-specific Increases in Arginase Expression in Acute Silica-induced Pulmonary Inflammation

    PubMed Central

    Poljakovic, Mirjana; Porter, Dale W.; Millecchia, Lyndell; Kepka-Lenhart, Diane; Beighley, Christopher; Wolfarth, Michael G.; Castranova, Vincent; Morris, Sidney M.

    2009-01-01

    Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase was elucidated in lungs of Sprague-Dawley rats 24 hr following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time PCR, and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced 2- and 3-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no iNOS immunoreactivity was detected. In silica-treated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica. PMID:17365572

  4. Pulmonary function indices in children with sickle cell anemia in Enugu, south-east Nigeria

    PubMed Central

    Achigbu, Kingsley I.; Odetunde, Odutola I.; Chinawa, Josephat M.; Achigbu, Eberechukwu O.; Ikefuna, Anthony N.; Emodi, Ifeoma J.; Ibe, Bede C.

    2015-01-01

    Objectives: To determine the pulmonary function indices of children with sickle cell anemia (SCA) attending the pediatric sickle cell clinic at the University of Nigeria Teaching Hospital, Enugu, south-east Nigeria and to compare these indices with the results obtained from other regions. Methods: A case control study of lung function in children with SCA aged 6-20 years. The study was carried out in the University of Nigeria/University of Nigeria Teaching Hospital, Enugu State, Nigeria between October 2014 and January 2015. Measurements of the peak expiratory flow rate, forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were evaluated. Results: A total of 80 subjects were recruited into the study, comprising 40 homozygous HbSS (hemoglobin SS) patients and an equal number of controls. Children with SCA had statistically lower values of FEV1 (1.6±0.52), FVC (1.76±0.95), and peak expiratory flow rate (PEFR) (309.00±82.64) when compared with normal hemoglobin genotype FEV1 (12.01±0.53), FVC (2.12±0.54), and PEFR (364.10±87.85). The mean FVC, FEV1/FVC, and PEFR were also higher in the male control group compared with the HbSS male group, but these differences were not statistically significant. Female controls had significantly larger FEV1, FVC, and PEFR values compared with the HbSS females. Conclusion: The lung function indices were significantly lower in children and adolescents with SCA compared with the matched controls with a hemoglobin genotype AA. PMID:26219442

  5. The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human Pulmonary Cells.

    PubMed

    Angelini, Daniel J; Moyer, Robert A; Cole, Stephanie; Willis, Kristen L; Oyler, Jonathan; Dorsey, Russell M; Salem, Harry

    2015-01-01

    Organophosphorus (OP) pesticides are known to induce pulmonary toxicity in both humans and experimental animals. To elucidate the mechanism of OP-induced cytotoxicity, we examined the effects of parathion and malathion and their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells. Exposure to paraoxon and malaoxon produced a dose-dependent increase in cytotoxicity following a 24-hour exposure, while treatment with parathion or malathion produced no effects at clinically relevant concentrations. Exposure to paraoxon-induced caspase activation, but malaoxon failed to induce this response. Since caspases have a major role in the regulation of apoptosis and cell death, we evaluated OP-induced cell death in the presence of a caspase inhibitor. Pharmacological caspase inhibition protected against paraoxon-induced cell death but not malaoxon-induced cell death. These data suggest that caspase activation is a key signaling element in paraoxon-induced cell death, but not malaoxon-induced cellular death in the pulmonary epithelium. PMID:26173615

  6. Nontoxic impact of PEG-coated gold nanospheres on functional pulmonary surfactant-secreting alveolar type II cells.

    PubMed

    Bouzas, Virginia; Haller, Thomas; Hobi, Nina; Felder, Edward; Pastoriza-Santos, Isabel; Pérez-Gil, Jesús

    2014-12-01

    The outstanding properties of gold nanoparticles (NPs) make them very attractive for biomedical applications. In particular, the inhalation route has gained considerable interest as an innovative strategy for diagnosis and treatment of pulmonary diseases. It is, therefore, important to scrutinise the potentially deleterious or side effects of NPs on lung epithelium. The present study investigates, for the first time, the impact of polyethylene glycol (PEG)-coated NPs on freshly purified primary cultures of rat alveolar type II (ATII) cells. These cells play a central role in the respiratory function of the lungs. They are responsible for synthesizing and secreting pulmonary surfactant (PS), which is required to stabilise the respiratory surface during breathing dynamics. Cytotoxicity and cellular uptake of NPs was evaluated by analysing morphology, viability and exocytotic activity of ATII cells (PS secretion). The impact of ATII cells' exposure to NPs was studied in a wide range of gold concentration with particles sizes of 15 and 100 nm. The results show that PEG-coated NPs are very modestly internalised by ATII cells and it neither leads to detectable morphological changes nor to decreased cell viability nor to alterations in basic functional parameters such as PS secretion, even on exposure to high gold concentration (~0.2 mM) during relatively long periods of time (24-48 h). PMID:23914786

  7. Effects of carbon dioxide level (PCO sub 2 ) on the fibrinolytic activity (FA) of pulmonary artery endothelial cells (PAEC)

    SciTech Connect

    Langleben, D.; Moroz, L.A.; Danes, D. )

    1990-02-26

    Recovery from pulmonary thromboembolism depends on the rapidity and completeness of clot lysis. This involves endogenous fibrinolytic mechanisms, particularly the balance between plasminogen activators and inhibitors produced by endothelial cells. Hypocapnia is common in pulmonary embolism, however it is not known if endothelial fibrinolytic function is affected by PCO{sub 2}. The authors therefore measured the FA in medium (MCDB-131, 0.5% albumin) conditioned for 20 hours in-vitro by exposure to confluent cultures of bovine proximal PAEC. During conditioning, cells were exposed to 5% CO{sub 2} in air (PCO{sub 2} - 36-40mm Hg, CONTROL), or various PCO{sub 2} levels (30-55 mmHg, in air). FA of conditioned medium was determined by {sup 125}I-fibrin solid phase assay, with addition of plasminogen (10 ug/ml). With PCO{sub 2} levels {le} 35 mmHg, FA in the conditioned medium was 5 to 18% higher than CONTROL FA. When PCO{sub 2} was {ge} 45 mmHg, FA decreased 5 to 60% as compared to CONTROL FA. There was a significant negative linear relationship between PCO{sub 2} and FA. Thus, PCO{sub 2} level can affect PAEC mediated plasminogen activation. This finding may be relevant to in-vivo clearance of clots from pulmonary arteries.

  8. Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling

    PubMed Central

    Ni, Shirong; Wang, Dexuan; Qiu, Xiaoxiao; Pang, Lingxia; Song, Zhangjuan; Guo, Kunyuan

    2015-01-01

    Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant may play an important role in many of the processes of inflammation and fibrosis. Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress. Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. In the present study, we investigated bone marrow mesenchymal stem cells (BMSCs) for the treatment of bleomycin-induced pulmonary fibrosis. Our results showed that BMSCs administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. The gene expression levels of NAD(P)H: quinine oxidoreductase 1 (NQO1), gama-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), attenuated by bleomycin, were increased up to basal levels after BMSCs transplantation. BMSCs significantly increased superoxide dismutase (SOD) activity and inhibited malondialdehyde (MDA) production in the injured lung. The present study provides evidence that BMSCs may be a potential therapeutic reagent for the treatment of lung fibrosis. PMID:26339340

  9. Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells

    PubMed Central

    Kwok, Hoi-Hin; Poon, Po-Ying; Fok, Siu-Ping; Ying-Kit Yue, Patrick; Mak, Nai-Ki; Chan, Michael Chi-Wai; Peiris, Joseph Sriyal Malik; Wong, Ricky Ngok-Shun

    2016-01-01

    Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3′-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3′-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-β and IFN-γ1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection. PMID:26732368

  10. Simultaneous bilateral spontaneous pneumothorax following high-dose chemotherapy and bone marrow transplantation for mantle cell lymphoma without evidence of pulmonary disease.

    PubMed

    Schneider, Ashley E; Talmon, Geoffrey A

    2010-12-01

    Simultaneous bilateral spontaneous pneumothorax (SBSP) during high-dose chemotherapy has been described in patients with pulmonary involvement by malignancy, including sarcoma, trophoblastic tumor, non-seminomatous testicular cancer, and non-Hodgkin lymphoma. We present a case of SBSP developing in a patient 11 days after a high-dose chemotherapy preparative regimen and stem cell transplantation without underlying pulmonary disease or evidence of lung lesions. It is important to recognize spontaneous pneumothorax as a potential complication of high-dose chemotherapy, especially in patients with known pulmonary lesions. PMID:20589405

  11. Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

    PubMed Central

    Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

    2016-01-01

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy

  12. Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

    DOE PAGESBeta

    Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

    2016-06-23

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic

  13. Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.

    PubMed

    Warsinske, Hayley C; Wheaton, Amanda K; Kim, Kevin K; Linderman, Jennifer J; Moore, Bethany B; Kirschner, Denise E

    2016-01-01

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy

  14. Impact of pre-transplant pulmonary infection developed in horizontal laminar flow unit on the outcome of subsequent allogeneic hematopoietic stem cell transplantation

    PubMed Central

    He, Gan-Lin; Chang, Ying-Jun; Xu, Lan-Ping; Zhang, Xiao-Hui; Wang, Yu; Liu, Kai-Yan

    2016-01-01

    Background So far, there is very little literature on how pre-transplant pulmonary infection developed in horizontal laminar flow unit (HLFU) affects outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A retrospective analysis was performed on allo-HSCT recipients who were diagnosed with pre-transplant pulmonary infection developed in HLFU between January 2012 and December 2012. Various tests were analyzed to evaluate the overall survival (OS) and pulmonary infection rate after allo-HSCT. Results Among 317 patients who received allo-HSCT from related donors, 7 cases of human leukocyte antigen (HLA)-haploidentical transplantation reported a fever, cough, and other symptoms before transplantation. Chest radiography findings showed pulmonary infection, and the C-reactive protein (CRP) level was higher than normal, which confirmed pulmonary infection (incidence rate 2.21%). The Breslow test suggested that the early survival rate was lower in the group with pre-transplant pulmonary infection than in the group without pre-transplant pulmonary infection (OS: 28.4 vs. 42.4 months; P=0.023); the early survival rate was lower in patients with a pulmonary infection accompanied by bilateral pleural effusion than in patients without pleural effusion (OS: 1.5 vs. 36.3 months; P=0.010). In the first month after transplantation, the difference in the CD4CD45RO+CD45RA- and CD4CD45RO-CD45RA+ between the groups with and without pre-transplant pulmonary infection was statistically significant (P<0.05). Patients with pre-transplant pulmonary infection who survived >3 years had a higher rate of pulmonary infection in the first 2 months after allo-HSCT than those without pre-transplant pulmonary infection [100% (5/5 patients) vs. 38.1% (118/310); χ2=5.542, P=0.019]. Conclusions Development of pre-transplant pulmonary infection in the HLFU in patients with hematological malignancies who receive HLA-haploidentical HSCT is associated with an increased risk

  15. Pulmonary valve stenosis

    MedlinePlus

    ... valve pulmonary stenosis; Pulmonary stenosis; Stenosis - pulmonary valve; Balloon valvuloplasty - pulmonary ... water pills) Treat abnormal heartbeats and rhythms Percutaneous balloon pulmonary dilation (valvuloplasty) may be performed when no ...

  16. Variation in the pulmonary hypertensive responsiveness of broilers to lipopolysaccharide and innate variation in nitric oxide production by mononuclear cells.

    PubMed

    Bowen, O T; Wideman, R F; Anthony, N B; Erf, G F

    2006-08-01

    Variability among broilers in their pulmonary hypertensive (PH) responsiveness to lipopolysaccharide (LPS) appears to reflect innate variation in the types or proportions of vasodilators and vasoconstrictors released by leukocytes and endothelial cells. Two experiments were designed to evaluate possible correlations between the PH responsiveness to LPS in vivo and the quantities of nitric oxide (NO; a potent pulmonary vasodilator) produced by mononuclear cells in vitro. In Experiment 1, blood samples were collected from male broilers from a base population (control group) and from survivors of a 60% lethal dose i.v. injection of cellulose microparticles (MP survivor group). In Experiment 2, blood samples were collected from male broilers from a relaxed line and from lines known to be susceptible or resistant to pulmonary hypertension syndrome. Peripheral mononuclear cells (PMNC) from each blood sample were cultured at 2 million cells per well, remained unstimulated, or were stimulated with LPS to elicit the expression of inducible NO synthase, and the 24-h production of NO was measured. In both experiments, unstimulated PMNC cultures did not produce consistently detectable levels of NO, whereas LPS-stimulated cultures produced quantities of NO that varied widely among individuals. Nitric oxide production by cultured PMNC also was evaluated by flow cytometry, demonstrating that LPS-stimulated PMNC produced substantially more NO than did unstimulated cells in all of the groups evaluated. Moreover, NO-producing PMNC were identified to be monocytes. The same broilers from which PMNC had been isolated were catheterized subsequently to record pulmonary arterial pressure, LPS was injected i.v. to assess the amplitudes of peak and postpeak PH responses, then N(omega)-nitro-L-arginine methyl ester was injected to inhibit ongoing NO production. In Experiment 1, the amplitude of the peak and postpeak PH responses to LPS were correlated with the quantity of NO produced by LPS

  17. A chronic obstructive pulmonary disease related signature in squamous cell lung cancer.

    PubMed

    Boelens, Mirjam C; Gustafson, Adam M; Postma, Dirkje S; Kok, Klaas; van der Vries, Gerben; van der Vlies, Pieter; Spira, Avrum; Lenburg, Marc E; Geerlings, Marie; Sietsma, Hannie; Timens, Wim; van den Berg, Anke; Groen, Harry J M

    2011-05-01

    The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2-31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD. PMID:20832896

  18. Risk Factors of Pulmonary Hypertension in Brazilian Patients with Sickle Cell Anemia

    PubMed Central

    Lobo, Clarisse Lopes de Castro; do Nascimento, Emilia Matos; Abelha, Renato; Queiroz, Ana Maria Mach; Connes, Philippe; Cardoso, Gilberto Perez; Ballas, Samir K.

    2015-01-01

    This study was a prospective cross-sectional cohort study of 125 patients with sickle cell anemia (SS) between the ages of 16 to 60 years. Enrolled patients were followed-up prospectively for 15 months. Demographic, clinical, hematological and routine biochemical data were obtained on all patients. Six-minute walk test and Doppler Echocardiography were performed on all patients. A tricuspid regurgitant jet velocity (TRJV) < 2.5 m/sec was considered normal, 2.5 ≤ TRJV ≤ 3.0 was considered mild-moderate and > 3.0 m/sec, severe. Patients with abnormal TRJV were significantly older and more anemic, had significantly higher lactate dehydrogenase (LDH) levels, reticulocyte count and incidence of death. The logistic multimodal model implemented for the 125 patients indicated that age was the covariate that influenced the outcome of normal or abnormal TRJV with a cutoff age of thirty-two years. The survival rate for the group of patients with creatinine (Cr) > 1.0 mg/dL was lower than the group with Cr ≤ 1 and normal TRJV. A coefficient matrix showed that the LDH values were weakly correlated with the reticulocyte count but strongly correlated with hemoglobin suggesting that the TRJV values were not correlated with the hemolytic rate but with anemia. Ten patients died during the follow-up of whom 7 had TRJV > 2.5 m/sec. Acute chest syndrome was the most common cause of death followed by sepsis. In conclusion, this study shows that patients with SS older than thirty-two years with high LDH, elevated TRJV, severe anemia and Cr > 1 have poor prognosis and may be at risk of having pulmonary hypertension and should undergo RHC. PMID:26335226

  19. Zinc-related metallothionein metabolism in bovine pulmonary artery endothelial cells.

    PubMed

    Bobilya, D J; Reynolds, J T; Faia, K L; Briske-Anderson, M; Reeves, P G

    1999-03-01

    Bovine pulmonary artery endothelial cells (BPAEC) were cultured in vitro under a variety of conditions to investigate how metallothionein (MT) might participate in zinc homeostasis. Experimental conditions included 10% serum to ensure that the in vitro environment would be a better reflection of the in vivo situation than with protein-free medium. MT was increased by acutely high zinc concentrations (100-200 micromol/L) in the extracellular environment. MT was relatively insensitive to moderate changes in zinc concentration (2-50 micromol/L), even after prolonged exposure for 7 to 12 days. BPAEC had reduced MT content when grown in medium containing serum that had been dialyzed to remove components with a molecular mass of less than 1,000, including zinc. Because the principal source of the major minerals in the experimental medium was not the serum, their concentrations in the final medium were not significantly influenced by serum dialysis. Restoring the zinc concentration in the medium containing the dialyzed serum did not restore MT content in BPAEC, suggesting that some small molecular weight molecule other than zinc established their basal MT content. This study did not identify these putative factors in serum, but hormones are likely candidates. Forty-eight-hour incubations of BPAEC with interleukin (IL-6) or dexamethasone increased cellular MT; however, 17beta-estradiol decreased MT, and IL-1 and adenosine 3',5'-cyclic phosphate (cAMP) had no discernible effect. We conclude that extracellular zinc concentrations have relatively little impact on the cellular concentrations of MT and zinc of BPAEC in vitro. Zinc homeostasis by BPAEC is not maintained by changing the MT concentration in response to changes in the extracellular zinc environment. (J. Nutr. Biochem. 10:00-00, 1999). PMID:15539281

  20. Enhancement of nitric oxide production by pulmonary cells following silica exposure.

    PubMed

    Castranova, V; Huffman, L J; Judy, D J; Bylander, J E; Lapp, L N; Weber, S L; Blackford, J A; Dey, R D

    1998-10-01

    In vivo exposure of rat lungs to crystalline silica either by intratracheal instillation or by inhalation results in an increase in mRNA levels for inducible nitric oxide synthase (iNOS) in bronchoalveolar lavage cells (BALC), elevated nitric oxide (.NO) production by BALC, and an increase in .NO-dependent chemiluminescence (CL) from alveolar macrophages (AM). Induction of iNOS message occurs in both AM and polymorphonuclear leukocytes (PMN) harvested from silica-exposed lungs but is not significantly elevated in lavaged lung tissue. In vitro exposure of AM to silica does not stimulate .NO production or enhance iNOS message. However, treatment of naive AM with conditioned media from BALC harvested from silica-exposed rats does increase iNOS message and .NO production by these AM. The potency of this conditioned medium is dependent on interaction between AM and PMN. In the rat model, a relationship exists between the ability of various dusts to cause PMN recruitment or protein leakage into the alveolar space and the induction of iNOS message in BALC, i.e., silica > coal mine dust > carbonyl iron > titanium dioxide. Similarly, a comparison of BALC from a healthy volunteer, a silica-exposed coal miner with a normal chest radiograph, and a silica-exposed coal miner with an abnormal chest radiograph shows a correlation between pathology and both the level of iNOS message in BALC and the magnitude of .NO-dependent CL from AM. These data suggest that .NO may play a role in silicosis and that human pulmonary phagocytes exhibit enhanced .NO production in response to an inflammatory insult. PMID:9788892

  1. p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor.

    PubMed

    Damico, Rachel; Simms, Tiffany; Kim, Bo S; Tekeste, Zenar; Amankwan, Henry; Damarla, Mahendra; Hassoun, Paul M

    2011-03-01

    Exposure to cigarette smoke (CS) is the most common cause of emphysema, a debilitating pulmonary disease histopathologically characterized by the irreversible destruction of lung architecture. Mounting evidence links enhanced endothelial apoptosis causally to the development of emphysema. However, the molecular determinants of human endothelial cell apoptosis and survival in response to CS are not fully defined. Such determinants could represent clinically relevant targets for intervention. We show here that CS extract (CSE) triggers the death of human pulmonary macrovascular endothelial cells (HPAECs) through a caspase 9-dependent apoptotic pathway. Exposure to CSE results in the increased expression of p53 in HPAECs. Using the p53 inhibitor, pifithrin-α (PFT-α), and RNA interference (RNAi) directed at p53, we demonstrate that p53 function and expression are required for CSE-mediated apoptosis. The expression of macrophage migration inhibitory factor (MIF), an antiapoptotic cytokine produced by HPAECs, also increases in response to CSE exposure. The addition of recombinant human MIF prevents cell death from exposure to CSE. Further, the suppression of MIF or its receptor/binding partner, Jun activation domain-binding protein 1 (Jab-1), with RNAi enhances the sensitivity of human pulmonary endothelial cells to CSE via a p53-dependent (PFT-α-inhibitable) pathway. Finally, we demonstrate that MIF is a negative regulator of p53 expression in response to CSE, placing MIF upstream of p53 as an antagonist of CSE-induced apoptosis. We conclude that MIF can protect human vascular endothelium from the toxic effects of CSE via the antagonism of p53-mediated apoptosis. PMID:20448056

  2. Intercalation of methotrexatum into layered double hydroxides via exfoliation-reassembly process

    NASA Astrophysics Data System (ADS)

    Liu, Su-Qing; Li, Shu-Ping; Li, Xiao-Dong

    2015-03-01

    In this paper, the intercalation of methotrexatum (MTX) into layered double hydroxides (LDHs) via an exfoliation-reassembly process was reported and the resulting hybrids were then characterized by X-ray diffraction (XRD) patterns, Fourier transform infrared (FTIR) spectroscopy and atomic force microscopy (AFM) patterns etc. In the synthesis procedure, LDHs particles were firstly delaminated into well-dispersed 2D nanosheets in formamide by ultrasonic treatment at room temperature, and then the resulting LDH nanosheets were reassembled in MTX solution to form MTX intercalated LDH (MTX/LDHs) hybrids. AFM images showed that during the exfoliation process a large part of LDHs particles were delaminated into single and double brucite layers. XRD patterns and FTIR investigations manifested the successful intercalation of MTX anions into LDHs interlayers for the final samples. It was also found out that the drug-loading capacity of the hybrids increased with the concentrations of MTX solutions, while the morphology became even aggregated. At last, the cell cytotoxicity of the hybrids was estimated by MTT assays on the human lung cancer cells (A549), and the results stated that MTX/LDHs hybrids had effective suppress role on the proliferation of cancer cells.

  3. Triangular Black Phosphorus Atomic Layers by Liquid Exfoliation.

    PubMed

    Seo, Soonjoo; Lee, Hyun Uk; Lee, Soon Chang; Kim, Yooseok; Kim, Hyeran; Bang, Junhyeok; Won, Jonghan; Kim, Youngjun; Park, Byoungnam; Lee, Jouhahn

    2016-01-01

    Few-layer black phosphorus (BP) is the most promising material among the two-dimensional materials due to its layered structure and the excellent semiconductor properties. Currently, thin BP atomic layers are obtained mostly by mechanical exfoliation of bulk BP, which limits applications in thin-film based electronics due to a scaling process. Here we report highly crystalline few-layer black phosphorus thin films produced by liquid exfoliation. We demonstrate that the liquid-exfoliated BP forms a triangular crystalline structure on SiO2/Si (001) and amorphous carbon. The highly crystalline BP layers are faceted with a preferred orientation of the (010) plane on the sharp edge, which is an energetically most favorable facet according to the density functional theory calculations. Our results can be useful in understanding the triangular BP structure for large-area applications in electronic devices using two-dimensional materials. The sensitivity and selectivity of liquid-exfoliated BP to gas vapor demonstrate great potential for practical applications as sensors. PMID:27026070

  4. Triangular Black Phosphorus Atomic Layers by Liquid Exfoliation

    NASA Astrophysics Data System (ADS)

    Seo, Soonjoo; Lee, Hyun Uk; Lee, Soon Chang; Kim, Yooseok; Kim, Hyeran; Bang, Junhyeok; Won, Jonghan; Kim, Youngjun; Park, Byoungnam; Lee, Jouhahn

    2016-03-01

    Few-layer black phosphorus (BP) is the most promising material among the two-dimensional materials due to its layered structure and the excellent semiconductor properties. Currently, thin BP atomic layers are obtained mostly by mechanical exfoliation of bulk BP, which limits applications in thin-film based electronics due to a scaling process. Here we report highly crystalline few-layer black phosphorus thin films produced by liquid exfoliation. We demonstrate that the liquid-exfoliated BP forms a triangular crystalline structure on SiO2/Si (001) and amorphous carbon. The highly crystalline BP layers are faceted with a preferred orientation of the (010) plane on the sharp edge, which is an energetically most favorable facet according to the density functional theory calculations. Our results can be useful in understanding the triangular BP structure for large-area applications in electronic devices using two-dimensional materials. The sensitivity and selectivity of liquid-exfoliated BP to gas vapor demonstrate great potential for practical applications as sensors.

  5. Preparation of colloidal graphene in quantity by electrochemical exfoliation.

    PubMed

    Chen, Kunfeng; Xue, Dongfeng

    2014-12-15

    We reported the preparation of colloidal graphene in quantity via the anodic exfoliation of graphite in (NH4)2SO4 aqueous solution. In the currently designed electrochemical exfoliation route, mass high-quality graphene was produced within short reaction time, around 1h. The proposed electrochemical exfoliation mechanism showed that SO4(2-) and H2O can be intercalated into those graphite sheets, monolayer and few-layer graphene were obtained by the formation of gaseous SO2 and O2 within graphite sheets. Stability evaluation showed that our exfoliated colloidal graphene can be perfectly stabilized in DMF solvent more than 1 week. The colloidal graphene can be used to construct various simple and complex patterns by writing it on A4 paper, which can be applied to flexible printed electronic devices. Furthermore, colloidal graphene can show promising applications in the fabrication of binder- and additive-free electrodes for supercapacitors and lithium-ion batteries. Our present method shows huge potential for industrial-scale synthesis of high-quality graphene and further commercialization of graphene colloid for numerous advanced applications in flexible printed electronics and energy storage devices. PMID:25265584

  6. Determination of dimensions of exfoliating materials in aqueous suspensions.

    PubMed

    Karpovich, Anastasia L; Vlasova, Maria F; Sapronova, Natalya I; Sukharev, Valentin S; Ivanov, Victor V

    2016-01-01

    A method for measurement of dimensions of platy particles of exfoliating, or delaminating, materials, such as clays, in aqueous suspensions in situ is proposed. Equivalent spherical diameter (esd), measured by many common methods, depends more on the major (lateral) dimension of a particle, while it is less sensitive to changes of the particle thickness. Addition of the second method, results of which are a function of the particle diameter and thickness too, would provide more accurate determination of the particle dimensions. Previously, a combination of low-temperature nitrogen adsorption (BET) and dynamic light scattering (DLS) methods for determination of specific surface area of dry powder of platy particles and their esd in suspension was suggested. While such combination was suitable for measurement of particle size for non-exfoliating materials, it gave incorrect results for exfoliating materials, which dramatically change their surface area when dispersed in liquid. We modify this method by substituting BET method with NMR relaxometry, which allows to measure wetted surface area of the dispersed material directly in suspension. The advantages of this method are:•More accurate determination of diameter and thickness of platy, particularly exfoliating, materials directly in suspension.•Possibility of routine monitoring of particle size changes during the dispersing process. PMID:27408825

  7. Triangular Black Phosphorus Atomic Layers by Liquid Exfoliation

    PubMed Central

    Seo, Soonjoo; Lee, Hyun Uk; Lee, Soon Chang; Kim, Yooseok; Kim, Hyeran; Bang, Junhyeok; Won, Jonghan; Kim, Youngjun; Park, Byoungnam; Lee, Jouhahn

    2016-01-01

    Few-layer black phosphorus (BP) is the most promising material among the two-dimensional materials due to its layered structure and the excellent semiconductor properties. Currently, thin BP atomic layers are obtained mostly by mechanical exfoliation of bulk BP, which limits applications in thin-film based electronics due to a scaling process. Here we report highly crystalline few-layer black phosphorus thin films produced by liquid exfoliation. We demonstrate that the liquid-exfoliated BP forms a triangular crystalline structure on SiO2/Si (001) and amorphous carbon. The highly crystalline BP layers are faceted with a preferred orientation of the (010) plane on the sharp edge, which is an energetically most favorable facet according to the density functional theory calculations. Our results can be useful in understanding the triangular BP structure for large-area applications in electronic devices using two-dimensional materials. The sensitivity and selectivity of liquid-exfoliated BP to gas vapor demonstrate great potential for practical applications as sensors. PMID:27026070

  8. Exfoliated black phosphorus gas sensing properties at room temperature

    NASA Astrophysics Data System (ADS)

    Donarelli, M.; Ottaviano, L.; Giancaterini, L.; Fioravanti, G.; Perrozzi, F.; Cantalini, C.

    2016-06-01

    Room temperature gas sensing properties of chemically exfoliated black phosphorus (BP) to oxidizing (NO2, CO2) and reducing (NH3, H2, CO) gases in a dry air carrier have been reported. To study the gas sensing properties of BP, chemically exfoliated BP flakes have been drop casted on Si3N4 substrates provided with Pt comb-type interdigitated electrodes in N2 atmosphere. Scanning electron microscopy and x-ray photoelectron spectroscopy characterizations show respectively the occurrence of a mixed structure, composed of BP coarse aggregates dispersed on BP exfoliated few layer flakes bridging the electrodes, and a clear 2p doublet belonging to BP, which excludes the occurrence of surface oxidation. Room temperature electrical tests in dry air show a p-type response of multilayer BP with measured detection limits of 20 ppb and 10 ppm to NO2 and NH3 respectively. No response to CO and CO2 has been detected, while a slight but steady sensitivity to H2 has been recorded. The reported results confirm, on an experimental basis, what was previously theoretically predicted, demonstrating the promising sensing properties of exfoliated BP.

  9. Automotive body panel containing thermally exfoliated graphite oxide

    NASA Technical Reports Server (NTRS)

    Prud'Homme, Robert K. (Inventor); Aksay, Ilhan A. (Inventor); Adamson, Douglas (Inventor); Abdala, Ahmed (Inventor)

    2011-01-01

    An automotive body panel containing a polymer composite formed of at least one polymer and a modified graphite oxide material, which is a thermally exfoliated graphite oxide with a surface area of from about 300 m.sup.2/g to 2600 m.sup.2/g.

  10. High-quality thin graphene films from fast electrochemical exfoliation.

    PubMed

    Su, Ching-Yuan; Lu, Ang-Yu; Xu, Yanping; Chen, Fu-Rong; Khlobystov, Andrei N; Li, Lain-Jong

    2011-03-22

    Flexible and ultratransparent conductors based on graphene sheets have been considered as one promising candidate for replacing currently used indium tin oxide films that are unlikely to satisfy future needs due to their increasing cost and losses in conductivity on bending. Here we demonstrate a simple and fast electrochemical method to exfoliate graphite into thin graphene sheets, mainly AB-stacked bilayered graphene with a large lateral size (several to several tens of micrometers). The electrical properties of these exfoliated sheets are readily superior to commonly used reduced graphene oxide, which preparation typically requires many steps including oxidation of graphite and high temperature reduction. These graphene sheets dissolve in dimethyl formamide (DMF), and they can self-aggregate at air-DMF interfaces after adding water as an antisolvent due to their strong surface hydrophobicity. Interestingly, the continuous films obtained exhibit ultratransparency (∼96% transmittance), and their sheet resistance is <1k Ω/sq after a simple HNO3 treatment, superior to those based on reduced graphene oxide or graphene sheets by other exfoliation methods. Raman and STM characterizations corroborate that the graphene sheets exfoliated by our electrochemical method preserve the intrinsic structure of graphene. PMID:21309565

  11. Differential concentration-specific effects of caffeine on cell viability, oxidative stress, and cell cycle in pulmonary oxygen toxicity in vitro

    SciTech Connect

    Tiwari, Kirti Kumar; Chu, Chun; Couroucli, Xanthi; Moorthy, Bhagavatula; Lingappan, Krithika

    2014-08-08

    Highlights: • Caffeine at 0.05 mM decreases oxidative stress in hyperoxia. • Caffeine at 1 mM decreases cell viability, increases oxidative stress in hyperoxia. • Caffeine at 1 but not 0.05 mM, abrogates hyperoxia-induced G2/M arrest. - Abstract: Caffeine is used to prevent bronchopulmonary dysplasia (BPD) in premature neonates. Hyperoxia contributes to the development of BPD, inhibits cell proliferation and decreases cell survival. The mechanisms responsible for the protective effect of caffeine in pulmonary oxygen toxicity remain largely unknown. A549 and MLE 12 pulmonary epithelial cells were exposed to hyperoxia or maintained in room air, in the presence of different concentrations (0, 0.05, 0.1 and 1 mM) of caffeine. Caffeine had a differential concentration-specific effect on cell cycle progression, oxidative stress and viability, with 1 mM concentration being deleterious and 0.05 mM being protective. Reactive oxygen species (ROS) generation during hyperoxia was modulated by caffeine in a similar concentration-specific manner. Caffeine at 1 mM, but not at the 0.05 mM concentration decreased the G2 arrest in these cells. Taken together this study shows the novel funding that caffeine has a concentration-specific effect on cell cycle regulation, ROS generation, and cell survival in hyperoxic conditions.

  12. Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients.

    PubMed

    Jantunen, E; Piilonen, A; Volin, L; Ruutu, P; Parkkali, T; Koukila-Kähkölä, P; Ruutu, T

    2002-02-01

    Lung problems are common in allogeneic stem cell transplant (SCT) recipients. To evaluate the feasibility and diagnostic yield of radiologically guided fine needle lung biopsy (FNLB) in allogeneic SCT recipients with focal pulmonary lesions, a retrospective analysis was carried out. Between 1989 and 1998, radiologists performed a total of 30 FNLBs in 21 allogeneic SCT recipients, guided either by ultrasound (n = 17) or computed tomography (n = 13). The median time from SCT to the first FNLB was 131 days (20-343 days). Prophylactic platelet transfusions were given in 19 procedures (66%). The complications of FNLB included clinically insignificant pneumothorax in four procedures (13%) and self-limiting haemoptysis in one case (3%). The first FNLB was suggestive of invasive pulmonary aspergillosis (IPA) in five patients (24%). Additional clinically useful findings of FNLB included Pseudomonas (two patients) and Nocardia (one patient). The final diagnosis of pulmonary lesions was IPA in 14 patients, immunological lung problems in four patients and other in three patients. Radiologically guided FNLB is feasible in allogeneic SCT recipients and has a low complication rate. The diagnostic yield is high especially for IPA. PMID:11896433

  13. Effect of pulmonary surfactant on the dissolution, stability and uptake of zinc oxide nanowires by human respiratory epithelial cells.

    PubMed

    Theodorou, Ioannis G; Ruenraroengsak, Pakatip; Gow, Andrew; Schwander, Stephan; Zhang, Junfeng Jim; Chung, Kian Fan; Tetley, Teresa D; Ryan, Mary P; Porter, Alexandra E

    2016-11-01

    Inhaled nanoparticles (NPs) have high-deposition rates in th