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Sample records for lung vascular filter

  1. Strategic Plan for Lung Vascular Research

    PubMed Central

    Erzurum, Serpil; Rounds, Sharon I.; Stevens, Troy; Aldred, Micheala; Aliotta, Jason; Archer, Stephen L.; Asosingh, Kewal; Balaban, Robert; Bauer, Natalie; Bhattacharya, Jahar; Bogaard, Harm; Choudhary, Gaurav; Dorn, Gerald W.; Dweik, Raed; Fagan, Karen; Fallon, Michael; Finkel, Toren; Geraci, Mark; Gladwin, Mark T.; Hassoun, Paul M.; Humbert, Marc; Kaminski, Naftali; Kawut, Steven M.; Loscalzo, Joseph; McDonald, Donald; McMurtry, Ivan F.; Newman, John; Nicolls, Mark; Rabinovitch, Marlene; Shizuru, Judy; Oka, Masahiko; Polgar, Peter; Rodman, David; Schumacker, Paul; Stenmark, Kurt; Tuder, Rubin; Voelkel, Norbert; Sullivan, Eugene; Weinshilboum, Richard; Yoder, Mervin C.; Zhao, Yingming; Gail, Dorothy; Moore, Timothy M.

    2010-01-01

    The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype–phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes. PMID:20833821

  2. Increased Sheep Lung Vascular Permeability Caused by Pseudomonas Bacteremia

    PubMed Central

    Brigham, Kenneth L.; Woolverton, William C.; Blake, Lynn H.; Staub, Norman C.

    1974-01-01

    In awake sheep, we compared the responses of lung lymph flow and lymph and plasma protein concentrations to steady state elevations of pulmonary vascular pressures made by inflating a left atrial balloon with those after an intravenous infusion of 105-1010Pseudomonas aeruginosa. Lymph flow increased when pressure was increased, but lymph-plasma protein concentration ratios always fell and lymph protein flow (lymph flow × lymph protein concentration) increased only slightly. After Pseudomonas, sheep had transient chills, fever, leukopenia, hypoxemia, increased pulmonary artery pressure and lymph flow and decreased left atrial pressure and lymph protein concentration, 3-5 h after Pseudomonas, when vascular pressures and lymph protein concentrations had returned to near base line, lymph flow increased further to 3-10 times base line and remained at a steady level for many hours. During this steady state period, lymph-plasma protein concentration ratios were similar to base line and lymph protein flow was higher than in the increased pressure studies. Two sheep died of pulmonary edema 7 and 9 h after Pseudomonas, but in 16 studies, five other sheep appeared well during the period of highest lymph flow and all variables returned to base line in 24-72 h. Six serial indicator dilution lung water studies in five sheep changed insignificantly from base line after Pseudomonas. Postmortem lung water was high in the two sheep dead of pulmonary edema and one other, but six sheep killed 1-6 h after Pseudomonas had normal lung water. Because of the clear difference between the effects of increased pressure and Pseudomonas on lymphplasma protein concentration ratios and lymph protein flow, we conclude that Pseudomonas causes a prolonged increase in lung vessel permeability to protein. Because we saw lung lymph flow as high as 10 times base line without pulmonary edema, we conclude that lung lymphatics are a sensitive high-capacity mechanism for removing excess filtered fluid. An

  3. Vascular leiomyoma of the lung arising from pulmonary artery.

    PubMed

    Terada, Tadashi

    2013-01-01

    Leiomyoma of the lung is extremely rare. The entity is not described in WHO blue book. Less than 100 cases of leiomyoma of the lung have been reported in the literature. However, vascular leiomyoma has not been reported in the literature, to the author's best knowledge. Herein reported is the first case of vascular leiomyoma of the lung arising from smooth muscles of the pulmonary artery. A 62-year-old woman (non-smoker) was found to have a small tumor in the upper lobe in the right lung in routine check. Imaging modalities including CT demonstrated no metastatic lesions. Although clinical cytology and biopsy revealed no malignant cell, right upper lobectomy was performed under the clinical diagnosis of lung carcinoma. Grossly, a white tumor of 1 x 0.8 cm was recognized in the lung. Microscopically, the tumor was connected to the pulmonary arteries. The tumor was composed of mature smooth muscles. Small pulmonary arteries are embedded in the tumor. No lymphatics were seen. Immunohistochemically, the tumor cells were poisitive for alpha-smooth muscle actin, vimentin and Ki-67 (labeling 2%). However, they were negative for cytokeratin (CK) AE1/3, CK CAM5.2, desmin, S100 protein, p53, CD34, KIT, HMB45, estrogen receptor, progesterone receptor, and myoglobin. A pathological diagnosis of primary vascular leiomyoma arising from the smooth muscle of pulmonary artery was made. The patient is now free from tumor, and is now alive 10 year after the operation. PMID:23236548

  4. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis.

    PubMed

    Huang, Yujie; Song, Nan; Ding, Yanping; Yuan, Shaopeng; Li, Xuhui; Cai, Hongchen; Shi, Hubing; Luo, Yongzhang

    2009-10-01

    Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-beta1 and tumor necrosis factor-alpha signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis. PMID:19773447

  5. Adiponectin protects against hyperoxic lung injury and vascular leak

    PubMed Central

    Sliman, Sean M.; Patel, Rishi B.; Cruff, Jason P.; Kotha, Sainath R.; Newland, Christie A.; Schrader, Carrie A.; Sherwani, Shariq I.; Gurney, Travis O.; Magalang, Ulysses J.; Parinandi, Narasimham L.

    2014-01-01

    Adiponectin (Ad), an adipokine exclusively secreted by the adipose tissue, has emerged as a paracrine metabolic regulator as well as a protectant against oxidative stress. Pharmacological approaches of protecting against clinical hyperoxic lung injury during oxygen therapy/treatment are limited. Earlier, we have reported that Ad inhibits the NADPH oxidase-catalyzed formation of superoxide from molecular oxygen in human neutrophils. Having this as the premise, we conducted studies to determine whether (i) exogenous Ad would protect against the hyperoxia-induced barrier dysfunction in the lung endothelial cells (ECs) in vitro and (ii) endogenously synthesized Ad would protect against hyperoxic lung injury in wild type (WT) and Ad-overexpressing transgenic (AdTg) mice in vivo. The results demonstrated that exogenous Ad protected against the hyperoxia-induced oxidative stress, loss of glutathione (GSH), cytoskeletal reorganization, barrier dysfunction, and leak in the lung ECs in vitro. Furthermore, the hyperoxia-induced lung injury, vascular leak, and lipid peroxidation were significantly attenuated in AdTg mice in vivo. Also, AdTg mice exhibited elevated levels of total thiols and GSH in the lungs as compared to WT mice. For the first time, our studies demonstrated that Ad protected against the hyperoxia-induced lung damage apparently through attenuation of oxidative stress and modulation of thiol-redox status. PMID:22183615

  6. Attenuation of Lipopolysaccharide-Induced Lung Vascular Stiffening by Lipoxin Reduces Lung Inflammation

    PubMed Central

    Meng, Fanyong; Mambetsariev, Isa; Tian, Yufeng; Beckham, Yvonne; Meliton, Angelo; Leff, Alan; Gardel, Margaret L.; Allen, Michael J.; Birukov, Konstantin G.

    2015-01-01

    Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action. PMID:24992633

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

    PubMed

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

    1999-04-01

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

  8. Radioimmunotherapy of micrometastases in lung with vascular targeted213Bi

    PubMed Central

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

    1999-01-01

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

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

    PubMed

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

    1992-02-01

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

  10. Prognostic value of vascularity and vascular endothelial growth factor expression in non-small cell lung cancer

    PubMed Central

    Baillie, R; Carlile, J; Pendleton, N; Schor, A

    2001-01-01

    Aims—High expression of the angiogenic factor vascular endothelial growth factor (VEGF) in tumours has been found to be associated with poor prognosis in some studies, but not in others. The aims of this study were to determine the prognostic value of VEGF in operable non-small cell lung cancer (NSCLC) and its possible association with vascularity. Methods—Sections from 81 NSCLC archival specimens were stained with antibodies to von Willebrand factor (vWF) and VEGF. Vascularity was measured by the average density of vWF positive vessels. VEGF expression in tumour cells was assessed by consensus of two independent observers according to three indices, namely: (1) percentage of area stained, (2) intensity of staining, and (3) final score (product of area and intensity). Results—VEGF immunoreactivity was present in all tumours and adjacent normal lung tissue. None of the three VEGF indices was associated with vascularity or the clinical parameters examined. Mean survival times were shorter in patients with high VEGF expression, but the difference was not significant. This applied to the full cohort of patients, or when analysed separately according to tumour type or stage. However, high VEGF expression was associated with poor survival in patients with high vascularity (p = 0.02). VEGF had no discriminant value among patients with low vascularity. Vascularity had no prognostic value, except for late stage patients (UICC stages II and IIIa combined; n = 36), where high vascularity was associated with longer survival (p = 0.01). Conclusions—VEGF on its own has no prognostic value in NSCLC, but may become a useful indicator when combined with vascularity. VEGF may play a physiological role in the normal lung. Key Words: non-small cell lung cancer • vascular endothelial growth factor • vascularity • prognosis PMID:11215279

  11. Vascular Tree Segmentation in Medical Images Using Hessian-Based Multiscale Filtering and Level Set Method

    PubMed Central

    Jin, Jiaoying; Yang, Linjun; Zhang, Xuming

    2013-01-01

    Vascular segmentation plays an important role in medical image analysis. A novel technique for the automatic extraction of vascular trees from 2D medical images is presented, which combines Hessian-based multiscale filtering and a modified level set method. In the proposed algorithm, the morphological top-hat transformation is firstly adopted to attenuate background. Then Hessian-based multiscale filtering is used to enhance vascular structures by combining Hessian matrix with Gaussian convolution to tune the filtering response to the specific scales. Because Gaussian convolution tends to blur vessel boundaries, which makes scale selection inaccurate, an improved level set method is finally proposed to extract vascular structures by introducing an external constrained term related to the standard deviation of Gaussian function into the traditional level set. Our approach was tested on synthetic images with vascular-like structures and 2D slices extracted from real 3D abdomen magnetic resonance angiography (MRA) images along the coronal plane. The segmentation rates for synthetic images are above 95%. The results for MRA images demonstrate that the proposed method can extract most of the vascular structures successfully and accurately in visualization. Therefore, the proposed method is effective for the vascular tree extraction in medical images. PMID:24348738

  12. Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs.

    PubMed

    da Palma, Renata Kelly; Nonaka, Paula Naomi; Campillo, Noelia; Uriarte, Juan J; Urbano, Jessica Julioti; Navajas, Daniel; Farré, Ramon; Oliveira, Luis V F

    2016-05-01

    Bioengineering of functional lung tissue by using whole lung scaffolds has been proposed as a potential alternative for patients awaiting lung transplant. Previous studies have demonstrated that vascular resistance (Rv) could be altered to optimize the process of obtaining suitable lung scaffolds. Therefore, this work was aimed at determining how lung inflation (tracheal pressure) and perfusion (pulmonary arterial pressure) affect vascular resistance. This study was carried out using the lungs excised from 5 healthy male Sprague-Dawley rats. The trachea was cannulated and connected to a continuous positive airway pressure (CPAP) device to provide a tracheal pressure ranging from 0 to 15cmH2O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30cmH2O. Effective Rv was calculated by ratio of pulmonary artery pressure (PPA) by pulmonary artery flow (V'PA). Rv in the decellularized lungs scaffolds decreased at increasing V'PA, stabilizing at a pulmonary arterial pressure greater than 20cmH2O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5cmH2O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs. PMID:26949099

  13. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs

    PubMed Central

    Syed, Mansoor A.; Choo-Wing, Rayman; Homer, Robert J.; Bhandari, Vineet

    2016-01-01

    Background The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury. Methodology We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated. Results VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2−/− and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect. Conclusion Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung. PMID:26799210

  14. [Research in Austria - the Ludwig Boltzmann Institute for Lung Vascular Research].

    PubMed

    Kovacs, G; Kleinschek, D; Kwapiszewska, G; Bálint, Z; Olschewski, H; Olschewski, A

    2016-05-01

    The Ludwig Boltzmann Institute for Lung Vascular Research was founded in 2010 and performs basic and clinical research on the field of chronic pulmonary vascular diseases. The major projects of the institute focus on the investigation of the pathomechanisms of pulmonary vascular remodeling, the development of novel non-invasive diagnostic techniques of pulmonary hypertension and the early detection of pulmonary vascular diseases. The institute closely cooperates with patient organizations and aims to contribute to the development of improved diagnostic and therapeutic approaches for patients with pulmonary vascular diseases. In this short overview the most important results of the first six years of the institute will be summarized. PMID:27168041

  15. Segmental pulmonary vascular resistances during oleic acid lung injury in rabbits.

    PubMed

    Maarek, J M; Grimbert, F

    1994-10-01

    We studied in isolated rabbit lungs the effects of oleic acid (OA) injury on the segmental distribution of vascular resistance. Vascular occlusion pressures were measured in control and OA-injured preparations over 90 min. Capillary filtration coefficient KF,C increased from 0.61 (+/- 0.10) to 0.91 (+/- 0.14) g.min-1.mmHg-1.(100 g)-1 in OA-injured lungs whereas it remained constant in control lungs. Total pulmonary vascular resistance changed little in both control and OA-injured lungs. OA injury resulted in a 15% increase of the double occlusion capillary pressure. In addition, the contribution of the microvascular to the total vascular resistance rose from 8% to 22%. The increase in microvascular resistance was significant 15 min after OA on the arteriolar side and became significant 30 min later on the venular side. Oleic acid injury does not change the total pulmonary vascular resistance but alters the distribution of segmental resistances in the isolated rabbit lung, thereby contributing to the accumulation of lung water in this model of low pressure permeability edema. PMID:7817049

  16. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling

    PubMed Central

    Heise, Rebecca L.; Link, Patrick A.; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  17. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling.

    PubMed

    Heise, Rebecca L; Link, Patrick A; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  18. Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS.

    PubMed

    Yang, Jie; Zhao, Yanfeng; Zhang, Peng; Li, Yuehua; Yang, Yong; Yang, Yang; Zhu, Junjie; Song, Xiao; Jiang, Gening; Fan, Jie

    2016-01-01

    Hemorrhagic shock (HS) often renders patients more susceptible to lung injury by priming for an exaggerated response to a second infectious stimulus. Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome following HS and regularly serves as a major cause of patient mortality. The lung vascular endothelium is an active organ that has a central role in the development of ALI through synthesizing and releasing of a number of inflammatory mediators. Cell pyroptosis is a caspase-1-dependent regulated cell death, which features rapid plasma membrane rupture and release of proinflammatory intracellular contents. In this study, we demonstrated an important role of HS in priming for LPS-induced lung endothelial cell (EC) pyroptosis. We showed that LPS through TLR4 activates Nlrp3 (NACHT, LRR, and PYD domains containing protein 3) inflammasome in mouse lung vascular EC, and subsequently induces caspase-1 activation. However, HS induced release of high-mobility group box 1 (HMGB1), which acting through the receptor for advanced glycation end products initiates EC endocytosis of HMGB1, and subsequently triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. These HS-induced events enhance LPS-induced EC pyroptosis. We further showed that lung vascular EC pyroptosis significantly exaggerates lung inflammation and injury. The present study explores a novel mechanism underlying HS-primed ALI and thus presents a potential therapeutic target for post-HS ALI. PMID:27607578

  19. MiR-221 and miR-130a Regulate Lung Airway and Vascular Development

    PubMed Central

    Mujahid, Sana

    2013-01-01

    Epithelial-mesenchymal interactions play a crucial role in branching morphogenesis, but very little is known about how endothelial cells contribute to this process. Here, we examined how anti-angiogenic miR-221 and pro-angiogenic miR-130a affect airway and vascular development in the fetal lungs. Lung-specific effects of miR-130a and miR-221 were studied in mouse E14 whole lungs cultured for 48 hours with anti-miRs or mimics to miR-130a and miR-221. Anti-miR 221 treated lungs had more distal branch generations with increased Hoxb5 and VEGFR2 around airways. Conversely, mimic 221 treated lungs had reduced airway branching, dilated airway tips and decreased Hoxb5 and VEGFR2 in mesenchyme. Anti-miR 130a treatment led to reduced airway branching with increased Hoxa5 and decreased VEGFR2 in the mesenchyme. Conversely, mimic 130a treated lungs had numerous finely arborized branches extending into central lung regions with diffusely localized Hoxa5 and increased VEGFR2 in the mesenchyme. Vascular morphology was analyzed by GSL-B4 (endothelial cell-specific lectin) immunofluorescence. Observed changes in airway morphology following miR-221 inhibition and miR-130a enhancement were mirrored by changes in vascular plexus formation around the terminal airways. Mouse fetal lung endothelial cells (MFLM-91U) were used to study microvascular cell behavior. Mimic 221 treatment resulted in reduced tube formation and cell migration, where as the reverse was observed with mimic 130a treatment. From these data, we conclude that miR-221 and miR-130a have opposing effects on airway and vascular morphogenesis of the developing lung. PMID:23409087

  20. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    PubMed

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

  1. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

    PubMed Central

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

    2016-01-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

  2. Mechanistic Insights into the Relationship between Lung and Vascular Response to Ambient Particulate Matter (PM)

    EPA Science Inventory

    The mechanisms by which pulmonary-encountered ambient PM induces vascular response are not well understood. We examined lung and aortic response of rats following intratracheal instillation of three ambient PM. Chemically characterized PM10 and PM2.5 from th...

  3. Disturbed Homeostasis of Lung Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1 During Sepsis

    PubMed Central

    Laudes, Ines J.; Guo, Ren-Feng; Riedemann, Niels C.; Speyer, Cecilia; Craig, Ron; Sarma, J. Vidya; Ward, Peter A.

    2004-01-01

    Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with perturbations in vascular adhesion molecules. In CLP mice, lung vascular binding of 125I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of anti-ICAM-1 and significantly reduced binding of anti-VCAM-1. In whole lung homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein levels) during sepsis, whereas very little increase in VCAM-1 could be measured although some increased mRNA was found. During CLP soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1) appeared in the serum. When mouse dermal microvascular endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the supernatant fluids. Under the same conditions, ICAM-1 cell content increased in MDMECs. When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum caused increased adhesion of neutrophils and decreased adhesion of macrophages and T cells. The progressive build-up in lung myeloperoxidase after CLP was ICAM-1-dependent and independent of VLA-4 and VCAM-1. These data suggest that sepsis disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the lung microvasculature, thereby putting the lung at increased risk of injury. PMID:15039231

  4. Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease

    PubMed Central

    Wieck, Minna M.; Spurrier, Ryan G.; Levin, Daniel E.; Mojica, Salvador Garcia; Hiatt, Michael J.; Reddy, Raghava; Hou, Xiaogang; Navarro, Sonia; Lee, Jooeun; Lundin, Amber; Driscoll, Barbara; Grikscheit, Tracy C.

    2016-01-01

    Rationale Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. Objectives To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. Methods Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. Measurements and Main Results Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes. Conclusions These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions. PMID:26863115

  5. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

    PubMed

    Guignabert, Christophe; Phan, Carole; Seferian, Andrei; Huertas, Alice; Tu, Ly; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  6. Perfusion and ventilation filters for Fourier-decomposition MR lung imaging.

    PubMed

    Wujcicki, Artur; Corteville, Dominique; Materka, Andrzej; Schad, Lothar R

    2015-03-01

    MR imaging without the use of contrast agents has recently been used for creating perfusion and ventilation functional lung images. The technique incorporates frequency- or wavelet-domain filters to separate the MR signal components. This paper presents a new, subject-adaptive algorithm for perfusion and ventilation filters design. The proposed algorithm uses a lung signal model for separation of the signal components in the frequency domain. Non-stationary lung signals are handled by a short time Fourier transform. This method was applied to sets of 192 and 90 co-registered non-contrast MR lung images measured for five healthy subjects at the rate of 3,33 images per second, using different slice thicknesses. In each case, the resulted perfusion and ventilation images showed a smaller amount of mutual information, when compared to those obtained using the known lowpass/highpass filter approach. PMID:25466452

  7. Role played by Prx1-dependent extracellular matrix properties in vascular smooth muscle development in embryonic lungs

    PubMed Central

    Ames, Juliana; Chokshi, Mithil; Aiad, Norman; Sanyal, Sonali; Kawabata, Kimihito C.; Levental, Ilya; Sundararaghavan, Harini G.; Burdick, Jason A.; Janmey, Paul; Miyazono, Kohei; Wells, Rebecca G.; Jones, Peter L.

    2015-01-01

    Abstract Although there are many studies focusing on the molecular pathways underlying lung vascular morphogenesis, the extracellular matrix (ECM)–dependent regulation of mesenchymal cell differentiation in vascular smooth muscle development needs better understanding. In this study, we demonstrate that the paired related homeobox gene transcription factor Prx1 maintains the elastic ECM properties, which are essential for vascular smooth muscle precursor cell differentiation. We have found that Prx1null mouse lungs exhibit defective vascular smooth muscle development, downregulated elastic ECM expression, and compromised transforming growth factor (TGF)–β localization and signaling. Further characterization of ECM properties using decellularized lung ECM scaffolds derived from Prx1 mice demonstrated that Prx1 is required to maintain lung ECM stiffness. The results of cell culture using stiffness-controlled 2-D and 3-D synthetic substrates confirmed that Prx1-dependent ECM stiffness is essential for promotion of smooth muscle precursor differentiation for effective TGF-β stimulation. Supporting these results, both decellularized Prx1null lung ECM and Prx1WT (wild type) ECM scaffolds with blocked TGF-β failed to support mesenchymal cell to 3-D smooth muscle cell differentiation. These results suggest a novel ECM-dependent regulatory pathway of lung vascular development wherein Prx1 regulates lung vascular smooth muscle precursor development by coordinating the ECM biophysical and biochemical properties. PMID:26064466

  8. Pigment epithelium-derived factor mediates impaired lung vascular development in neonatal hyperoxia.

    PubMed

    Chetty, Anne; Bennett, Michelle; Dang, Linh; Nakamura, Daisy; Cao, Gong-Jie; Mujahid, Sana; Volpe, MaryAnn; Herman, Ira; Becerra, S Patricia; Nielsen, Heber C

    2015-03-01

    Bronchopulmonary dysplasia is a chronic lung disease of preterm infants characterized by arrested microvascularization and alveolarization. Studies show the importance of proangiogenic factors for alveolarization, but the importance of antiangiogenic factors is unknown. We proposed that hyperoxia increases the potent angiostatin, pigment epithelium-derived factor (PEDF), in neonatal lungs, inhibiting alveolarization and microvascularization. Wild-type (WT) and PEDF(-/-) mice were exposed to room air (RA) or 0.9 fraction of inspired oxygen from Postnatal Day 5 to 13. PEDF protein was increased in hyperoxic lungs compared with RA-exposed lungs (P < 0.05). In situ hybridization and immunofluorescence identified PEDF production primarily in alveolar epithelium. Hyperoxia reduced alveolarization in WT mice (P < 0.05) but not in PEDF(-/-) mice. WT hyperoxic mice had fewer platelet endothelial cell adhesion molecule (PECAM)-positive cells per alveolus (1.4 ± 0.4) than RA-exposed mice (4.3 ± 0.3; P < 0.05); this reduction was absent in hyperoxic PEDF(-/-) mice. The interactive regulation of lung microvascularization by vascular endothelial growth factor and PEDF was studied in vitro using MFLM-91U cells, a fetal mouse lung endothelial cell line. Vascular endothelial growth factor stimulation of proliferation, migration, and capillary tube formation was inhibited by PEDF. MFLM-91U cells exposed to conditioned medium (CM) from E17 fetal mouse lung type II (T2) cells cultured in 0.9 fraction of inspired oxygen formed fewer capillary tubes than CM from T2 cells cultured in RA (hyperoxia CM, 51 ± 10% of RA CM, P < 0.05), an effect abolished by PEDF antibody. We conclude that PEDF mediates reduced vasculogenesis and alveolarization in neonatal hyperoxia. Bronchopulmonary dysplasia likely results from an altered balance between pro- and antiangiogenic factors. PMID:25054647

  9. Vascular effects of cigarette smoke in isolated pig lungs

    SciTech Connect

    Gilman, M.J.; Sylvester, J.T.; Kennedy, T.P.; Menkes, H.A.; Traystman, R.J.

    1981-11-01

    To determine the local effects of cigarette smoke on the pulmonary vasculature, we measured pulmonary artery pressure--flow curves in isolated, blood-perfused pig lungs before and after 4 exposures to cigarette smoke. During each exposure, smoke was administered into the trachea for 3 to 4 min at a rate of 20 to 25 puffs/min and a puff volume of 35 to 50 ml with a smoking machine. During hypoxia (inspired PO2, 50 mmHg), when baseline vasomotor tone was high, cigarette smoke caused an acute transient vasodilation. During control (inspired PO2, 200 mmHg), when baseline tone was low, no significant effect was observed. In addition to this acute effect, cigarette smoke caused a depression of the pulmonary pressor response to hypoxia, which developed gradually during the course of the experiment. Indomethacin, at perfusate concentrations of 20 and 100 micrograms/ml, did not significantly alter the acute vasodilating effect of smoking, suggesting that prostaglandins synthesized by cyclooxygenase were not the mediators of this response. Indomethacin did, however, prevent the gradual depression of the pulmonary vasoconstrictor response to hypoxia.

  10. Induction of vascular remodeling in the lung by chronic house dust mite exposure.

    PubMed

    Rydell-Törmänen, Kristina; Johnson, Jill R; Fattouh, Ramzi; Jordana, Manel; Erjefält, Jonas S

    2008-07-01

    Structural changes to the lung are associated with chronic asthma. In addition to alterations to the airway wall, asthma is associated with vascular modifications, although this aspect of remodeling is poorly understood. We sought to evaluate the character and kinetics of vascular remodeling in response to chronic aeroallergen exposure. Because many ovalbumin-driven models used to investigate allergic airway disease do so in the absence of persistent airway inflammation, we used a protocol of chronic respiratory exposure to house dust mite extract (HDME), which has been shown to induce persistent airway inflammation consistent with that seen in humans with asthma. Mice were exposed to HDME intranasally for 7 or 20 consecutive weeks, and resolution of the inflammatory and remodeling response to allergen was investigated 4 weeks after the end of a 7-week exposure protocol. Measures of vascular remodeling, including total collagen deposition, procollagen I production, endothelial and smooth muscle cell proliferation, smooth muscle area, and presence of myofibroblasts, were investigated histologically in lung vessels of different sizes and locations. We observed an increase in total collagen content, which did not resolve upon cessation of allergen exposure. Other parameters were significantly increased after 7 and/or 20 weeks of allergen exposure but returned to baseline after allergen withdrawal. We conclude that respiratory HDME exposure induces airway remodeling and pulmonary vascular remodeling, and, in accordance with airway remodeling, some components of these structural changes may be irreversible. PMID:18314535

  11. Relationship between vascularity, age and survival in non-small-cell lung cancer.

    PubMed Central

    Chandrachud, L. M.; Pendleton, N.; Chisholm, D. M.; Horan, M. A.; Schor, A. M.

    1997-01-01

    Lung tumours in the elderly show reduced growth potential; impaired angiogenesis may contribute to this phenomenon. Recent studies have suggested that the angiogenic potential of a tumour may be inferred by the vascularity measured in histological sections. The purpose of this study has been to determine whether vascularity is related to age, survival or other clinical parameters in resected non-small-cell lung cancer (NSCLC). A group of 88 consecutive patients with a follow-up period of at least 5 years was selected. The group exhibited a wide age range (37-78 years) and similar survival characteristics to those of the general NSCLC population. Tumour sections were stained with a pan-endothelial antibody (vWF) and vascularity was quantitated, without knowledge of the clinical details, by three methods: highest microvascular density; average microvascular density; and average microvascular volume. The results were analysed by non-parametric statistical tests. A correlation was found between all three methods of quantitation. Vascularity was not associated with age, sex, tumour type, stage, volume, size (TNM-T) nodal status (TNM-N) or survival. However, survival time was generally longer for patients with higher vascularity, reaching borderline significance (P = 0.06) for the average microvascular density values. Higher tumour volume (P = 0.02) and stage (P = 0.05) were associated with lower survival times. Using multivariate survival analysis, tumour volume was the only factor related to survival. We conclude that vascularity is not associated with age and has no significant prognostic value in NSCLC. Images Figure 1 PMID:9374385

  12. Vascular effects of acetylcholine in the perfused rabbit lung

    SciTech Connect

    Cherry, P.D.; Gillis, C.N.

    1986-03-05

    Acetylcholine (ACh) relaxes large, isolated arteries by releasing an endothelium-derived relaxing factor (EDRF). The authors decided to determine if ACh releases EDRF in rabbit lungs (RL) perfused in situ and if chemical injury with tetradecanoyl phorbol myristate acetate (TPA) could modify EDRF release in RL and in rabbit pulmonary arteries (RPA) in vitro. RL were perfused at 15 ml/min with Krebs-dextran solution. 1 ..mu..M ACh infusion raised perfusion pressure (P) in RL that was blocked by 30 ..mu..M indomethacin (IND) in the perfusate. However, when IND-treated RL were perfused with the stable endoperoxide analog, U46619 (2-6nM) to increase P, ACh infusion (0.01-1.0 ..mu..M) consistently decreased elevated P. The vasodilator response to infusion of 1 ..mu..M ACh was acutely antagonized by infusion of either 20 ..mu..M quinacrine (Q) or 10 ..mu..M Fe/sup + +/-hemoglobin (Hb). ACh did not decrease P in IND-treated RL pre-equilibrated with Q or Hb. TPA (10 nM) antagonized ACh-reduction of P and the ACh-induced relaxation of isolated RPA. The TPA antagonism of ACh-relaxation of RPA was prevented by catalase (300 U/ml). From these results they conclude that: 1) ACh-induced vasoconstriction in RL depends on cyclooxygenase product(s). 2) IND unmasks ACh-induced vasodilatation in RL that is inhibited by Q and by Hb suggesting that the effect is mediated by EDRF. 3) TPA inhibits ACh-induced vasodilatation and relaxation of RPA via the release of H/sub 2/O/sub 2/ or a related oxidant that injures the endothelium.

  13. VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development.

    PubMed

    Yun, Eun Jun; Lorizio, Walter; Seedorf, Gregory; Abman, Steven H; Vu, Thiennu H

    2016-02-15

    Prevention or treatment of lung diseases caused by the failure to form, or destruction of, existing alveoli, as observed in infants with bronchopulmonary dysplasia and adults with emphysema, requires understanding of the molecular mechanisms of alveolar development. In addition to its critical role in gas exchange, the pulmonary circulation also contributes to alveolar morphogenesis and maintenance by the production of paracrine factors, termed "angiocrines," that impact the development of surrounding tissue. To identify lung angiocrines that contribute to alveolar formation, we disrupted pulmonary vascular development by conditional inactivation of the Vegf-A gene during alveologenesis. This resulted in decreased pulmonary capillary and alveolar development and altered lung elastin and retinoic acid (RA) expression. We determined that RA is produced by pulmonary endothelial cells and regulates pulmonary angiogenesis and elastin synthesis by induction of VEGF-A and fibroblast growth factor (FGF)-18, respectively. Inhibition of RA synthesis in newborn mice decreased FGF-18 and elastin expression and impaired alveolarization. Treatment with RA and vitamin A partially reversed the impaired vascular and alveolar development induced by VEGF inhibition. Thus we identified RA as a lung angiocrine that regulates alveolarization through autocrine regulation of endothelial development and paracrine regulation of elastin synthesis via induction of FGF-18 in mesenchymal cells. PMID:26566904

  14. Platelet-derived SDF1 primes pulmonary capillary vascular niche to drive lung alveolar regeneration

    PubMed Central

    Rafii, Shahin; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Ding, Bi-Sen

    2016-01-01

    The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that activated platelets trigger lung regeneration by supplying stromal cell-derived-factor1 (SDF1/CXCL12). After PNX, platelets stimulate SDF1-receptor CXCR4 and CXCR7 on pulmonary capillary endothelial cells (PCECs) to deploy membrane-type metalloproteinase MMP14, stimulating proliferation of alveolar epithelial cells (AECs) and neo-alveolarization. In mice lacking platelets or platelet Sdf1, PNX-induced alveologenesis was diminished. Reciprocally, infusion of Sdf1+/+ but not Sdf1-deficient platelets rescued lung regeneration in platelet-depleted mice. Endothelial-specific ablation of Cxcr4 and Cxcr7 in adult mice similarly impeded lung regeneration. Notably, mice with endothelial-specific Mmp14 deletion (Mmp14iΔEC/iΔEC) exhibited impaired expansion of AECs but not PCECs, which could not be rescued by platelet infusion. Therefore, platelets prime PCECs to initiate lung regeneration, extending beyond their hemostatic contribution. Therapeutic targeting of this hemo-vascular niche could enable regenerative therapy for lung diseases. PMID:25621952

  15. An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth.

    PubMed

    Chen, Yan; Liu, Xin; Jin, Cong Guo; Zhou, Yong Chun; Navab, Roya; Jakobsen, Kristine Raaby; Chen, Xiao Qun; Li, Jia; Li, Ting Ting; Luo, Lu; Wang, Xi Cai

    2016-02-01

    Lung cancer is the leading cause of mortality and 5-year survival rate is very low worldwide. Recent studies show that vascular endothelial growth factor receptor-3 (VEGFR-3) signaling pathway contributes to lung cancer progression. So we hypothesize that an oral DNA vaccine that targets VEGFR-3 carried by attenuated Salmonella enterica serovar typhimurium strain SL3261 has impacts on lung cancer progression. In this study, the oral VEGFR-3-based vaccine-immunized mice showed appreciable inhibition of tumor growth and tumor lymphatic microvessels in lung cancer mice model. Moreover, the oral VEGFR-3-based vaccine-immunized mice showed remarkable increases in both VEGFR-3-specific antibody levels and cytotoxic activity. Furthermore, the oral VEGFR-3-based vaccine-immunized mice showed a significant increase in the levels of T helper type 1 (Th1) cell intracellular cytokine expression (IL-2, IFN-γ, and TNF-α). After inoculation with murine Lewis lung carcinoma (LLC) cells, CD4(+) or CD8(+) T cell numbers obviously declined in control groups whereas high levels were maintained in the oral VEGFR-3-based vaccine group. These results demonstrated that the oral VEGFR-3-based vaccine could induce specific humoral and cellular immune responses and then significantly inhibit lung carcinoma growth via suppressing lymphangiogenesis. PMID:26376999

  16. Pressure- and flow-controlled media perfusion differently modify vascular mechanics in lung decellularization.

    PubMed

    da Palma, Renata K; Campillo, Noelia; Uriarte, Juan J; Oliveira, Luis V F; Navajas, Daniel; Farré, Ramon

    2015-09-01

    Organ biofabrication is a potential future alternative for obtaining viable organs for transplantation. Achieving intact scaffolds to be recellularized is a key step in lung bioengineering. Perfusion of decellularizing media through the pulmonary artery has shown to be effective. How vascular perfusion pressure and flow vary throughout lung decellularization, which is not well known, is important for optimizing the process (minimizing time) while ensuring scaffold integrity (no barotrauma). This work was aimed at characterizing the pressure/flow relationship at the pulmonary vasculature and at how effective vascular resistance depends on pressure- and flow-controlled variables when applying different methods of media perfusion for lung decellularization. Lungs from 43 healthy mice (C57BL/6; 7-8 weeks old) were investigated. After excision and tracheal cannulation, lungs were inflated at 10 cmH2O airway pressure and subjected to conventional decellularization with a solution of 1% sodium dodecyl sulfate (SDS). Pressure (PPA) and flow (V'PA) at the pulmonary artery were continuously measured. Decellularization media was perfused through the pulmonary artery: (a) at constant PPA=20 cmH2O or (b) at constant V'PA=0.5 and 0.2 ml/min. Effective vascular resistance was computed as Rv=PPA/V'PA. Rv (in cmH2O/(ml/min)); mean±SE) considerably varied throughout lung decellularization, particularly for pressure-controlled perfusion (from 29.1±3.0 in baseline to a maximum of 664.1±164.3 (p<0.05), as compared with flow-controlled perfusion (from 49.9±3.3 and 79.5±5.1 in baseline to a maximum of 114.4±13.9 and 211.7±70.5 (p<0.05, both), for V'PA of 0.5 and 0.2 ml/min respectively. Most of the media infused to the pulmonary artery throughout decellularization circulated to the airways compartment across the alveolar-capillary membrane. This study shows that monitoring perfusion mechanics throughout decellularization provides information relevant for optimizing the process

  17. Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma.

    PubMed

    Togashi, Yosuke; Masago, Katsuhiro; Kubo, Takeshi; Fujimoto, Daichi; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Togashi, Kaori; Mishima, Michiaki

    2012-12-01

    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P < 0.0001), and tumors without vascular-poor area (P < 0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers (P = 0.0046), lack of vascular-poor area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency. PMID:22492281

  18. Effects of thromboxane A2 analogue on vascular resistance distribution and permeability in isolated blood-perfused dog lungs.

    PubMed

    Shibamoto, T; Wang, H G; Yamaguchi, Y; Hayashi, T; Saeki, Y; Tanaka, S; Koyama, S

    1995-01-01

    This study was designed to determine the effects of thromboxane A2 (TxA2) on the distribution of vascular resistance, lung weight, and microvascular permeability in isolated dog lungs perfused at a constant pressure with autologous blood. The stable TxA2 analogue (STA2; 30 micrograms, n = 5) caused an increase in pulmonary capillary pressure (Pc) assessed as double-occlusion pressure to 14.0 +/- 0.4 mmHg from the baseline of 7.9 +/- 0.3 mmHg with progressive lung weight gain. Pulmonary vascular resistance increased threefold exclusively due to pulmonary venoconstriction. Pulmonary venoconstriction was confirmed in lungs perfused in a reverse direction from the pulmonary vein to the artery (n = 5), as evidenced by marked precapillary vasoconstriction and a sustained lung weight loss. Furthermore, in lungs perfused at a constant blood flow (n = 5), STA2 also caused selective pulmonary venoconstriction. Vascular permeability measured by the capillary filtration coefficient and the isogravimetric Pc at 30 and 60 min after STA2 infusion did not change significantly from baseline in any lungs studied. Moreover, elevation of Pc by raising the venous reservoir of the intact lobes (n = 5) to the same level as the STA2 lungs caused a greater or similar weight gain compared with the STA2 lungs. Thus, we conclude that TxA2 constricts selectively the pulmonary vein resulting in an increase in Pc and lung weight gain without significant changes in vascular permeability in isolated blood-perfused dog lungs. PMID:7564480

  19. The use of the Kalman filter in the automated segmentation of EIT lung images.

    PubMed

    Zifan, A; Liatsis, P; Chapman, B E

    2013-06-01

    In this paper, we present a new pipeline for the fast and accurate segmentation of impedance images of the lungs using electrical impedance tomography (EIT). EIT is an emerging, promising, non-invasive imaging modality that produces real-time, low spatial but high temporal resolution images of impedance inside a body. Recovering impedance itself constitutes a nonlinear ill-posed inverse problem, therefore the problem is usually linearized, which produces impedance-change images, rather than static impedance ones. Such images are highly blurry and fuzzy along object boundaries. We provide a mathematical reasoning behind the high suitability of the Kalman filter when it comes to segmenting and tracking conductivity changes in EIT lung images. Next, we use a two-fold approach to tackle the segmentation problem. First, we construct a global lung shape to restrict the search region of the Kalman filter. Next, we proceed with augmenting the Kalman filter by incorporating an adaptive foreground detection system to provide the boundary contours for the Kalman filter to carry out the tracking of the conductivity changes as the lungs undergo deformation in a respiratory cycle. The proposed method has been validated by using performance statistics such as misclassified area, and false positive rate, and compared to previous approaches. The results show that the proposed automated method can be a fast and reliable segmentation tool for EIT imaging. PMID:23719169

  20. Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease.

    PubMed Central

    Bush, A; Busst, C M; Haworth, S G; Hislop, A A; Knight, W B; Corrin, B; Shinebourne, E A

    1988-01-01

    Pulmonary vascular resistance was measured in air, oxygen, and after administration of vasodilators in 14 children with pulmonary hypertension and congenital heart disease. Lung morphology was examined by light microscopy and assessed quantitatively. In this selected group of patients (a) medial muscle thickness of greater than 20% in the intra-acinar arteries and Heath-Edwards changes of I or II were significantly associated with perioperative death from pulmonary complications after cardiac surgery; (b) children with lower percentage medial muscle thickness had a higher baseline resistance (r = -0.84) associated with Heath-Edwards grade III or higher changes (most of these patients were not offered corrective surgery); (c) when the lowest pulmonary vascular resistance was less than 3 units, Heath-Edwards grading was I or II (n = 4). When the pulmonary vascular resistance was greater than 6 units, however, there was no direct correlation with Heath-Edwards grading (n = 9). Four patients with a resistance of greater than 6 units had only grade I or II changes. Three had a medial muscle thickness above 20%, and were among those who died at or soon after operation. It is concluded that (a) patients with a lowest pulmonary vascular resistance of greater than 6 units have a bad prognosis whatever their lung morphology; and (b) some patients with Heath-Edwards grade I or II will have a high resistance (this group has a high medial muscle mass and a poor prognosis and would not be detected by Heath-Edwards grading alone). PMID:3370183

  1. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury.

    PubMed

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2015-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  2. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury

    PubMed Central

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2014-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  3. Serum vascular endothelial growth factor is related to systemic oxidative stress in patients with lung cancer.

    PubMed

    Katsabeki-Katsafli, A; Kerenidi, T; Kostikas, K; Dalaveris, E; Kiropoulos, T S; Gogou, E; Papaioannou, A I; Gourgoulianis, K I

    2008-05-01

    Vascular endothelial growth factor (VEGF) is known to play crucial role in tumour angiogenesis. It is demonstrated that VEGF can be up-regulated by oxidative stress. The aim of this study was to determine the serum VEGF levels and oxidative stress in patients with primary lung cancer and to investigate their association with clinicopathologic factors. We measured serum VEGF levels and oxidative stress in 63 patients (age 63.02+/-1.12 S.E.M.) with primary lung cancer before any treatment (39 NSCLC and 24 SCLC; 6 patients stage I, 3 stage II, 25 stage III and 29 stage IV) and 25 normal subjects. The serum VEGF levels were measured with enzyme linked immunosorbent assay. Serum oxidative stress levels were detected by a commercially available assay (D-ROMs test, Diacron, Grossetto, Italy). The levels of oxidative stress in patients were higher than those in normal subjects (555.3+/-30.35 UCarr vs. 360.1+/-17.46 UCarr). Additionally, a significant difference was found in serum VEGF levels between lung cancer patients and healthy control subjects (428.1+/-38.42pg/ml vs. 298.8+/-19.89pg/ml, respectively, p=0.040). Interestingly, serum oxidative stress presented a significant correlation with serum VEGF levels in patients with lung cancer (r=0.542, p=0.002). Serum VEGF levels were significantly associated with the clinical staging (N-stage) of the patients (p=0.023), performance status (p=0.004) and age (p=0.004). In conclusion, oxidative stress and VEGF are significantly increased in patients with primary lung cancer. The correlation between them might implicate new aspects of the mechanisms controlling tumour angiogenesis and may present clinical interest in the future. Further studies are warranted to evaluate the role of oxidative stress and VEGF as possible biomarkers for the diagnosis and follow-up of patients with lung cancer. PMID:18242763

  4. Asef controls vascular endothelial permeability and barrier recovery in the lung

    PubMed Central

    Tian, Xinyong; Tian, Yufeng; Gawlak, Grzegorz; Meng, Fanyong; Kawasaki, Yoshihiro; Akiyama, Tetsu; Birukova, Anna A.

    2015-01-01

    Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac-GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef−/− mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury. PMID:25518936

  5. Dysregulation of Vascular Endothelial Progenitor Cells Lung-Homing in Subjects with COPD

    PubMed Central

    Salter, Brittany M.; Manzoor, Fizza; Beaudin, Suzanne; Kjarsgaard, Melanie; Nair, Parameswaran; Gauvreau, Gail M.; Sehmi, Roma

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow limitation and progressive decline of lung function and punctuated by occasional exacerbations. The disease pathogenesis may involve activation of the bone marrow stimulating mobilization and lung-homing of progenitor cells. We investigated the hypothesis that lower circulating numbers of vascular endothelial progenitor cells (VEPCs) are a consequence of increased lung-sequestration in COPD. Nonatopic, current or ex-smokers with diagnosed COPD and nonatopic, nonsmoking normal controls were enrolled. Blood and induced sputum extracted primitive hemopoietic progenitors (HPCs) and VEPC were enumerated by flow cytometry. Migration and adhesive responses to fibronectin were assessed. In sputum, VEPC numbers were significantly greater in COPD compared to normal controls. In blood, VEPCs were significantly lower in COPD versus normal controls. There were no differences in HPC levels between the two groups in either compartment. Functionally, there was a greater migrational responsiveness of progenitors from COPD subjects to stromal cell-derived factor-1alpha (SDF-1α) compared to normal controls. This was associated with greater numbers of CXCR4+ progenitors in sputum from COPD. Increased migrational responsiveness of progenitor cells may promote lung-homing of VEPC in COPD which may disrupt maintenance and repair of the airways and contribute to COPD disease pathogenesis. PMID:27445517

  6. Pulmonary Vascular Congestion: A Mechanism for Distal Lung Unit Dysfunction in Obesity

    PubMed Central

    Oppenheimer, Beno W.; Berger, Kenneth I.; Ali, Saleem; Segal, Leopoldo N.; Donnino, Robert; Katz, Stuart; Parikh, Manish; Goldring, Roberta M.

    2016-01-01

    Rationale Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. Objectives We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. Methods 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. Measurements and Main Results Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. Conclusions Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the

  7. Genetic Variation in Vascular Endothelial Growth Factor-A and Lung Function

    PubMed Central

    Custovic, Adnan; Tepper, Robert; Graves, Penelope; Stern, Debra A.; Jones, Marcus; Hankinson, Jenny; Curtin, John A.; Wu, Jiakai; Blekic, Mario; Bukvic, Blazenka Kljaic; Aberle, Neda; Marinho, Susana; Belgrave, Danielle; Morgan, Wayne J.; Martinez, Fernando D.

    2012-01-01

    Rationale: Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function. Objectives: The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood. Methods: Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A165b/panVEGF-A165 among homozygotes. Measurements and Main Results: In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow50, and forced expiratory flow25–75 compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV1/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A165b/panVEGF-A165 was significantly higher among CC versus GG homozygotes (P ≤ 0.02) at birth, in school-age children, and in adults. Conclusions: We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A165, which may be determined by alternative splicing. PMID:22461367

  8. Neuronal Wiskott-Aldrich syndrome protein regulates TGF-β1-mediated lung vascular permeability.

    PubMed

    Wagener, Brant M; Hu, Meng; Zheng, Anni; Zhao, Xueke; Che, Pulin; Brandon, Angela; Anjum, Naseem; Snapper, Scott; Creighton, Judy; Guan, Jun-Lin; Han, Qimei; Cai, Guo-Qiang; Han, Xiaosi; Pittet, Jean-Francois; Ding, Qiang

    2016-07-01

    TGF-β1 induces an increase in paracellular permeability and actin stress fiber formation in lung microvascular endothelial and alveolar epithelial cells via small Rho GTPase. The molecular mechanism involved is not fully understood. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) has an essential role in actin structure dynamics. We hypothesized that N-WASP plays a critical role in these TGF-β1-induced responses. In these cell monolayers, we demonstrated that N-WASP down-regulation by short hairpin RNA prevented TGF-β1-mediated disruption of the cortical actin structure, actin stress filament formation, and increased permeability. Furthermore, N-WASP down-regulation blocked TGF-β1 activation mediated by IL-1β in alveolar epithelial cells, which requires actin stress fiber formation. Control short hairpin RNA had no effect on these TGF-β1-induced responses. TGF-β1-induced phosphorylation of Y256 of N-WASP via activation of small Rho GTPase and focal adhesion kinase mediates TGF-β1-induced paracellular permeability and actin cytoskeleton dynamics. In vivo, compared with controls, N-WASP down-regulation increases survival and prevents lung edema in mice induced by bleomycin exposure-a lung injury model in which TGF-β1 plays a critical role. Our data indicate that N-WASP plays a crucial role in the development of TGF-β1-mediated acute lung injury by promoting pulmonary edema via regulation of actin cytoskeleton dynamics.-Wagener, B. M., Hu, M., Zheng, A., Zhao, X., Che, P., Brandon, A., Anjum, N., Snapper, S., Creighton, J., Guan, J.-L., Han, Q., Cai, G.-Q., Han, X., Pittet, J.-F., Ding, Q. Neuronal Wiskott-Aldrich syndrome protein regulates TGF-β1-mediated lung vascular permeability. PMID:27025963

  9. Antithrombin Attenuates Vascular Leakage via Inhibiting Neutrophil Activation in Acute Lung Injury

    PubMed Central

    Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda E.; Jonkam, Collette; Zhu, Yong; Traber, Lillian D.; Cox, Robert A.; Prough, Donald S.; Traber, Daniel L.; Enkhbaatar, Perenlei

    2014-01-01

    Objective To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. Design Randomized controlled laboratory experiment. Setting University animal research facility. Subjects Eighteen chronically instrumented sheep. Interventions Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. Measurements and Main Results Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12–48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12–48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. Conclusions The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological

  10. Vascular Endothelial Growth Factor A Regulates the Secretion of Different Angiogenic Factors in Lung Cancer Cells.

    PubMed

    Frezzetti, Daniela; Gallo, Marianna; Roma, Cristin; D'Alessio, Amelia; Maiello, Monica R; Bevilacqua, Simona; Normanno, Nicola; De Luca, Antonella

    2016-07-01

    Vascular endothelial growth factor A (VEGFA) is one of the main mediators of angiogenesis in non-small cell lung cancer (NSCLC). Recently, it has been described an autocrine feed-forward loop in NSCLC cells in which tumor-derived VEGFA promoted the secretion of VEGFA itself, amplifying the proangiogenic signal. In order to investigate the role of VEGFA in lung cancer progression, we assessed the effects of recombinant VEGFA on proliferation, migration, and secretion of other angiogenic factors in A549, H1975, and HCC827 NSCLC cell lines. We found that VEGFA did not affect NSCLC cell proliferation and migration. On the other hand, we demonstrated that VEGFA not only produced a strong and persistent increase of VEGFA itself but also significantly induced the secretion of a variety of angiogenic factors, including follistatin (FST), hepatocyte growth factor (HGF), angiopoietin-2 (ANGPT2), granulocyte-colony stimulating factor (G-CSF), interleukin (IL)-8, leptin (LEP), platelet/endothelial cell adhesion molecule 1 (PECAM-1), and platelet-derived growth factor bb (PDGF-BB). PI3K/AKT, RAS/ERK, and STAT3 signalling pathways were found to mediate the effects of VEGFA in NSCLC cell lines. We also observed that VEGFA regulation mainly occurred at post-transcriptional level and that NSCLC cells expressed different isoforms of VEGFA. Collectively, our data suggested that VEGFA contributes to lung cancer progression by inducing a network of angiogenic factors, which might offer potential for therapeutic intervention. PMID:26542886

  11. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. PMID:26432864

  12. Automated detection of lung tumors in PET/CT images using active contour filter

    NASA Astrophysics Data System (ADS)

    Teramoto, Atsushi; Adachi, Hayato; Tsujimoto, Masakazu; Fujita, Hiroshi; Takahashi, Katsuaki; Yamamuro, Osamu; Tamaki, Tsuneo; Nishio, Masami; Kobayashi, Toshiki

    2015-03-01

    In a previous study, we developed a hybrid tumor detection method that used both computed tomography (CT) and positron emission tomography (PET) images. However, similar to existing computer-aided detection (CAD) schemes, it was difficult to detect low-contrast lesions that touch to the normal organs such as the chest wall or blood vessels in the lung. In the current study, we proposed a novel lung tumor detection method that uses active contour filters to detect the nodules deemed "difficult" in previous CAD schemes. The proposed scheme detects lung tumors using both CT and PET images. As for the detection in CT images, the massive region was first enhanced using an active contour filter (ACF), which is a type of contrast enhancement filter that has a deformable kernel shape. The kernel shape involves closed curves that are connected by several nodes that move iteratively in order to enclose the massive region. The final output of ACF is the difference between the maximum pixel value on the deformable kernel, and pixel value on the center of the filter kernel. Subsequently, the PET images were binarized to detect the regions of increased uptake. The results were integrated, followed by the false positive reduction using 21 characteristic features and three support vector machines. In the experiment, we evaluated the proposed method using 100 PET/CT images. More than half of nodules missed using previous methods were accurately detected. The results indicate that our method may be useful for the detection of lung tumors using PET/CT images.

  13. siRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway.

    PubMed

    Miyawaki-Shimizu, Kayo; Predescu, Dan; Shimizu, Jun; Broman, Michael; Predescu, Sanda; Malik, Asrar B

    2006-02-01

    Caveolin-1, the principal integral membrane protein of caveolae, has been implicated in regulating the structural integrity of caveolae, vesicular trafficking, and signal transduction. Although the functions of caveolin-1 are beginning to be explored in caveolin-1-/- mice, these results are confounded by unknown compensatory mechanisms and the development of pulmonary hypertension, cardiomyopathy, and lung fibrosis. To address the role of caveolin-1 in regulating lung vascular permeability, in the present study we used small interfering RNA (siRNA) to knock down caveolin-1 expression in mouse lung endothelia in vivo. Intravenous injection of siRNA against caveolin-1 mRNA incorporated in liposomes selectively reduced the expression of caveolin-1 by approximately 90% within 96 h of injection compared with wild-type mice. We observed the concomitant disappearance of caveolae in lung vessel endothelia and dilated interendothelial junctions (IEJs) as well as increased lung vascular permeability to albumin via IEJs. The reduced caveolin-1 expression also resulted in increased plasma nitric oxide concentration. The nitric oxide synthase inhibitor L-NAME, in part, blocked the increased vascular albumin permeability. These morphological and functional effects of caveolin-1 knockdown were reversible within 168 h after siRNA injection, corresponding to the restoration of caveolin-1 expression. Thus our results demonstrate the essential requirement of caveolin-1 in mediating the formation of caveolae in endothelial cells in vivo and in negatively regulating IEJ permeability. PMID:16183667

  14. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury

    PubMed Central

    Shah, Dilip; Romero, Freddy; Duong, Michelle; Wang, Nadan; Paudyal, Bishnuhari; Suratt, Benjamin T.; Kallen, Caleb B.; Sun, Jianxin; Zhu, Ying; Walsh, Kenneth; Summer, Ross

    2015-01-01

    Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans. PMID:26068229

  15. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Duong, Michelle; Wang, Nadan; Paudyal, Bishnuhari; Suratt, Benjamin T; Kallen, Caleb B; Sun, Jianxin; Zhu, Ying; Walsh, Kenneth; Summer, Ross

    2015-01-01

    Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans. PMID:26068229

  16. Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension

    PubMed Central

    Galambos, Csaba; Minic, Angela D.; Bush, Douglas; Nguyen, Dominique; Dodson, Blair; Seedorf, Gregory; Abman, Steven H.

    2016-01-01

    Background and Aims Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero. Methods Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis. Results The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects. Conclusions We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and

  17. Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis.

    PubMed

    Ong, Evan; Gao, Xiao-Pei; Predescu, Dan; Broman, Michael; Malik, Asrar B

    2005-12-01

    We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury. PMID:16183669

  18. The role of vascular endothelial growth factor receptor-1 signaling in compensatory contralateral lung growth following unilateral pneumonectomy.

    PubMed

    Matsui, Yoshio; Amano, Hideki; Ito, Yoshiya; Eshima, Koji; Tamaki, Hideaki; Ogawa, Fumihiro; Iyoda, Akira; Shibuya, Masafumi; Kumagai, Yuji; Satoh, Yukitoshi; Majima, Masataka

    2015-05-01

    Compensatory lung growth models have been widely used to investigate alveolization because the remaining lung can be kept intact and volume loss can be controlled. Vascular endothelial growth factor (VEGF) plays an important role in blood formation during lung growth and repair, but the precise mechanisms involved are poorly understood; therefore, the aim of this study was to investigate the role of VEGF signaling in compensatory lung growth. After left pneumonectomy, the right lung weight was higher in VEGF transgenic mice than wild-type (WT) mice. Compensatory lung growth was suppressed significantly in mice injected with a VEGF neutralizing antibody and in VEGF receptor-1 tyrosine kinase-deficient mice (TK(-/-) mice). The mobilization of progenitor cells expressing VEGFR1(+) cells from bone marrow and the recruitment of these cells to lung tissue were also suppressed in the TK(-/-) mice. WT mice transplanted with bone marrow from TK(-/-)transgenic GFP(+) mice had significantly lower numbers of GFP(+)/aquaporin 5(+), GFP(+)/surfactant protein A(+), and GFP(+)/VEGFR1(+) cells than WT mice transplanted with bone marrow from WTGFP(+) mice. The GFP(+)/VEGFR1(+) cells also co-stained for aquaporin 5 and surfactant protein A. Overall, these results suggest that VEGF signaling contributes to compensatory lung growth by mobilizing VEGFR1(+) cells. PMID:25642830

  19. Hypertensive Rat Lungs Retain Hallmarks of Vascular Disease upon Decellularization but Support the Growth of Mesenchymal Stem Cells

    PubMed Central

    Scarritt, Michelle E.; Bonvillain, Ryan W.; Burkett, Brian J.; Wang, Guangdi; Glotser, Elana Y.; Zhang, Qiang; Sammarco, Mimi C.; Betancourt, Aline M.; Sullivan, Deborah E.

    2014-01-01

    .79±2.03% vs. 1.05±1.02% of airway-seeded rASCs, and 4.47±1.21% vs. 2.66±0.10% of vascular seeded rASCs). The ECM of cell-seeded scaffolds showed no signs of degradation by the cells after 14 days in culture. These data suggest that diseased hypertensive lungs can be efficiently decellularized similar to control lungs and have the potential to be recellularized with mesenchymal stem cells with the ultimate goal of generating healthy, functional pulmonary tissue. PMID:24378017

  20. The M2 macrophages induce autophagic vascular disorder and promote mouse sensitivity to urethane-related lung carcinogenesis.

    PubMed

    Li, G-G; Guo, Z-Z; Ma, X-F; Cao, N; Geng, S-N; Zheng, Y-Q; Meng, M-J; Lin, H-H; Han, G; Du, G-J

    2016-06-01

    Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Here, we investigated whether polarized macrophage phenotypes are involved in tumor abnormal angiogenesis and what is its mechanism. We found that there was no difference in chemotaxis of polarized M1 and M2 macrophages to lewis lung carcinoma (LLC) cells and that either M1 or M2 macrophage-conditioned media had no effect on LLC cell proliferation. Unexpectedly, the M2 but not M1 macrophage-conditioned media promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and simultaneously increased endothelial cell permeability in vitro and angiogenic index in the chick embryo chorioallantoic membrane (CAM). The treatment with M2 but not M1 macrophage-conditioned media increased autophagosomes as well as microtubule-associated protein light chain 3B (LC3-B) expression (a robust marker of autophagosomes) but decreased p62 protein expression (a selective autophagy substrate) in HUVECs, the treatment with chloroquine that blocked autophagy abrogated the abnormal angiogenic efficacy of M2 macrophage-conditioned media. These results were confirmed in urethane-induced lung carcinogenic progression. Urethane-induced lung carcinogenesis led to more M2 macrophage phenotype and increased abnormal angiogenesis concomitant with the upregulation of LC3-B and the downregulation of p62. Clodronate liposome-induced macrophage depletion, chloroquine-induced autophagic prevention or salvianolic acid B-induced vascular protection decreased abnormal angiogenesis and lung carcinogenesis. In addition, we found that the tendency of age-related M2 macrophage polarization also promoted vascular permeability and carcinogenesis in urethane carcinogenic progression. These findings indicate that the M2 macrophages induce autophagic vascular disorder to promote lung cancer progression, and the autophagy improvement represents an efficacious strategy for abnormal angiogenesis and cancer

  1. Feeding rates and under-ice foraging strategies of the smallest lunge filter feeder, the Antarctic minke whale (Balaenoptera bonaerensis).

    PubMed

    Friedlaender, A S; Goldbogen, J A; Nowacek, D P; Read, A J; Johnston, D; Gales, N

    2014-08-15

    Body size and feeding mode are two fundamental characteristics that determine foraging performance and ecological niche. As the smallest obligate lunge filter feeders, minke whales represent an ideal system for studying the physical and energetic limits of filter feeding in endotherms. We used multi-sensor suction cup tags to quantify the feeding performance of Antarctic minke whales. Foraging dives around and beneath sea ice contained up to 24 lunges per dive, the highest feeding rates for any lunge-feeding whale. Their small size allows minke whales access to krill in sea-ice environments not easily accessible to larger baleen whales. Furthermore, their ability to filter feed provides an advantage over other smaller sympatric krill predators such as penguins and seals that feed on individual prey. The unique combination of body size, feeding mechanism and sea-ice habitat of Antarctic minke whales defines a previously undocumented energetic niche that is unique among aquatic vertebrates. PMID:25122916

  2. Accumulation of brown pigment-laden macrophages associated with vascular lesions in the lungs of cynomolgus monkeys(Macaca fascicularis).

    PubMed

    Yamakawa, Yoshika; Ide, Tetsuya; Mitori, Hikaru; Oishi, Yuji; Matsumoto, Masahiro

    2016-07-01

    Accumulation of macrophages containing brown pigments in the lungs is a well-known spontaneous lesion found in cynomolgus monkey. However, its pathogenesis has not been clearly described. In our survey, brown pigment-laden macrophages were found in the lungs of 4 out of 43 cases. Brown pigments were mostly found in the macrophages of the perivascular interstitium, which proved to be hemosiderin. Some small- to medium-sized vessels that exhibited prominent accumulation of brown pigment-laden macrophages showed degeneration and necrosis of the smooth muscle cells of tunica media. Furthermore, ruptures of the internal and external elastic laminae were seen in some of the vessels. These findings suggested that partial fragmentation of the vascular elastic lamina followed by degeneration and necrosis of the tunica media caused blood leakage leading to the accumulation of hemosiderin-laden macrophages in the perivascular interstitium of the lungs. PMID:27559243

  3. Accumulation of brown pigment-laden macrophages associated with vascular lesions in the lungs of cynomolgus monkeys(Macaca fascicularis)

    PubMed Central

    Yamakawa, Yoshika; Ide, Tetsuya; Mitori, Hikaru; Oishi, Yuji; Matsumoto, Masahiro

    2016-01-01

    Accumulation of macrophages containing brown pigments in the lungs is a well-known spontaneous lesion found in cynomolgus monkey. However, its pathogenesis has not been clearly described. In our survey, brown pigment-laden macrophages were found in the lungs of 4 out of 43 cases. Brown pigments were mostly found in the macrophages of the perivascular interstitium, which proved to be hemosiderin. Some small- to medium-sized vessels that exhibited prominent accumulation of brown pigment-laden macrophages showed degeneration and necrosis of the smooth muscle cells of tunica media. Furthermore, ruptures of the internal and external elastic laminae were seen in some of the vessels. These findings suggested that partial fragmentation of the vascular elastic lamina followed by degeneration and necrosis of the tunica media caused blood leakage leading to the accumulation of hemosiderin-laden macrophages in the perivascular interstitium of the lungs.

  4. Optimization of leaf margins for lung stereotactic body radiotherapy using a flattening filter-free beam

    SciTech Connect

    Wakai, Nobuhide; Sumida, Iori; Otani, Yuki; Suzuki, Osamu; Seo, Yuji; Isohashi, Fumiaki; Yoshioka, Yasuo; Ogawa, Kazuhiko; Hasegawa, Masatoshi

    2015-05-15

    Purpose: The authors sought to determine the optimal collimator leaf margins which minimize normal tissue dose while achieving high conformity and to evaluate differences between the use of a flattening filter-free (FFF) beam and a flattening-filtered (FF) beam. Methods: Sixteen lung cancer patients scheduled for stereotactic body radiotherapy underwent treatment planning for a 7 MV FFF and a 6 MV FF beams to the planning target volume (PTV) with a range of leaf margins (−3 to 3 mm). Forty grays per four fractions were prescribed as a PTV D95. For PTV, the heterogeneity index (HI), conformity index, modified gradient index (GI), defined as the 50% isodose volume divided by target volume, maximum dose (Dmax), and mean dose (Dmean) were calculated. Mean lung dose (MLD), V20 Gy, and V5 Gy for the lung (defined as the volumes of lung receiving at least 20 and 5 Gy), mean heart dose, and Dmax to the spinal cord were measured as doses to organs at risk (OARs). Paired t-tests were used for statistical analysis. Results: HI was inversely related to changes in leaf margin. Conformity index and modified GI initially decreased as leaf margin width increased. After reaching a minimum, the two values then increased as leaf margin increased (“V” shape). The optimal leaf margins for conformity index and modified GI were −1.1 ± 0.3 mm (mean ± 1 SD) and −0.2 ± 0.9 mm, respectively, for 7 MV FFF compared to −1.0 ± 0.4 and −0.3 ± 0.9 mm, respectively, for 6 MV FF. Dmax and Dmean for 7 MV FFF were higher than those for 6 MV FF by 3.6% and 1.7%, respectively. There was a positive correlation between the ratios of HI, Dmax, and Dmean for 7 MV FFF to those for 6 MV FF and PTV size (R = 0.767, 0.809, and 0.643, respectively). The differences in MLD, V20 Gy, and V5 Gy for lung between FFF and FF beams were negligible. The optimal leaf margins for MLD, V20 Gy, and V5 Gy for lung were −0.9 ± 0.6, −1.1 ± 0.8, and −2.1 ± 1.2 mm, respectively, for 7 MV FFF compared

  5. Pulmonary vascular disease in different types of congenital heart disease. Implications for interpretation of lung biopsy findings in early childhood.

    PubMed Central

    Haworth, S G

    1984-01-01

    Pulmonary vascular structure was studied by analysing serial reconstructions of the arterial pathways and random sections of tissue in the lungs of 16 children who died with different types of congenital heart disease and pulmonary hypertension. Cases of ventricular septal defect showed an appreciable increase in muscularity of both preacinar and intra-acinar (respiratory unit) arteries, and intimal proliferation was infrequent and mild. By contrast, cases of transposition of the great arteries with ventricular septal defect and atrioventricular septal defect showed an increase in preacinar muscularity, a short heavily muscularised arterial segment containing intimal proliferation at the entrance to the acinus, whereas the intra-acinar arteries beyond showed only a moderate increase in muscularity. In these children who were less than 1 year of age an increase in pulmonary vascular resistance was due to strategically placed small areas of intimal proliferation and not to widespread obliterative pulmonary vascular disease. The study demonstrated and explained differences in the appearance of the peripheral pulmonary arteries in different types of congenital heart disease, which help interpret the findings of lung biopsies. Images PMID:6498033

  6. Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice.

    PubMed

    Goto, Hisatsugu; Yano, Seiji; Zhang, Helong; Matsumori, Yuka; Ogawa, Hirohisa; Blakey, David C; Sone, Saburo

    2002-07-01

    ZD6126 (ANG453) is a novel vascular targeting agent that selectively disrupts the cytoskeleton of endothelial cells in tumor. In mouse s.c. xenograft models, ZD6126 was found to induce selective occlusion of tumor blood vessels, cessation of tumor blood flow, and death of tumor cells because of the starvation of oxygen and nutrition. Here, we investigated whether ZD6126 inhibited the metastatic formation of human non-small cell lung cancer cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells were injected into the tail vein of nude mice, and lung metastases were estimated. ZD6126 treatment involved either a single dose on 24 h before killing or daily doses from day 14 until the end of the experiment. Single treatment with i.p. injection of 200 mg/kg ZD6126 caused bleeding and necrotic changes in the tumor by 24 h. Histological analysis revealed that apoptotic tumor cells were markedly increased in the ZD6126-treated group. Moreover, ZD6126 induced the apoptosis of CD31-positive vascular endothelial cells in tumors but not in the normal lung parenchyma. When mice were treated daily with 100 mg/kg ZD6126 from day 14 until the end of the experiment, the lung weight was significantly less in the ZD6126-treated group than that of the control group, despite no difference in the number of metastatic nodules. These data suggest that ZD6126 could demonstrate its antitumor activity against both already established and early phase of lung cancer metastasis by causing the selective apoptosis of tumor endothelial cells and destruction of the tumor vasculature. PMID:12097279

  7. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  8. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

    PubMed Central

    Van der Velden, Joanne; Harkness, Louise M.; Barker, Donna M.; Barcham, Garry J.; Ugalde, Cathryn L.; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A.; Tokanovic, Ana; Burgess, Janette K.; Snibson, Kenneth J.

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10+–20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  9. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma.

    PubMed

    Van der Velden, Joanne; Harkness, Louise M; Barker, Donna M; Barcham, Garry J; Ugalde, Cathryn L; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A; Tokanovic, Ana; Burgess, Janette K; Snibson, Kenneth J

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10(+)-20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  10. Multicentre knowledge sharing and planning/dose audit on flattening filter free beams for SBRT lung

    NASA Astrophysics Data System (ADS)

    Hansen, C. R.; Sykes, J. R.; Barber, J.; West, K.; Bromley, R.; Szymura, K.; Fisher, S.; Sim, J.; Bailey, M.; Chrystal, D.; Deshpande, S.; Franji, I.; Nielsen, T. B.; Brink, C.; Thwaites, D. I.

    2015-01-01

    When implementing new technology into clinical practice, there will always be a need for large knowledge gain. The aim of this study was twofold, (I) audit the treatment planning and dose delivery of Flattening Filter Free (FFF) beam technology for Stereotactic Body Radiation Therapy (SBRT) of lung tumours across a range of treatment planning systems compared to the conventional Flatting Filter (FF) beams, (II) investigate how sharing knowledge between centres of different experience can improve plan quality. All vendor/treatment planning system (TPS) combinations investigated were able to produce acceptable treatment plans and the dose accuracy was clinically acceptable for all plans. By sharing knowledge between the different centres, the minor protocol violations (MPV) could be significantly reduced, from an average of 1.9 MPV per plan to 0.6 after such sharing of treatment planning knowledge. In particular, for the centres with less SBRT and/or volumetric- modulated arc therapy (VMAT) experience the MPV average per plan improved. All vendor/TPS combinations were also able to successfully deliver the FF and FFF SBRT VMAT plans. The plan quality and dose accuracy were found to be clinically acceptable.

  11. Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6.

    PubMed

    Meliton, Angelo; Meng, Fanyong; Tian, Yufeng; Shah, Alok A; Birukova, Anna A; Birukov, Konstantin G

    2015-12-01

    Mechanisms of vascular endothelial cell (EC) barrier regulation during acute lung injury (ALI) or other pathologies associated with increased vascular leakiness are an active area of research. Adaptor protein krev interaction trapped-1 (KRIT1) participates in angiogenesis, lumen formation, and stabilization of EC adherens junctions (AJs) in mature vasculature. We tested a role of KRIT1 in the regulation of Rho-GTPase signaling induced by mechanical stimulation and barrier dysfunction relevant to ventilator-induced lung injury and investigated KRIT1 involvement in EC barrier protection by prostacyclin (PC). PC stimulated Ras-related protein 1 (Rap1)-dependent association of KRIT1 with vascular endothelial cadherin at AJs, with KRIT1-dependent cortical cytoskeletal remodeling leading to EC barrier enhancement. KRIT1 knockdown exacerbated Rho-GTPase activation and EC barrier disruption induced by pathologic 18% cyclic stretch and thrombin receptor activating peptide (TRAP) 6 and attenuated the protective effects of PC. In the two-hit model of ALI caused by high tidal volume (HTV) mechanical ventilation and TRAP6 injection, KRIT1 functional deficiency in KRIT1(+/-) mice increased basal lung vascular leak and augmented vascular leak and lung injury caused by exposure to HTV and TRAP6. Down-regulation of KRIT1 also diminished the protective effects of PC against TRAP6/HTV-induced lung injury. These results demonstrate a KRIT1-dependent mechanism of vascular EC barrier control in basal conditions and in the two-hit model of ALI caused by excessive mechanical forces and TRAP6 via negative regulation of Rho activity and enhancement of cell junctions. We also conclude that the stimulation of the Rap1-KRIT1 signaling module is a major mechanism of vascular endothelial barrier protection by PC in the injured lung. PMID:25923142

  12. Acute tumor vascular effects following fractionated radiotherapy in human lung cancer: In vivo whole tumor assessment using volumetric perfusion computed tomography

    SciTech Connect

    Ng, Q.-S.; Goh, Vicky; Milner, Jessica; Padhani, Anwar R.; Saunders, Michele I.; Hoskin, Peter J. . E-mail: peterhoskin@nhs.net

    2007-02-01

    Purpose: To quantitatively assess the in vivo acute vascular effects of fractionated radiotherapy for human non-small-cell lung cancer using volumetric perfusion computed tomography (CT). Methods and Materials: Sixteen patients with advanced non-small-cell lung cancer, undergoing palliative radiotherapy delivering 27 Gy in 6 fractions over 3 weeks, were scanned before treatment, and after the second (9 Gy), fourth (18 Gy), and sixth (27 Gy) radiation fraction. Using 16-detector CT, multiple sequential volumetric acquisitions were acquired after intravenous contrast agent injection. Measurements of vascular blood volume and permeability for the whole tumor volume were obtained. Vascular changes at the tumor periphery and center were also measured. Results: At baseline, lung tumor vascularity was spatially heterogeneous with the tumor rim showing a higher vascular blood volume and permeability than the center. After the second, fourth, and sixth fractions of radiotherapy, vascular blood volume increased by 31.6% (paired t test, p = 0.10), 49.3% (p = 0.034), and 44.6% (p = 0.0012) respectively at the tumor rim, and 16.4% (p = 0.29), 19.9% (p = 0.029), and 4.0% (p = 0.0050) respectively at the center of the tumor. After the second, fourth, and sixth fractions of radiotherapy, vessel permeability increased by 18.4% (p = 0.022), 44.8% (p = 0.0048), and 20.5% (p = 0.25) at the tumor rim. The increase in permeability at the tumor center was not significant after radiotherapy. Conclusion: Fractionated radiotherapy increases tumor vascular blood volume and permeability in human non-small-cell lung cancer. We have established the spatial distribution of vascular changes after radiotherapy; greater vascular changes were demonstrated at the tumor rim compared with the center.

  13. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice.

    PubMed

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene; Bland, Richard

    2015-03-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice. PMID:25539853

  14. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

    PubMed Central

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene

    2014-01-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice. PMID:25539853

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

    PubMed Central

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

    2015-01-01

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

  16. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior.

    PubMed

    Roudsari, Laila C; Jeffs, Sydney E; Witt, Amber S; Gill, Bartley J; West, Jennifer L

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm(2), circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  17. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    PubMed Central

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  18. Crosstalk between ACE2 and PLGF regulates vascular permeability during acute lung injury

    PubMed Central

    Wang, Lantao; Li, Yong; Qin, Hao; Xing, Dong; Su, Jie; Hu, Zhenjie

    2016-01-01

    Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI), through antagonizing hydrolyzing angiotensin II (AngII) and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with placental growth factor (PLGF) remain ill-defined. In the current study, we examined the relationship between ACE2 and PLGF in ALI model in mice. We used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of PLGF in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5 µg/kg Visudyne. PLGF pump or soluble Flt-1 (sFlt-1) pump was given to augment or suppress PLGF effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. We found that ACE2 treatment did not alter PLGF levels in lung, but antagonized the effects of PLGF on increases of lung vessel permeability. Ectogenic PLGF abolished the antagonizing effects of ACE2 on the vessel permeability against PLGF. On the other hand, suppression of PLGF signaling mimicked the effects of ACE2 on the vessel permeability against PLGF. The suppression of vessel permeability resulted in improvement of lung function after ALI. Thus, ACE2 may antagonize the PLGF-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI. PMID:27158411

  19. Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities

    PubMed Central

    Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili; Bonini, Marcelo G.; Gothert, Joachim; Shen, Tang-Long; Guan, Jun-Lin; Predescu, Sanda; Sadikot, Ruxana

    2013-01-01

    Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK−/− ECs and lung vascular integrity in EC-FAK−/− mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities. PMID:23771883

  20. Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities.

    PubMed

    Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili; Bonini, Marcelo G; Gothert, Joachim; Shen, Tang-Long; Guan, Jun-Lin; Predescu, Sanda; Sadikot, Ruxana; Mehta, Dolly

    2013-08-15

    Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK-/- ECs and lung vascular integrity in EC-FAK-/- mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities. PMID:23771883

  1. Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells.

    PubMed

    Yano, S; Shinohara, H; Herbst, R S; Kuniyasu, H; Bucana, C D; Ellis, L M; Fidler, I J

    2000-12-01

    We determined the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage of human, non-small-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)-localized vascular hyperpermeability. Lung lesions produced by H226 cells were confined to the lung parenchyma with no PE. The level of expression of VEGF mRNA and protein by the cell lines directly correlated with extent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 genes induced localized vascular hyperpermeability and produced PE only after direct implantation into the thoracic cavity. The production of PE was thus associated with the ability of tumor cells to invade the pleura, a property associated with expression of high levels of urokinase-type plasminogen activator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGF/VPF. PMID:11106562

  2. Production of Experimental Malignant Pleural Effusions Is Dependent on Invasion of the Pleura and Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor by Human Lung Cancer Cells

    PubMed Central

    Yano, Seiji; Shinohara, Hisashi; Herbst, Roy S.; Kuniyasu, Hiroki; Bucana, Corazon D.; Ellis, Lee M.; Fidler, Isaiah J.

    2000-01-01

    We determined the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage of human, non-small-cell lung cancer. Intravenous injection of human PC14 and PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)-localized vascular hyperpermeability. Lung lesions produced by H226 cells were confined to the lung parenchyma with no PE. The level of expression of VEGF mRNA and protein by the cell lines directly correlated with extent of PE formation. Transfection of PC14PE6 cells with antisense VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation. H226 cells transfected with either sense VEGF 165 or sense VEGF 121 genes induced localized vascular hyperpermeability and produced PE only after direct implantation into the thoracic cavity. The production of PE was thus associated with the ability of tumor cells to invade the pleura, a property associated with expression of high levels of urokinase-type plasminogen activator and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGF/VPF. PMID:11106562

  3. Effects of N omega-nitro-L-arginine on total and segmental vascular resistances in developing lamb lungs.

    PubMed

    Gordon, J B; Tod, M L

    1993-07-01

    To determine whether endothelium-derived nitic oxide (EDNO), like dilator prostaglandins, attenuates pulmonary vasomotor tone more in younger than in older newborns, we examined the effects of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA), on total and segmental pulmonary vascular resistance (PVR) in isolated blood-perfused cyclooxygenase-inhibited lungs of < 2-day-old (2D) and 1-mo-old (1M) lambs. Total PVR was determined both from steady-state pressure-flow curves and total pressure gradients (delta PT) measured at constant flow (100 ml.kg-1 x min-1). Pressure gradients across arterial (delta Pa), middle (delta Pm), and venous (delta Pv) segments were determined by inflow-outflow occlusion. In 1M lungs (n = 6), L-NA increased delta PT, delta Pa, and delta Pv during normoxia and hypoxia. However, delta Pm increased only during hypoxia, suggesting that EDNO attenuates resistance of small vessels more when tone is high. The response to L-NA in 2D lungs was variable. In four "responders" (2D"R"), normoxic and hypoxic delta PT and all segmental resistances increased markedly after L-NA, but in five "nonresponders" (2D"NR"), L-NA had an insignificant effect on delta PT. Moreover, control delta PT values were higher in 2D"NR" than in 2D"R" lungs, suggesting that basal EDNO activity was minimal in some young newborns. Nonetheless, EDNO appears to attenuate venous resistance in newborns, because L-NA increased delta Pv in all groups. The significance of and mechanism(s) responsible for lesser modulation of PVR by EDNO in some young newborns remain to be determined. PMID:8376304

  4. The Vascular Endothelial Growth Factors-Expressing Character of Mesenchymal Stem Cells Plays a Positive Role in Treatment of Acute Lung Injury In Vivo

    PubMed Central

    Yang, Yi; Hu, Shuling; Xu, Xiuping; Li, Jinze; Liu, Airan; Han, Jibin; Liu, Songqiao; Liu, Ling; Qiu, Haibo

    2016-01-01

    Recently, mesenchymal stem cells (MSC) have been proved to be beneficial in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) is an important angiogenesis factor that MSC release. However, the precise role of VEGF-expressing character of MSC in the MSC treatment for ARDS remains obscure. Here, we firstly knocked down the gene VEGF in MSC (MSC-ShVEGF) with lentiviral transduction. Then we injected the MSC-ShVEGF to rats with lipopolysaccharide-induced acute lung injury (ALI) via the tail vein. Data showed that MSC transplantation significantly increased VEGF levels in the lung, reduced lung permeability, protected lung endothelium from apoptosis, facilitated VE-cadherin recovery, controlled inflammation, and attenuated lung injury. However, VEGF gene knockdown in MSC led to relatively insufficient VEGF expression in the injured lung and significantly diminished the therapeutic effects of MSC on ALI, suggesting an important role of VEGF-expressing behavior of MSC in the maintenance of VEGF in the lung and the MSC treatment for ALI. Hence, we conclude that MSC restores the lung permeability and attenuates lung injury in rats with ALI in part by maintaining a “sufficient” VEGF level in the lung and the VEGF-expressing character of MSC plays a positive role in the therapeutic effects of MSC on ARDS. PMID:27313398

  5. The lung in sickle cell disease: a clinical overview of common vascular, infectious, and other problems.

    PubMed

    Young, R C; Castro, O; Baxter, R P; Dunn, R; Armstrong, E M; Cook, F J; Sampson, C C

    1981-01-01

    Acute pulmonary complications of sickle cell anemia are sickle cell lung disease and bacterial pneumonias. Chronic abnormalities in lung function include a restrictive ventilatory defect and perhaps increased venous admixture to the pulmonary circulation. Coexisting sarcoidosis may complicate sickle cell anemia and interact to potentiate sickling. Sickle cell lung disease, or acute "chest syndrome," occurs with greatest frequency in adults, is due primarily to pulmonary infarction, and may lead to cor pulmonale. On the other hand, bacterial pneumonia due to Streptococcus pneumoniae occurs with greater frequency in infancy and childhood. Mycoplasma and other organisms may also cause pneumonia with protracted illness and slow resolution. Bacteremia and meningitis may be further complications, particularly in children. Precise diagnosis of the acute febrile pulmonary episode is often difficult. In adults the illness is commonly self-limited. However, a vigorous diagnostic approach is warranted in all severely ill patients. PMID:7463492

  6. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

    PubMed Central

    O'Byrne, K J; Koukourakis, M I; Giatromanolaki, A; Cox, G; Turley, H; Steward, W P; Gatter, K; Harris, A L

    2000-01-01

    High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1–3, N0–2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P = 0.009 and P = 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r = 0.21;P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P< 0.02) and microvessel density (P< 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC. © 2000 Cancer Research Campaign PMID:10780522

  7. The H2S-generating enzymes cystathionine β-synthase and cystathionine γ-lyase play a role in vascular development during normal lung alveolarization.

    PubMed

    Madurga, Alicia; Golec, Anita; Pozarska, Agnieszka; Ishii, Isao; Mižíková, Ivana; Nardiello, Claudio; Vadász, István; Herold, Susanne; Mayer, Konstantin; Reichenberger, Frank; Fehrenbach, Heinz; Seeger, Werner; Morty, Rory E

    2015-10-01

    The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine β-synthase (Cbs) and cystathionine γ-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs(-/-) and Cth(-/-) mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser-capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small- and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization. PMID:26232299

  8. Vascular endothelial growth factor C complements the ability of positron emission tomography to predict nodal disease in lung cancer

    PubMed Central

    Farjah, Farhood; Madtes, David K.; Wood, Douglas E.; Flum, David R.; Zadworny, Megan E.; Waworuntu, Rachel; Hwang, Billanna; Mulligan, Michael S.

    2016-01-01

    Objective Vascular endothelial growth factors (VEGFs) C and D are biologically rational markers of nodal disease that could improve the accuracy of lung cancer staging. We hypothesized that these biomarkers would improve the ability of positron emission tomography (PET) to predict nodal disease among patients with suspected or confirmed non–small cell lung cancer (NSCLC). Methods A cross-sectional study (2010–2013) was performed of patients prospectively enrolled in a lung nodule biorepository, staged by computed tomography (CT) and PET, and who underwent pathologic nodal evaluation. Enzyme-linked immunosorbent assay was used to measure biomarker levels in plasma from blood drawn before anesthesia. Likelihood ratio testing was used to compare the following logistic regression prediction models: ModelPET, ModelPET/VEGF-C, ModelPET/VEGF-D, and ModelPET/VEGF-C/VEGF-D. To account for 5 planned pairwise comparisons, P values<.01 were considered significant. Results Among 62 patients (median age, 67 years; 48% men; 87% white; and 84% NSCLC), 58% had fluorodeoxyglucose uptake in hilar and/or mediastinal lymph nodes. The prevalence of pathologically confirmed lymph node metastases was 40%. Comparisons of prediction models revealed the following: ModelPET/VEGF-C versus ModelPET (P = .0069), ModelPET/VEGF-D versus ModelPET (P = .1886), ModelPET/VEGF-C/VEGF-D versus ModelPET (P = .0146), ModelPET/VEGF-C/VEGF-D versus ModelPET/VEGF-C (P = .2818), and ModelPET/VEGF-C/VEGF-D versus ModelPET/VEGF-D (P = .0095). In ModelPET/VEGF-C, higher VEGF-C levels were associated with an increased risk of nodal disease (odds ratio, 2.96; 95% confidence interval, 1.26–6.90). Conclusions Plasma levels of VEGF-C complemented the ability of PET to predict nodal disease among patients with suspected or confirmed NSCLC. VEGF-D did not improve prediction. PMID:26320776

  9. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53.

    PubMed Central

    Ambs, S.; Bennett, W. P.; Merriam, W. G.; Ogunfusika, M. O.; Oser, S. M.; Khan, M. A.; Jones, R. T.; Harris, C. C.

    1998-01-01

    Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlation suggests the hypothesis that oncogenes and tumour suppressors regulate VEGF, and a significant correlation between p53 alteration and increased VEGF expression in human lung cancer was reported recently. To further examine this hypothesis, we analysed VEGF protein expression and mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC): 16 squamous cell, six adenocarcinomas, one large cell, two carcinoids and two undifferentiated tumours. VEGF was expressed in 50% of the squamous cell carcinomas (SCC) and carcinoids but none of the others. p53 mutations occurred in 14 tumours (52%), and K-ras mutations were found in two adenocarcinomas and one SCC; there was no correlation between the mutations and VEGF expression. As nitric oxide also regulates angiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent NOS activity, which indicates NOS1 and NOS3 expression, was significantly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indicates NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summary, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCLC progression that has been suggested for gynaecological and breast cancers. Images Figure 1 Figure 4 Figure 5 PMID:9683299

  10. Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma.

    PubMed

    Marrogi, A J; Travis, W D; Welsh, J A; Khan, M A; Rahim, H; Tazelaar, H; Pairolero, P; Trastek, V; Jett, J; Caporaso, N E; Liotta, L A; Harris, C C

    2000-12-01

    We have investigated the hypothesis that nitric oxide synthase (NOS2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) protein levels individually demonstrate a direct correlation with microvessel density (MVD) and clinical outcome in human non-small cell lung cancer (NSCLC). Furthermore, we hypothesized that MVD may explain the propensity of certain histological lung cancer subtypes for early metastasis via a hematological route. Immunohistochemically, we studied the protein expression levels of NOS2, COX2, and VEGF and MVD by counting CD31-reactive blood vessels (BVs) in 106 surgically resected NSCLC specimens. NOS2, COX2, and VEGF immunoreactivity were observed in 48, 48, and 58%, respectively, of the study subjects, and their levels correlated with MVD at the tumor-stromal interphase (P < or = 0.001). More adenocarcindmas and large cell carcinomas displayed overexpression of NOS2 when compared with squamous cell carcinoma (SCC; r = 0.44; P < 0.001). NOS2 and COX2 levels were found to correlate positively with VEGF status (r = 0.44; P < 0.001, 0.01, and 0.03, respectively). These results attest to the significant interaction of these factors in the angiogenesis of NSCLC. Although neither angiogenic factors nor MVD correlated with patient survival, the latter correlated with tumor clinical stage in both squamous (SCC; 73 BVs/mm2) and non-SCC (78 BVs/mm2) tumors. These results indicate that angiogenesis is a complex process that involves multiple factors including NOS2, COX2, and VEGF. Furthermore, the role of angiogenesis in the biology of various histological lung cancer types may be different. The complexity of angiogenesis may explain the modest results observed in antiangiogenesis therapy that target a single protein. PMID:11156228

  11. An audit into the efficacy of single use bacterial/viral filters for the prevention of equipment contamination during lung function assessment.

    PubMed

    Unstead, M; Stearn, M D; Cramer, D; Chadwick, M V; Wilson, R

    2006-05-01

    Lung function testing has been suggested to provide a potential risk regarding cross-infection between patients. About 155 patients (86 infectious, 69 non-infectious) used a single use bacterial/viral filter when performing routine lung function tests. Swabs from the patient side of the filter (Proximal) and the equipment side (Distal), and two sections of the filter itself were cultured. About 33/155 samples showed bacterial growth on the Proximal compared with 2/155 on the Distal side (P<0.01). Growth was obtained from the filter in 125/155 (80.6%) of cases. Pathogenic micro-organisms such as Pseudomonas aeruginosa (4 cases) and Staphylococcus aureus (5 cases) were isolated. Appropriate infection control measures should be used when performing lung function tests. PMID:16242312

  12. Dosimetric comparison of a 6-MV flattening-filter and a flattening-filter-free beam for lung stereotactic ablative radiotherapy treatment

    NASA Astrophysics Data System (ADS)

    Kim, Yon-Lae; Chung, Jin-Beom; Kim, Jae-Sung; Lee, Jeong-Woo; Kim, Jin-Young; Kang, Sang-Won; Suh, Tae-Suk

    2015-11-01

    The purpose of this study was to test the feasibility of clinical usage of a flattening-filter-free (FFF) beam for treatment with lung stereotactic ablative radiotherapy (SABR). Ten patients were treated with SABR and a 6-MV FFF beam for this study. All plans using volumetric modulated arc therapy (VMAT) were optimized in the Eclipse treatment planning system (TPS) by using the Acuros XB (AXB) dose calculation algorithm and were delivered by using a Varian TrueBeam ™ linear accelerator equipped with a high-definition (HD) multi-leaf collimator. The prescription dose used was 48 Gy in 4 fractions. In order to compare the plan using a conventional 6-MV flattening-filter (FF) beam, the SABR plan was recalculated under the condition of the same beam settings used in the plan employing the 6-MV FFF beam. All dose distributions were calculated by using Acuros XB (AXB, version 11) and a 2.5-mm isotropic dose grid. The cumulative dosevolume histograms (DVH) for the planning target volume (PTV) and all organs at risk (OARs) were analyzed. Technical parameters, such as total monitor units (MUs) and the delivery time, were also recorded and assessed. All plans for target volumes met the planning objectives for the PTV ( i.e., V95% > 95%) and the maximum dose ( i.e., Dmax < 110%) revealing adequate target coverage for the 6-MV FF and FFF beams. Differences in DVH for target volumes (PTV and clinical target volume (CTV)) and OARs on the lung SABR plans from the interchange of the treatment beams were small, but showed a marked reduction (52.97%) in the treatment delivery time. The SABR plan with a FFF beam required a larger number of MUs than the plan with the FF beam, and the mean difference in MUs was 4.65%. This study demonstrated that the use of the FFF beam for lung SABR plan provided better treatment efficiency relative to 6-MV FF beam. This strategy should be particularly beneficial for high dose conformity to the lung and decreased intra-fraction movements because of

  13. The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury.

    PubMed

    Stevens, Trevor C; Ochoa, Cristhiaan D; Morrow, K Adam; Robson, Matthew J; Prasain, Nutan; Zhou, Chun; Alvarez, Diego F; Frank, Dara W; Balczon, Ron; Stevens, Troy

    2014-05-15

    Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103ΔexoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (ΔPcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ΔPcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury. PMID:24705722

  14. Anti-Vascular Endothelial Growth Factor Antibody Suppresses ERK and NF-κB Activation in Ischemia-Reperfusion Lung Injury.

    PubMed

    Lan, Chou-Chin; Peng, Chung-Kan; Tang, Shih-En; Wu, Shu-Yu; Huang, Kun-Lun; Wu, Chin-Pyng

    2016-01-01

    Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti-VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-α, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues. PMID:27513332

  15. Anti-Vascular Endothelial Growth Factor Antibody Suppresses ERK and NF-κB Activation in Ischemia-Reperfusion Lung Injury

    PubMed Central

    Lan, Chou-Chin; Peng, Chung-Kan; Tang, Shih-En; Wu, Shu-Yu

    2016-01-01

    Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti-VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-α, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues. PMID:27513332

  16. Effects of autocrine vascular endothelial growth factor (VEGF) in non-small cell lung cancer cell line A549.

    PubMed

    Wang, Ying; Huang, Lu; Yang, Yunmei; Xu, Liqian; Yang, Ji; Wu, Yue

    2013-04-01

    It is reported that the autocrine loop of the vascular endothelial growth factor (VEGF) is crucial for the survival and proliferation of non-small cell lung cancer (NSCLC) tumors. In this study we aimed to systematically investigate the role of autocrine vascular VEGF in NSCLC cell line A549 through inhibition of endogenous VEGF. A549 cells were transfected with florescence-labeled VEGF oligodeoxynucleotide with lipofectamine. For the experimental group, cells were transfected with VEGF anti-sense oligodeoxynucleotide (ASODN), sense oligodeoxynucleotide (SODN) and mutant oligodeoxynuleotide (MODN) respectively. For the control group cells were mock transfected with lipofectamine or culture medium. At indicated time point after transfection, the expression levels of VEGF mRNA and protein in A549 cells were analyzed by RT-PCR and ELISA respectively. Cell viability was measured by the MTT assay. Cell cycle distribution was detected by flow cytometry. As revealed by RT-PCR assay, the mRNA level of VEGF in cells transfected with ASDON was significantly lower than the other four groups (P < 0.05) at 24 and 48 h after transfection. ELISA assay yielded similar result with significantly decreased level of VEGF protein expression (P < 0.05). The survival fraction of A549 cells transfected with ASDON was significantly lower than the other four groups (P < 0.05) at 24 h after transfection. Also the percentage of G2 phase cells of ASODN group was significantly lower than other four groups. Our data indicate that VEGF expression is efficiently inhibited in A549 cells by ASODN transfection and this inhibition leads to inhibited cell growth and impaired cell cycle distribution. PMID:23459872

  17. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

    PubMed Central

    Heist, Rebecca S.; Duda, Dan G.; Sahani, Dushyant V.; Ancukiewicz, Marek; Fidias, Panos; Sequist, Lecia V.; Temel, Jennifer S.; Shaw, Alice T.; Pennell, Nathan A.; Neal, Joel W.; Gandhi, Leena; Lynch, Thomas J.; Engelman, Jeffrey A.; Jain, Rakesh K.

    2015-01-01

    Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non–small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population—may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy. PMID:25605928

  18. Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney.

    PubMed

    Muhl, Lars; Moessinger, Christine; Adzemovic, Milena Z; Dijkstra, Marike H; Nilsson, Ingrid; Zeitelhofer, Manuel; Hagberg, Carolina E; Huusko, Jenni; Falkevall, Annelie; Ylä-Herttuala, Seppo; Eriksson, Ulf

    2016-07-01

    Metabolic diseases, such as obesity and diabetes, are a serious burden for the health system. Vascular endothelial growth factor (VEGF)-B has been shown to regulate tissue uptake and accumulation of fatty acids and is thus involved in these metabolic diseases. However, the cell-type-specific expression pattern of Vegfb and its receptor (VEGFR1, gene Flt1) remains unclear. We explore the expression of Vegfb and Flt1 in the murine heart, lung and kidney by utilizing β-galactosidase knock-in mouse models and combining the analysis of reporter gene expression and immunofluorescence microscopy. Furthermore, Flt1 heterozygous mice were analyzed with regard to muscular fatty acid accumulation and peripheral insulin sensitivity. Throughout the heart, Vegfb expression was found in cardiomyocytes with a postnatal ventricular shift corresponding to known changes in energy requirements. Vegfb expression was also found in the pulmonary myocardium of the lung and in renal epithelial cells of the thick ascending limb of Henle's loop, the connecting tubule and the collecting duct. In all analyzed organs, VEGFR1 expression was restricted to endothelial cells. We also show that reduced expression of VEGFR1 resulted in decreased cardiac fatty acid accumulation and increased peripheral insulin sensitivity, possibly as a result of attenuated VEGF-B/VEGFR1 signaling. Our data therefore support a tightly controlled, paracrine signaling mechanism of VEGF-B to VEGFR1. The identified cell-specific expression pattern of Vegfb and Flt1 might form the basis for the development of cell-type-targeted research models and contributes to the understanding of the physiological and pathological role of VEGF-B/VEGFR1 signaling. PMID:26928042

  19. Transforming Growth Factor-β1 Downregulates Vascular Endothelial Growth Factor-D Expression in Human Lung Fibroblasts via the Jun NH2-Terminal Kinase Signaling Pathway

    PubMed Central

    Cui, Ye; Osorio, Juan C; Risquez, Cristobal; Wang, Hao; Shi, Ying; Gochuico, Bernadette R; Morse, Danielle; Rosas, Ivan O; El-Chemaly, Souheil

    2014-01-01

    Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF. PMID:24515257

  20. ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model.

    PubMed

    Matsumori, Yuka; Yano, Seiji; Goto, Hisatsugu; Nakataki, Emiko; Wedge, Stephen R; Ryan, Anderson J; Sone, Saburo

    2006-01-01

    ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC. PMID:16783964

  1. Hepatocyte growth factor as a downstream mediator of vascular endothelial growth factor-dependent preservation of growth in the developing lung.

    PubMed

    Seedorf, Gregory; Metoxen, Alexander J; Rock, Robert; Markham, Neil; Ryan, Sharon; Vu, Thiennu; Abman, Steven H

    2016-06-01

    Impaired vascular endothelial growth factor (VEGF) signaling contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that the effects of VEGF on lung structure during development may be mediated through its downstream effects on both endothelial nitric oxide synthase (eNOS) and hepatocyte growth factor (HGF) activity, and that, in the absence of eNOS, trophic effects of VEGF would be mediated through HGF signaling. To test this hypothesis, we performed an integrative series of in vitro (fetal rat lung explants and isolated fetal alveolar and endothelial cells) and in vivo studies with normal rat pups and eNOS(-/-) mice. Compared with controls, fetal lung explants from eNOS(-/-) mice had decreased terminal lung bud formation, which was restored with recombinant human VEGF (rhVEGF) treatment. Neonatal eNOS(-/-) mice were more susceptible to hyperoxia-induced inhibition of lung growth than controls, which was prevented with rhVEGF treatment. Fetal alveolar type II (AT2) cell proliferation was increased with rhVEGF treatment only with mesenchymal cell (MC) coculture, and these effects were attenuated with anti-HGF antibody treatment. Unlike VEGF, HGF directly stimulated isolated AT2 cells even without MC coculture. HGF directly stimulates fetal pulmonary artery endothelial cell growth and tube formation, which is attenuated by treatment with JNJ-38877605, a c-Met inhibitor. rHGF treatment preserves alveolar and vascular growth after postnatal exposure to SU-5416, a VEGF receptor inhibitor. We conclude that the effects of VEGF on AT2 and endothelial cells during lung development are partly mediated through HGF-c-Met signaling and speculate that reciprocal VEGF-HGF signaling between epithelia and endothelia is disrupted in infants who develop BPD. PMID:27036872

  2. Ability of plasmid DNA complexed with histidinylated lPEI and lPEI to cross in vitro lung and muscle vascular endothelial barriers.

    PubMed

    Gomez, Jean-Pierre; Pichon, Chantal; Midoux, Patrick

    2013-08-10

    DNA complexes made with cationic polymers (polyplexes) developed as nonviral vectors for gene therapy must be enabled to cross through vascular endothelium to transfect underlying tissues upon their administration in the blood circulation. Here, we evaluated the transendothelial passage (TEP) of DNA complexes made with histidinylated linear polyethylenimine (His-lPEI) or linear polyethylenimine (lPEI). In vitro studies were performed by using established transwell lung and skeletal muscle vascular endothelial barriers. The models were composed of a monolayer of human lung microvascular endothelial (HMVEC-L) cells and mouse cardiac endothelial (MCEC) cells formed on a PET insert and immortalized human tracheal epithelial (ΣCFTE29o-) cells and mouse myoblasts (C2C12) as target cells cultured in the lower chamber, respectively. When the vascular endothelium monolayer was established and characterized, the transfection efficiency of target (ΣCFTE29o- and C2C12) cells with plasmid DNA encoding luciferase was used to evaluate TEP of polyplexes. The luciferase activities with His-lPEI and lPEI polyplexes compared to those obtained in the absence of endothelial cell monolayer were 6.5% and 4.3% into ΣCFTE29o- cells, and 18.5% and 0.23% into C2C12 cells, respectively. The estimated rate for His-lPEI polyplexes was 0.135 μg/cm(2).h and 0.385 μg/cm(2).h through the HMVEC-L and MCEC monolayers, respectively. These results indicate that His-lPEI polyplexes can pass through the lung and skeletal muscle vascular endothelium and can transfect underlying cells. PMID:23562720

  3. Image filtering as an alternative to the application of a different reconstruction kernel in CT imaging: Feasibility study in lung cancer screening

    SciTech Connect

    Ohkubo, Masaki; Wada, Shinichi; Kayugawa, Akihiro; Matsumoto, Toru; Murao, Kohei

    2011-07-15

    Purpose: While the acquisition of projection data in a computed tomography (CT) scanner is generally carried out once, the projection data is often removed from the system, making further reconstruction with a different reconstruction filter impossible. The reconstruction kernel is one of the most important parameters. To have access to all the reconstructions, either prior reconstructions with multiple kernels must be performed or the projection data must be stored. Each of these requirements would increase the burden on data archiving. This study aimed to design an effective method to achieve similar image quality using an image filtering technique in the image space, instead of a reconstruction filter in the projection space for CT imaging. The authors evaluated the clinical feasibility of the proposed method in lung cancer screening. Methods: The proposed technique is essentially the same as common image filtering, which performs processing in the spatial-frequency domain with a filter function. However, the filter function was determined based on the quantitative analysis of the point spread functions (PSFs) measured in the system. The modulation transfer functions (MTFs) were derived from the PSFs, and the ratio of the MTFs was used as the filter function. Therefore, using an image reconstructed with a kernel, an image reconstructed with a different kernel was obtained by filtering, which used the ratio of the MTFs obtained for the two kernels. The performance of the method was evaluated by using routine clinical images obtained from CT screening for lung cancer in five subjects. Results: Filtered images for all combinations of three types of reconstruction kernels (''smooth,''''standard,'' and ''sharp'' kernels) showed good agreement with original reconstructed images regarded as the gold standard. On the filtered images, abnormal shadows suspected as being lung cancers were identical to those on the reconstructed images. The standard deviations (SDs) for

  4. Enhanced Pulmonary Vascular and Alveolar Development via Prenatal Administration of a Slow-Release Synthetic Prostacyclin Agonist in Rat Fetal Lung Hypoplasia

    PubMed Central

    Umeda, Satoshi; Miyagawa, Shigeru; Fukushima, Satsuki; Oda, Noriko; Saito, Atsuhiro; Sakai, Yoshiki; Sawa, Yoshiki; Okuyama, Hiroomi

    2016-01-01

    Lung hypoplasia and pulmonary hypertension are the major causes of mortality in neonates with congenital diaphragmatic hernia (CDH). Although the prostaglandin pathway plays a pivotal role in lung development, the reported efficacy of postnatal prostaglandin agonist treatment is suboptimal. We hypothesized that prenatal treatment with ONO-1301SR, a slow-release form of a novel synthetic prostacyclin agonist with thromboxane inhibitory activity, might enhance the development of lungs exhibiting hypoplasia in the fetal period. On embryonic day (E) 9.5, nitrofen was given to pregnant Sprague-Dawley rats to establish a CDH-related lung hypoplasia model, whereas normal rats received the vehicle only. The same day, either ONO-1301SR or a placebo was also randomly administered. On E21.5, the fetuses of the normal group and those exhibiting CDH were analyzed. Prenatal ONO-1301SR administration had no influence on the incidence of nitrofen-induced CDH. The lung-to-body weight ratio in the CDH+ONO group was greater than that in the CDH group. Histologically, the medial wall in the CDH+ONO group was two-thirds thinner than that in the CDH group. In addition, the number of Ttf-1-positive cells and the capillary density were ≥1.5 times greater in the CDH+ONO group than in the CDH group, and this increase was associated with higher expression of vascular endothelial growth factor and stromal cell-derived factor in the CDH+ONO group, suggesting enhanced development of the alveolar and capillary networks. Thus, prenatal ONO-1301SR was protective against the progression of lung hypoplasia associated with CDH in a nitrofen-induced rat model, indicating the potential of this treatment for pathologies exhibiting lung hypoplasia. PMID:27529478

  5. Enhanced Pulmonary Vascular and Alveolar Development via Prenatal Administration of a Slow-Release Synthetic Prostacyclin Agonist in Rat Fetal Lung Hypoplasia.

    PubMed

    Umeda, Satoshi; Miyagawa, Shigeru; Fukushima, Satsuki; Oda, Noriko; Saito, Atsuhiro; Sakai, Yoshiki; Sawa, Yoshiki; Okuyama, Hiroomi

    2016-01-01

    Lung hypoplasia and pulmonary hypertension are the major causes of mortality in neonates with congenital diaphragmatic hernia (CDH). Although the prostaglandin pathway plays a pivotal role in lung development, the reported efficacy of postnatal prostaglandin agonist treatment is suboptimal. We hypothesized that prenatal treatment with ONO-1301SR, a slow-release form of a novel synthetic prostacyclin agonist with thromboxane inhibitory activity, might enhance the development of lungs exhibiting hypoplasia in the fetal period. On embryonic day (E) 9.5, nitrofen was given to pregnant Sprague-Dawley rats to establish a CDH-related lung hypoplasia model, whereas normal rats received the vehicle only. The same day, either ONO-1301SR or a placebo was also randomly administered. On E21.5, the fetuses of the normal group and those exhibiting CDH were analyzed. Prenatal ONO-1301SR administration had no influence on the incidence of nitrofen-induced CDH. The lung-to-body weight ratio in the CDH+ONO group was greater than that in the CDH group. Histologically, the medial wall in the CDH+ONO group was two-thirds thinner than that in the CDH group. In addition, the number of Ttf-1-positive cells and the capillary density were ≥1.5 times greater in the CDH+ONO group than in the CDH group, and this increase was associated with higher expression of vascular endothelial growth factor and stromal cell-derived factor in the CDH+ONO group, suggesting enhanced development of the alveolar and capillary networks. Thus, prenatal ONO-1301SR was protective against the progression of lung hypoplasia associated with CDH in a nitrofen-induced rat model, indicating the potential of this treatment for pathologies exhibiting lung hypoplasia. PMID:27529478

  6. A protocol for phenotypic detection and characterization of vascular cells of different origins in a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Cohen, Kenneth S; Munn, Lance L; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    The goal of many current studies of neovascularization is to define the phenotype of vascular cell populations of different origins and to determine how such cells promote assembly of vascular channel. Here, we describe a protocol to immunophenotype vascular cells by high-resolution imaging and by fluorescence-activated flow cytometry in an in vivo rodent model of pulmonary microvascular remodeling. Analysis of cells by this combined approach will characterize their phenotype, quantify their number and identify their role in the assembly of vascular channels. PMID:18323810

  7. Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury.

    PubMed

    Gao, Xiao-Pei; Liu, Qinghui; Broman, Michael; Predescu, Dan; Frey, Randall S; Malik, Asrar B

    2005-04-14

    To inactivate chronically the beta2-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF(+/+) PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF(+/+) PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF(+/+) and Mac-1-deficient (Mac-1(-/-)) mice. Adhesion of both Mac-1(-/-) and NIF(+/+) PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF(+/+) PMNs but the blockade of CD11b function. CD11b inactivation in NIF(+/+) mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF(+/+) mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation. PMID:15831844

  8. CCL21/CCR7 up-regulate vascular endothelial growth factor-D expression via ERK pathway in human non-small cell lung cancer cells

    PubMed Central

    Sun, Limei; Zhang, Qingfu; Li, Yang; Tang, Na; Qiu, Xueshan

    2015-01-01

    Lymphangiogenesis has received considerable attention and become a new research hotspot of tumor metastasis. Recently, C-C chemokine receptor 7 (CCR7) is known to promote metastasis of non-small cell lung cancer (NSCLC) cells into lymph nodes. In this study, we investigated the relationship between CCL21/CCR7 and the lymphangiogenic factor vascular endothelial growth factor (VEGF)-D in human lung cancer cells and its impact on patients’ prognosis. We found that CCL21/CCR7 increase the expression of VEGF-D in NSCLC Cell Lines through induced ERK1/2 and Akt phosphorylation. In addition, our study found that the expression levels of CCR7 and CCL21 were correlated with VEGF-D, lymphatic vessels density (LVD), clinical stages, lymph node metastasis, and patient Survival in 90 human non-small cell lung cancer (NSCLC) specimens. Taken together, our results provide evidence that CCL21/CCR7 induce VEGF-D up-regulation and promote lymphangiogenesis via ERK/Akt pathway in lung cancer. PMID:26884842

  9. Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts.

    PubMed

    Bonanno, Anna; Albano, Giusy Daniela; Siena, Liboria; Montalbano, Angela Marina; Riccobono, Loredana; Anzalone, Giulia; Chiappara, Giuseppina; Gagliardo, Rosalia; Profita, Mirella; Sala, Angelo

    2016-03-01

    We studied the role of PGE2, its biosynthetic enzymes and its receptors, in regulating the functions of lung fibroblasts through the production of Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) in COPD subjects. Lung fibroblasts from Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE2, VEGF, and IL-8 measured in supernatants by ELISA. COX-1/COX-2 and EP receptors expression were assessed by western blot and by RT-PCR. Release of VEGF and IL-8 by human fetal lung fibroblasts (HFL-1; lung, diploid, human) was evaluated under different conditions. PGE2, VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. Low concentrations of synthetic PGE2 increased the release of VEGF in HFL-1, but higher concentrations were needed to induce the release of IL-8. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist. In the airways of COPD subjects, fibroblast-derived PGE2 may regulate angiogenesis and inflammation through the production of VEGF and IL-8 respectively, suggesting that the increase in expression of COX-2, EP2 and EP4 observed in COPD fibroblasts may contribute to steering the role of PGE2 from homeostatic to pro-inflammatory. PMID:26926362

  10. Hemoglobin induced lung vascular oxidation, inflammation, and remodeling contributes to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeat dose haptoglobin administration

    PubMed Central

    Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva

    2015-01-01

    Objective Haptoglobin (Hp) is an approved treatment in Japan with indications for trauma, burns and massive transfusion related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia mediated PH. Approach and results Rats were simultaneously exposed to chronic Hb-infusion (35 mg per day) and hypobaric hypoxia for five weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated non-heme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right ventricular hypertrophy, which suggest a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. Conclusions By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia; and (2) suggest a novel therapy for chronic hemolysis associated PH. PMID:25656991

  11. Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration.

    PubMed

    Irwin, David C; Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva; Buehler, Paul W

    2015-05-01

    Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH. PMID:25656991

  12. Lung tumorigenesis induced by human vascular endothelial growth factor (hVEGF)-A165 overexpression in transgenic mice and amelioration of tumor formation by miR-16

    PubMed Central

    Chou, Yu-Ching; Lai, Cheng-Wei; Wang, Hsiu-Po; Ho, Heng-Chien; Yen, Chih-Ching; Tu, Chih-Yen; Tsai, Tung-Chou; Yeh, Dah-Cherng; Wang, Jiun-Long; Chong, Kowit-Yu; Chen, Chuan-Mu

    2015-01-01

    Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A165 (hVEGF-A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes (hvegf-A165, cyclin b1, cdc2, egfr, mmp9, nrp-1, and kdr) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A165 in Clara cells increases CD105, fibrogenic genes (collagen α1, α-SMA, TGF-β1, and TIMP1), and inflammatory cytokines (IL-1, IL-6, and TNF-α) in the lungs of hVEGF-A165-overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma. PMID:25912305

  13. Expression of Tumor-Derived Vascular Endothelial Growth Factor and Its Receptors Is Associated With Outcome in Early Squamous Cell Carcinoma of the Lung

    PubMed Central

    Pajares, María J.; Agorreta, Jackeline; Larrayoz, Marta; Vesin, Aurélien; Ezponda, Teresa; Zudaire, Isabel; Torre, Wenceslao; Lozano, María D.; Brambilla, Elisabeth; Brambilla, Christian; Wistuba, Ignacio I.; Behrens, Carmen; Timsit, Jean-Francois; Pio, Ruben; Field, John K.; Montuenga, Luis M.

    2012-01-01

    Purpose Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non–small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Patients and Methods We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC. Results The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC. Conclusion Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC. PMID:22355056

  14. Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

    PubMed Central

    Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

    2011-01-01

    Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

  15. Metabolic Expenditures of Lunge Feeding Rorquals Across Scale: Implications for the Evolution of Filter Feeding and the Limits to Maximum Body Size

    PubMed Central

    Potvin, Jean; Goldbogen, Jeremy A.; Shadwick, Robert E.

    2012-01-01

    Bulk-filter feeding is an energetically efficient strategy for resource acquisition and assimilation, and facilitates the maintenance of extreme body size as exemplified by baleen whales (Mysticeti) and multiple lineages of bony and cartilaginous fishes. Among mysticetes, rorqual whales (Balaenopteridae) exhibit an intermittent ram filter feeding mode, lunge feeding, which requires the abandonment of body-streamlining in favor of a high-drag, mouth-open configuration aimed at engulfing a very large amount of prey-laden water. Particularly while lunge feeding on krill (the most widespread prey preference among rorquals), the effort required during engulfment involve short bouts of high-intensity muscle activity that demand high metabolic output. We used computational modeling together with morphological and kinematic data on humpback (Megaptera noveaangliae), fin (Balaenoptera physalus), blue (Balaenoptera musculus) and minke (Balaenoptera acutorostrata) whales to estimate engulfment power output in comparison with standard metrics of metabolic rate. The simulations reveal that engulfment metabolism increases across the full body size of the larger rorqual species to nearly 50 times the basal metabolic rate of terrestrial mammals of the same body mass. Moreover, they suggest that the metabolism of the largest body sizes runs with significant oxygen deficits during mouth opening, namely, 20% over maximum at the size of the largest blue whales, thus requiring significant contributions from anaerobic catabolism during a lunge and significant recovery after a lunge. Our analyses show that engulfment metabolism is also significantly lower for smaller adults, typically one-tenth to one-half . These results not only point to a physiological limit on maximum body size in this lineage, but also have major implications for the ontogeny of extant rorquals as well as the evolutionary pathways used by ancestral toothed whales to transition from hunting individual prey items to

  16. Metabolic expenditures of lunge feeding rorquals across scale: implications for the evolution of filter feeding and the limits to maximum body size.

    PubMed

    Potvin, Jean; Goldbogen, Jeremy A; Shadwick, Robert E

    2012-01-01

    Bulk-filter feeding is an energetically efficient strategy for resource acquisition and assimilation, and facilitates the maintenance of extreme body size as exemplified by baleen whales (Mysticeti) and multiple lineages of bony and cartilaginous fishes. Among mysticetes, rorqual whales (Balaenopteridae) exhibit an intermittent ram filter feeding mode, lunge feeding, which requires the abandonment of body-streamlining in favor of a high-drag, mouth-open configuration aimed at engulfing a very large amount of prey-laden water. Particularly while lunge feeding on krill (the most widespread prey preference among rorquals), the effort required during engulfment involve short bouts of high-intensity muscle activity that demand high metabolic output. We used computational modeling together with morphological and kinematic data on humpback (Megaptera noveaangliae), fin (Balaenoptera physalus), blue (Balaenoptera musculus) and minke (Balaenoptera acutorostrata) whales to estimate engulfment power output in comparison with standard metrics of metabolic rate. The simulations reveal that engulfment metabolism increases across the full body size of the larger rorqual species to nearly 50 times the basal metabolic rate of terrestrial mammals of the same body mass. Moreover, they suggest that the metabolism of the largest body sizes runs with significant oxygen deficits during mouth opening, namely, 20% over maximum VO2 at the size of the largest blue whales, thus requiring significant contributions from anaerobic catabolism during a lunge and significant recovery after a lunge. Our analyses show that engulfment metabolism is also significantly lower for smaller adults, typically one-tenth to one-half VO2|max. These results not only point to a physiological limit on maximum body size in this lineage, but also have major implications for the ontogeny of extant rorquals as well as the evolutionary pathways used by ancestral toothed whales to transition from hunting individual prey

  17. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts.

    PubMed

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with (111)In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of (111)In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of (111)In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of (111)In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, (111)In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of (111)In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  18. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    PubMed Central

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with 111In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of 111In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of 111In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of 111In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, 111In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of 111In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  19. Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

    PubMed Central

    Fontanini, G.; Vignati, S.; Lucchi, M.; Mussi, A.; Calcinai, A.; Boldrini, L.; Chiné, S.; Silvestri, V.; Angeletti, C. A.; Basolo, F.; Bevilacqua, G.

    1997-01-01

    Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation. Images Figure 1 Figure 3 Figure 8 PMID:9155049

  20. ROI for outlining an entire tumor is a reliable approach for quantification of lung cancer tumor vascular parameters using CT perfusion

    PubMed Central

    Ma, Ensen; Ren, An; Gao, Baoxiang; Yang, Minxing; Zhao, Qichao; Wang, Wu; Li, Kefeng

    2016-01-01

    Objective To investigate the effect of position and size of tumor region of interest (ROI) on the estimation of lung cancer vascular parameters using 256-slice computed tomography (CT) perfusion. Methods After institutional review board approval and written informed consent, 16 men and 11 women with lung cancer were enrolled in this CT perfusion study. Perfusion, blood volume, and peak enhancement were determined for 60 or 120 mm2 circular ROIs placed at the edge, center, and around (outlining) the visible tumor. Average values were obtained by performing ROI analysis twice by the same observers without any procedural changes. Results Perfusion, blood volume, and peak enhancement measurements were substantially higher at the edge than at the center for both 60 and 120 mm2 ROIs (all P<0.05). Measurements varied substantially depending on the ROI size. Perfusion, blood volume, and peak enhancement for the ROIs outlining tumor were intermediate between those at the tumor edge and center. There were significant correlations between median values and interquartile ranges as follows; perfusion (12.51 [7.91–28.10] mL⋅min−1⋅100 mL−1), blood volume (29.31 [21.82–37.65] mL⋅100 g−1), peak enhancement (12.93 [2.42–22.50]) for the ROIs outlining the tumor, and microvascular density ([19.43±8.78] vessels/0.74 mm2), respectively (r values were 0.732, 0.590, and 0.544 respectively, all P<0.05). Conclusion Spatial and size selection of ROI significantly affects CT perfusion analysis. ROI outlining of entire tumor provides efficient and reliable measurements for clinical assessment of lung cancer using CT perfusion. PMID:27175083

  1. The vascular surgeon-scientist: a 15-year report of the Society for Vascular Surgery Foundation/National Heart, Lung, and Blood Institute-mentored Career Development Award Program.

    PubMed

    Kibbe, Melina R; Dardik, Alan; Velazquez, Omaida C; Conte, Michael S

    2015-04-01

    The Society for Vascular Surgery (SVS) Foundation partnered with the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) in 1999 to initiate a competitive career development program that provides a financial supplement to surgeon-scientists receiving NIH K08 or K23 career development awards. Because the program has been in existence for 15 years, a review of the program's success has been performed. Between 1999 and 2013, 41 faculty members applied to the SVS Foundation program, and 29 from 21 different institutions were selected as awardees, resulting in a 71% success rate. Three women (10%) were among the 29 awardees. Nine awardees (31%) were supported by prior NIH F32 or T32 training grants. Awardees received their K award at an average of 3.5 years from the start of their faculty position, at the average age of 39.8 years. Thirteen awardees (45%) have subsequently received NIH R01 awards and five (17%) have received Veterans Affairs Merit Awards. Awardees received their first R01 at an average of 5.8 years after the start of their K award at the average age of 45.2 years. The SVS Foundation committed $9,350,000 to the Career Development Award Program. Awardees subsequently secured $45,108,174 in NIH and Veterans Affairs funds, resulting in a 4.8-fold financial return on investment for the SVS Foundation program. Overall, 23 awardees (79%) were promoted from assistant to associate professor in an average of 5.9 years, and 10 (34%) were promoted from associate professor to professor in an average of 5.2 years. Six awardees (21%) hold endowed professorships and four (14%) have secured tenure. Many of the awardees hold positions of leadership, including 12 (41%) as division chief and two (7%) as vice chair within a department of surgery. Eight (28%) awardees have served as president of a regional or national society. Lastly, 47 postdoctoral trainees have been mentored by recipients of the SVS Foundation Career Development

  2. Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case–control study

    PubMed Central

    Schenck, Edward J; Echevarria, Ghislaine C; Girvin, Francis G; Kwon, Sophia; Comfort, Ashley L; Rom, William N; Prezant, David J; Weiden, Michael D; Nolan, Anna

    2014-01-01

    Objectives We hypothesise that there is an association between an elevated pulmonary artery/aorta (PA/A) and World Trade Center-Lung Injury (WTC-LI). We assessed if serum vascular disease biomarkers were predictive of an elevated PA/A. Design Retrospective case-cohort analysis of thoracic CT scans of WTC-exposed firefighters who were symptomatic between 9/12/2001 and 3/10/2008. Quantification of vascular-associated biomarkers from serum collected within 200 days of exposure. Setting Urban tertiary care centre and occupational healthcare centre. Participants Male never-smoking firefighters with accurate pre-9/11 forced expiratory volume in 1 s (FEV1) ≥75%, serum sampled ≤200 days of exposure was the baseline cohort (n=801). A subcohort (n=97) with available CT scans and serum biomarkers was identified. WTC-LI was defined as FEV1≤77% at the subspecialty pulmonary evaluation (n=34) and compared with controls (n=63) to determine the associated PA/A ratio. The subcohort was restratified based on PA/A≥0.92 (n=38) and PA/A<0.92(n=59) to determine serum vascular biomarkers that were predictive of this vasculopathy. Outcome measures The primary outcome of this study was to identify a PA/A ratio in a cohort of individuals exposed to WTC dust that was associated with WTC-LI. The secondary outcome was to identify serum biomarkers predictive of the PA/A ratio using logistic regression. Results PA/A≥0.92 was associated with WTC-LI, OR of 4.02 (95% CI 1.21 to 13.41; p=0.023) when adjusted for exposure, body mass index and age at CT. Elevated macrophage derived chemokine and soluble endothelial selectin were predictive of PA/A≥0.92, (OR, 95% CI 2.08, 1.05 to 4.11, p=0.036; 1.33, 1.06 to 1.68, p=0.016, respectively), while the increased total plasminogen activator inhibitor 1 was predictive of not having PA/A≥0.92 (OR 0.88, 0.79 to 0.98; p=0.024). Conclusions Elevated PA/A was associated with WTC-LI. Development of an elevated PA/A was predicted by biomarkers of

  3. H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity

    PubMed Central

    Manley, Eugene; Waxman, David J.

    2014-01-01

    Cancer stem-like cells were isolated from several human tumor cell lines by limiting dilution assays and holoclone morphology, followed by assessment of self-renewal capacity, tumor growth, vascularity, and blood perfusion. H460 holoclone-derived tumors grew slower than parental H460 tumors, but displayed significantly increased microvessel density and tumor blood perfusion. Microarray analysis identified 177 differentially regulated genes in the holoclone-derived tumors, of which 47 were associated with angiogenesis. The dysregulated genes include several small leucine-rich proteoglycans that may modulate angiogenesis and serve as novel therapeutic targets for inhibiting cancer stem cell-driven angiogenesis. PMID:24334139

  4. Reduction in (pro-)inflammatory responses of lung cells exposed in vitro to diesel exhaust treated with a non-catalyzed diesel particle filter

    NASA Astrophysics Data System (ADS)

    Steiner, Sandro; Czerwinski, Jan; Comte, Pierre; Müller, Loretta L.; Heeb, Norbert V.; Mayer, Andreas; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2013-12-01

    Increasingly stringent regulation of particulate matter emissions from diesel vehicles has led to the widespread use of diesel particle filters (DPFs), the effect of which on exhaust toxicity is so far poorly understood. We exposed a cellular model of the human respiratory epithelium at the air-liquid interface to non-catalyzed wall-flow DPF-filtered diesel exhaust and compared the resulting biological responses to the ones observed upon exposure to unfiltered exhaust. Filtered diesel exhaust acted highly oxidative, even though to a lesser extent than unfiltered exhaust (quantification of total reduced glutathione), and both exhaust types triggered comparable responses to oxidative stress (measurement of heme-oxygenase 1 (HMOX1) and superoxide-dismutase (SOD1) gene expression). Further, diesel exhaust filtration significantly reduced pro-inflammatory responses (measurement of tumor necrosis factor (TNF) and interleukin-8 (IL-8) gene expression and quantification of the secretion of their gene products TNF-α and IL-8). Because inflammatory processes are central to the onset of adverse respiratory health effects caused by diesel exhaust inhalation, our results imply that DPFs may make a valuable contribution to the detoxification of diesel vehicle emissions. The induction of significant oxidative stress by filtered diesel exhaust however, also implies that the non-particulate exhaust components also need to be considered for lung cell risk assessment.

  5. Clinical Utility of Echocardiography for the Diagnosis and Management of Pulmonary Vascular Disease in Young Children With Chronic Lung Disease

    PubMed Central

    Mourani, Peter M.; Sontag, Marci K.; Younoszai, Adel; Ivy, D. Dunbar; Abman, Steven H.

    2011-01-01

    Objective The goal was to determine the clinical utility of Doppler echocardiography in predicting the presence and severity of pulmonary hypertension in patients with chronic lung disease who subsequently underwent cardiac catheterization. Methods A retrospective review of data for all patients <2 years of age with a diagnosis of bronchopulmonary dysplasia, congenital diaphragmatic hernia, or lung hypoplasia who underwent echocardiography and subsequently underwent cardiac catheterization for evaluation of pulmonary hypertension was performed. The accuracy of echocardiography in diagnosing pulmonary hypertension, on the basis of estimated systolic pulmonary artery pressure, was compared with the detection of pulmonary hypertension with the standard method of cardiac catheterization. Results Thirty-one linked measurements for 25 children were analyzed. Systolic pulmonary artery pressure could be estimated in 61% of studies, but there was poor correlation between echocardiography and cardiac catheterization measures of systolic pulmonary artery pressure in these infants. Compared with cardiac catheterization measurements, echocardiographic estimates of systolic pulmonary artery pressure diagnosed correctly the presence or absence of pulmonary hypertension in 79% of the studies in which systolic pulmonary artery pressure was estimated but determined the severity of pulmonary hypertension (severe pulmonary hypertension was defined as pulmonary/systemic pressure ratio of ≥0.67) correctly in only 47% of those studies. Seven (58%) of 12 children without estimated systolic pulmonary artery pressure demonstrated pulmonary hypertension during subsequent cardiac catheterization. In the absence of estimated systolic pulmonary artery pressure, qualitative echocardiographic findings, either alone or in combination, had worse predictive value for the diagnosis of pulmonary hypertension. Conclusion As used in clinical practice, echocardiography often identifies pulmonary

  6. The Role of Anion Exchanger on Pulmonary Vascular Response to Sustained Alveolar Hypoxia in the Isolated Perfused Rabbit Lung

    PubMed Central

    Ketabchi, Farzaneh; Mansoori, Somayeh; Moosavi, Seyed Mostafa Shid

    2015-01-01

    Background Some respiratory diseases may induce alveolar hypoxia thereby hypoxic pulmonary vasoconstriction (HPV). However, the mechanisms of this physiologic phenomenon are not fully understood. This study was the first to investigate the role of anion exchanger in sustained HPV. Methods Experiments were performed in the isolated perfused rabbit lung. After preparation, the lungs were divided into six groups: two DIDS (4,4-diisothiocyanostilbene 2,2-disulfonic acid, anion exchanger inhibitor)-treated [200 µM (n=5) or 400 µM (n=3)] hypoxic groups, two HCO3- free hypoxic groups, one control hypoxic group (n=7) and one control normoxic group (n=4). DIDS were added to the perfusate at 10 minutes before starting the experiments. In the HCO3- free groups, HEPES (4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid) were added to the perfusate instead of bicarbonate. Furthermore, in the HEPES1 (n=4) and HEPES2 (n=4) groups, the lungs were ventilated with hypoxic gas with or without CO2, respectively. Results Ventilation of the lungs with hypoxic gas resulted in biphasic HPV, the acute (0-20 minutes) and sustained (20-60 minutes) phases. No alteration in both phases of HPV was detected by DIDS (200 µM). However, DIDS (400 µM), extended the ascending part of acute HPV until min 24. Both phases of HPV were decreased in the HEPES1 group. However, in the HEPES 2 group, HPV tended to increase during the rising part of the acute phase of HPV. Conclusions Since DIDS (400 µM) extended acute phase of HPV, and HCO3- free perfusate buffer enhanced rising phase of it, therefore it can be suggested that anion exchanger may modulate HPV especially during the acute phase. The abstract of this article was presented as a poster in the congress of European Respiratory Society (ERS) on Monday, 08 September 2014, Munich, Germany and was published in the ERJ September 1, 2014 vol. 44 no. Suppl 58 P2343. PMID:25999626

  7. A combination of spatial and recursive temporal filtering for noise reduction when using region of interest (ROI) fluoroscopy for patient dose reduction in image guided vascular interventions with significant anatomical motion

    NASA Astrophysics Data System (ADS)

    Setlur Nagesh, S. V.; Khobragade, P.; Ionita, C.; Bednarek, D. R.; Rudin, S.

    2015-03-01

    Because x-ray based image-guided vascular interventions are minimally invasive they are currently the most preferred method of treating disorders such as stroke, arterial stenosis, and aneurysms; however, the x-ray exposure to the patient during long image-guided interventional procedures could cause harmful effects such as cancer in the long run and even tissue damage in the short term. ROI fluoroscopy reduces patient dose by differentially attenuating the incident x-rays outside the region-of-interest. To reduce the noise in the dose-reduced regions previously recursive temporal filtering was successfully demonstrated for neurovascular interventions. However, in cardiac interventions, anatomical motion is significant and excessive recursive filtering could cause blur. In this work the effects of three noise-reduction schemes, including recursive temporal filtering, spatial mean filtering, and a combination of spatial and recursive temporal filtering, were investigated in a simulated ROI dose-reduced cardiac intervention. First a model to simulate the aortic arch and its movement was built. A coronary stent was used to simulate a bioprosthetic valve used in TAVR procedures and was deployed under dose-reduced ROI fluoroscopy during the simulated heart motion. The images were then retrospectively processed for noise reduction in the periphery, using recursive temporal filtering, spatial filtering and a combination of both. Quantitative metrics for all three noise reduction schemes are calculated and are presented as results. From these it can be concluded that with significant anatomical motion, a combination of spatial and recursive temporal filtering scheme is best suited for reducing the excess quantum noise in the periphery. This new noise-reduction technique in combination with ROI fluoroscopy has the potential for substantial patient-dose savings in cardiac interventions.

  8. A Combination of Spatial and Recursive Temporal Filtering for Noise Reduction when Using Region of Interest (ROI) Fluoroscopy for Patient Dose Reduction in Image Guided Vascular Interventions with Significant Anatomical Motion

    PubMed Central

    Nagesh, S.V. Setlur; Khobragade, P.; Ionita, C.; Bednarek, D.R; Rudin, S.

    2015-01-01

    Because x-ray based image-guided vascular interventions are minimally invasive they are currently the most preferred method of treating disorders such as stroke, arterial stenosis, and aneurysms; however, the x-ray exposure to the patient during long image-guided interventional procedures could cause harmful effects such as cancer in the long run and even tissue damage in the short term. ROI fluoroscopy reduces patient dose by differentially attenuating the incident x-rays outside the region-of-interest. To reduce the noise in the dose-reduced regions previously recursive temporal filtering was successfully demonstrated for neurovascular interventions. However, in cardiac interventions, anatomical motion is significant and excessive recursive filtering could cause blur. In this work the effects of three noise-reduction schemes, including recursive temporal filtering, spatial mean filtering, and a combination of spatial and recursive temporal filtering, were investigated in a simulated ROI dose-reduced cardiac intervention. First a model to simulate the aortic arch and its movement was built. A coronary stent was used to simulate a bio-prosthetic valve used in TAVR procedures and was deployed under dose-reduced ROI fluoroscopy during the simulated heart motion. The images were then retrospectively processed for noise reduction in the periphery, using recursive temporal filtering, spatial filtering and a combination of both. Quantitative metrics for all three noise reduction schemes are calculated and are presented as results. From these it can be concluded that with significant anatomical motion, a combination of spatial and recursive temporal filtering scheme is best suited for reducing the excess quantum noise in the periphery. This new noise-reduction technique in combination with ROI fluoroscopy has the potential for substantial patient-dose savings in cardiac interventions. PMID:26900203

  9. Role of type II pneumocytes in pathogenesis of radiation pneumonitis: dose response of radiation-induced lung changes in the transient high vascular permeability period.

    PubMed

    Osterreicher, Jan; Pejchal, Jaroslav; Skopek, Jirí; Mokrỳ, Jaroslav; Vilasová, Zdena; Psutka, Jan; Vávrová, Jirina; Mazurová, Yvona

    2004-12-01

    We studied the dose response of pulmonary changes at 3 weeks after 1-25 Gy irradiation and we investigated the effects of an anti-inflammatory drug. Wistar rats were given a single dose of 1-25Gy irradiation to the thorax. Group one was treated with saline only, while group two was administered subcutaneously a combination of pentoxifylline (35 mg/kg) and dexamethasone (1 mg/kg) twice per week. Lungs were examined histochemically and number of neutrophile granulocytes, alveolar septal thickness, air/tissue ratio, number of alveoli per field, number of type II pneumocytes per alveolus, and occludin 1 expression were measured. A significant dose-dependent depletion of type II pneumocytes was found after irradiation with a dose of 1 Gy and higher. Alveolar neutrophils increased after 1 Gy with a dose dependency noted after 10-25Gy and alveolar septa thickening followed 5-25 Gy. A lower occludin 1 expression was observed in animals irradiated with the doses of 5 20 Gy, indicating an effect on vascular permeability. Anti-inflammatory therapy partially inhibited the increase of neutrophils at all radiation doses and the depletion of type II pneumocytes after doses of 1, 10, and 15 Gy. Occludin 1 did not decrease in the lungs of rats treated with the anti-inflammatory drugs as it did in most rats treated only with saline. Our results suggest that pneumocytes depletion is a major factor responsible for radiation pneumonitis development and that these changes may be compensated for provided radiation doses are below the threshold. PMID:15625787

  10. Control of HIF-1{alpha} and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock.

    PubMed

    Scott, C L; Walker, D J; Cwiklinski, E; Tait, C; Tee, A R; Land, S C

    2010-10-01

    Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH(2)-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po(2) (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1α by mTORC1 was abolished on expression of a HIF-1α (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po(2), FGF-10 induced mTORC1 and amplified HIF-1α activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator. PMID:20622121

  11. Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production.

    PubMed

    Chen, Jie; Liu, Bing; Yuan, Jiayi; Yang, Jie; Zhang, Jingjie; An, Yu; Tie, Lu; Pan, Yan; Li, Xuejun

    2012-02-01

    The high metastatic potential of non-small cell lung cancers (NSCLCs) is closely correlated with the elevated expression of vascular endothelial growth factor (VEGF) and resultant tumor angiogenesis. However, no effective strategies against VEGF expression have been available in NSCLCs therapy. This study demonstrated that elevated reactive oxygen species (ROS) levels derived from both mitochondria and NADPH oxidase were required for VEGF expression in NSCLC cells. Atorvastatin administration could significantly inhibit VEGF expression both in vitro and in vivo via inhibition of ROS production. Atorvastatin inhibited ROS generation partly through suppression of Rac1/NADPH oxidase activity. Specifically, atorvastatin could upregulate the activity of glutathione peroxidase (GPx) and catalase, which are responsible for elimination of hydrogen peroxide (H(2)O(2)) in the mitochondria and peroxisomes, respectively. Thus, inhibition of ROS production by concomitant suppression of Rac1/NADPH oxidase activity and upregulation of the activity of GPx and catalase contributes critically to atorvastatin-reduced VEGF expression in NSCLCs. Atorvastatin may be a potential alternative against VEGF expression and angiogenesis in NSCLCs therapy. PMID:22153388

  12. Decreased maspin combined with elevated vascular endothelial growth factor C is associated with poor prognosis in non-small cell lung cancer

    PubMed Central

    Wang, Xing; Wang, Yang; Li, Shaolei; Dong, Bin; Zheng, Qingfeng; Yan, Shi; Ma, Yuanyuan; Zhang, Jianzhi; Fang, Jian; Wu, Nan; Wu, Huijuan; Yang, Yue

    2014-01-01

    Background This study aimed to investigate the clinical significance of the combination of maspin and vascular endothelial growth factor (VEGF)-C expression in the prognosis of non-small cell lung cancer (NSCLC). Methods Immunohistochemistry was performed to assay the expression of maspin and VEGF-C in primary tumor tissues, metastatic, and non-metastatic lymph nodes in 98 NSCLC patients. Survival analysis was determined by Kaplan-Meier curves. Results The positive expression rate of maspin was 26.5% (26/98) in NSCLC primary tumor tissues, significantly associated with histological type (P = 0.005) and the absence of nodal metastasis (P < 0.001). The expression of maspin in primary tumor tissues was stronger than metastatic lymph nodes of the N1 group (P = 0.048), while the metastatic lymph nodes of the N1 group had a stronger maspin expression than the N2 group (P = 0.008). In survival analysis, a positive expression of maspin of the N1 lymph node was also found to be an independent positive prognostic factor in overall survival (P = 0.003). We also found that decreased maspin combined with elevated VEGF-C is associated with a poor prognosis for disease-free survival (P = 0.019). Conclusion Our results suggest that positive expression of maspin might significantly inhibit nodal metastasis in NSCLC. Decreased maspin combined with elevated VEGF-C might be associated with a poor prognosis in NSCLC. PMID:26767029

  13. Lung Cancer Lymph Node Micrometastasis Detection Using RT-PCR – Correlation with Vascular Endothelial Growth Factor (VEGF) expression

    PubMed Central

    Nwogu, Chukwumere E.; Yendamuri, Sai; Tan, Wei; Kannisto, Eric; Bogner, Paul; Morrison, Carl; Cheney, Richard; Dexter, Elisabeth; Picone, Anthony; Hennon, Mark; Hutson, Alan; Reid, Mary; Adjei, Alex; Demmy, Todd L.

    2013-01-01

    Objectives Lymph node (LN) staging provides critical information in non-small cell lung cancer (NSCLC) patients. Lymphangiogenesis may be an important contributor to the pathophysiology of lymphatic metastases. We hypothesized that the presence of lymph node micrometastases positively correlates with VEGF-A/C/D and VEGF-receptor-3 (lymphangiogenic factors) expression in lymph nodes. Methods Forty NSCLC patients had pre-operative PET-CT and mediastinoscopy. RT-PCR assays for mRNA expression of epithelial markers (CK-7, CEACAM-5 and PLUNC) were performed in selected fluorodeoxyglucose (FDG)-avid lymph nodes. VEGF-A/C/D and VEGF-receptor-3 expression levels were measured in primary tumors and lymph nodes. Wilcoxon rank sum test was run for the association between the RT-PCR epithelial marker levels and VEGF expression levels in the LNs. Results RT-PCR for CK-7, CEACAM5 or PLUNC indicated lymph node micrometastatic disease in 19 of 35 patients (54%). There was a high correlation between detection of micrometastases and VEGF-A/C/D or VEGF-receptor-3 expression levels in lymph nodes. Median follow-up was 12.6 months. Conclusions RT-PCR analysis of FDG-avid lymph nodes results in up-staging of patients. Micrometastases correlate with the expression of VEGF in lymph nodes in NSCLC patients. This may reflect the role of lymphangiogenesis in promoting metastases. PMID:23414988

  14. Comparison of Two RapidArc Delivery Strategies in Stereotactic Body Radiotherapy of Peripheral Lung Cancer with Flattening Filter Free Beams

    PubMed Central

    Lin, Pei-Xian; Chen, Jian-Zhou; Kuang, Yu; Chen, Chuang-Zhen

    2015-01-01

    Purpose To investigate the performance of using partial arc (PA) and full arc with avoidance sectors (FAAS) in stereotactic body radiotherapy (SBRT) of peripheral lung cancer with flattening filter free (FFF) beams. Methods Eighteen patients with primary (T1 or T2) non-small-cell lung cancer (NSCLC) or lung metastatic were selected for this study. Nine patients with a gross tumor volume (GTV) <= 10 cc were designated as the small tumor group. The other nine patients with a GTV between 10 cc and 44 cc were assigned to the large tumor group. The treatment plans were generated in eighteen patients using PA and FAAS techniques, respectively, and delivered with a Varian TrueBeam Linac. Dosimetry of the target and organs at risk (OARs), monitor unit (MU), out-of-field dose, and delivery time were statistically analyzed. Delta4 and portal dosimetry were employed to evaluate the delivery accuracy. Results For the small tumor group, compared with the PA plans, the FAAS plans significantly achieved a lower MU/fraction, out-of-field dose and a shorter treatment time (p<0.05), but the target dose was slightly higher than that delivered by PA plans (p<0.05). For the large tumor group, the PA plans significantly attained a shorter treatment time (p<0.05), whereas MU/fraction, out-of-field dose and dose to OARs were comparable between the two plans (p>0.05). Furthermore, all plans generated from the eighteen patients achieved a high pass rate in patient-specific quality assurance, with all the gamma indices greater than 97% at the Γ3mm, 3% threshold. Conclusion This study suggests that the FAAS technique is more beneficial for the small tumor patients undergoing lung SBRT with FFF beams because of its higher treatment efficiency and MU reduction. However, for the large tumor patients, the PA technique is recommended due to its higher treatment efficiency. PMID:26131554

  15. Vascular Lesions.

    PubMed

    Jahnke, Marla N

    2016-08-01

    Vascular lesions in childhood are comprised of vascular tumors and vascular malformations. Vascular tumors encompass neoplasms of the vascular system, of which infantile hemangiomas (IHs) are the most common. Vascular malformations, on the other hand, consist of lesions due to anomalous development of the vascular system, including the capillary, venous, arterial, and lymphatic systems. Capillary malformations represent the most frequent type of vascular malformation. IHs and vascular malformations tend to follow relatively predictable growth patterns in that IHs grow then involute during early childhood, whereas vascular malformations tend to exhibit little change. Both vascular tumors and vascular malformations can demonstrate a wide range of severity and potential associated complications necessitating specialist intervention when appropriate. Evaluation and treatment of the most common types of vascular lesions are discussed in this article. [Pediatr Ann. 2016;45(8):e299-e305.]. PMID:27517358

  16. Tumour necrosis factor-alpha-induced ICAM-1 expression in human vascular endothelial and lung epithelial cells: modulation by tyrosine kinase inhibitors.

    PubMed Central

    Burke-Gaffney, A.; Hellewell, P. G.

    1996-01-01

    1. Tumour necrosis factor-alpha (TNF alpha) increases the expression of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1) on cultured endothelial and epithelial cells and modulation of this may be important in controlling inflammation. Activation of tyrosine kinase(s) is known to be involved in the signal transduction pathways of many cytokines. In this study we have investigated the effects of the tyrosine kinase inhibitors, ST638, tyrphostin AG 1288 and genistein, on TNF alpha-induced ICAM-1 expression in human alveolar epithelial (A549) and vascular endothelial (EAhy926) cell lines and also normal human lung microvascular endothelial cells (HLMVEC). 2. ICAM-1 expression on cultured cells was determined by a sensitive enzyme-linked immunosorbant assay (ELISA). Endothelial or epithelial monolayers were exposed to increasing doses of TNF-alpha (0.01-10 ng ml-1), in the presence or absence of either ST638 (3-100 microM), AG 1288 (3-100 microM) or genistein (100 microM) and ICAM-1 expression was measured at 4 and 24 h. Control experiments examined the effect of ST638 on phorbol 12-myristate 13-acetate (PMA, 20 ng ml-1, 4 h)-stimulated ICAM-1 and compared it to that of a specific protein kinase C inhibitor, R031-8220 (10 microM). Also, functional consequences of changes in ICAM-1 expression were assessed by measuring adhesion of 111 In-labelled human neutrophils to EAhy926 endothelial and A549 epithelial monolayers treated with TNF alpha, in the presence or absence of ST638. 3. ST638 caused a concentration-dependent reduction in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial (at 4 h) and A549 epithelial monolayers (at 4 and 24 h). In contrast, ST638 caused a concentration-dependent increase in TNF alpha- (0.1-10 ng ml-1)-induced ICAM-1 on EAhy926 endothelial cells at 24 h. Similar effects were seen with AG 1288 or genistein. ST638 (100 microM) significantly (P < 0.01) inhibited ICAM-1 expression on HLMVEC endothelial cells induced by

  17. Optimizing the flattening filter free beam selection in RapidArc®-based stereotactic body radiotherapy for Stage I lung cancer

    PubMed Central

    Lu, J-Y; Lin, Z; Lin, P-X

    2015-01-01

    Objective: To optimize the flattening filter-free (FFF) beam selection in stereotactic body radiotherapy (SBRT) treatment for Stage I lung cancer in different fraction schemes. Methods: Treatment plans from 12 patients suffering from Stage I lung cancer were designed using the 6XFFF and 10XFFF beams in different fraction schemes of 4 × 12, 3 × 18 and 1 × 34 Gy. Plans were evaluated mainly in terms of organs at risk (OARs) sparing, normal tissue complication probability (NTCP) estimation and treatment efficiency. Results: Compared with the 10XFFF beam, 6XFFF beam showed statistically significant lower dose to all the OARs investigated. The percentage of NTCP reduction for both lung and chest wall was about 10% in the fraction schemes of 4 × 12 and 3 × 18 Gy, whereas only 7.4% and 2.6% was obtained in the 1 × 34 Gy scheme. For oesophagus, heart and spinal cord, the reduction was greater with the 6XFFF beam, but their absolute estimates were <10−6%. The mean beam-on time for 6XFFF and 10XFFF beams at 4 × 12, 3 × 18 and 1 × 34 Gy schemes were 2.2 ± 0.2 vs 1.5 ± 0.1, 3.3 ± 0.9 vs 2.0 ± 0.5 and 6.3 ± 0.9 vs 3.5 ± 0.4 min, respectively. Conclusion: The 6XFFF beam obtains better OARs sparing and lower incidence of NTCP in SBRT treatment of Stage I lung cancer, whereas the 10XFFF beam improves the treatment efficiency. To balance the OARs sparing and intrafractional variation owing to the prolonged treatment time, the authors recommend using the 6XFFF beam in the 4 × 12 and 3 × 18 Gy schemes but the 10XFFF beam in the 1 × 34 Gy scheme. Advances in knowledge: This study optimizes the FFF beam selection in different fraction schemes in SBRT treatment of Stage I lung cancer. PMID:26133073

  18. Effects of Feijining Decoction on vascular endothelial growth factor protein expression and changes of T cell subsets in Lewis lung carcinoma-bearing mice

    PubMed Central

    ZHOU, LIJIANG; PAN, YUZHEN; XING, YUQING; GAO, HONG; XIE, XIAODONG; YIN, DONGFENG

    2015-01-01

    Angiogenesis is crucial for cancer growth and metastasis. T cells are also key members of the adaptive immunity against tumorigenesis. The aim of the present study was to observe the effects of Feijining Decoction (FJND) on vascular endothelial growth factor (VEGF) protein expression and T cell subsets [cluster of differentiation 4+(CD4+) and CD8+ T lymphocyte] in Lewis lung carcinoma (LLC)-bearing mice. C57BL/6J mice were subcutaneously implanted with LLC cells. Forty carcinoma-bearing mice were randomly assigned to four groups (10 animals/group). The control group (CG) were the untreated group, the cisplatinum (DDP) group (DG) mice were treated with DDP, the FJND group (FG) were treated with FJND and the FJND + DDP group (FDG) were treated with FJND and DDP. Western blot and flow cytometry were used to evaluate the VEGF protein expression of tumor tissue and T cell subsets of the spleen. Spontaneous activity in 5 min was observed by the photoelectric counting method. DDP + FJND (FDG group) markedly inhibited tumor growth compared to the DG mice. The protein expression of VEGF was significantly downregulated in the carcinoma of FG mice compared to CG mice. VEGF protein expression was significantly reduced in FDG compared to DG mice. In the FG mice, the splenic CD4+ and CD4+/CD8+ cells were significantly increased compared to the CG mice, and the splenic CD4+ cells in the FDG mice were significantly increased compared to the DG group. In conclusion, FJND can inhibit tumor growth by downregulating VEGF protein expression and improving the immune function. PMID:26137245

  19. Novel functional germline variants in the vascular endothelial growth factor receptor 2 gene and their effect on gene expression and microvessel density in lung cancer

    PubMed Central

    Glubb, Dylan M; Cerri, Elisa; Giese, Alexandra; Zhang, Wei; Mirza, Osman; Thompson, Emma E.; Chen, Peixian; Das, Soma; Jassem, Jacek; Rzyman, Witold; Lingen, Mark W.; Salgia, Ravi; Hirsch, Fred R.; Dziadziuszko, Rafal; Ballmer-Hofer, Kurt; Innocenti, Federico

    2011-01-01

    Purpose VEGFR-2 plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function, and ultimately, the extent of tumor angiogenesis. Experimental Design We resequenced KDR using 24 DNAs each from healthy Caucasian, African American and Asian groups. Non-synonymous genetic variants were assessed for function using phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression, and microvessel density (MVD) were measured in non-small cell lung cancer (NSCLC) tumor samples and matching patient DNA samples were genotyped to test for associations with variants of interest. Results KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. −2854C and −2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. −271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. −906C and 23408G, associated with higher KDR mRNA levels in NSCLC samples. Conclusions This study has defined KDR genetic variation in three populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function. PMID:21712447

  20. Analysis of Expression of Vascular Endothelial Growth Factor A and Hypoxia Inducible Factor-1alpha in Patients Operated on Stage I Non-Small-Cell Lung Cancer

    PubMed Central

    Honguero Martínez, Antonio Francisco; Arnau Obrer, Antonio; Figueroa Almánzar, Santiago; León Atance, Pablo; Guijarro Jorge, Ricardo

    2014-01-01

    Objectives. Recent studies show that expression of hypoxia inducible factor-1alpha (HIF-1α) favours expression of vascular endothelial growth factor A (VEGF-A), and these biomarkers are linked to cellular proliferation, angiogenesis, and metastasis in different cancers. We analyze expression of HIF-1α and VEGF-A to clinicopathologic features and survival of patients operated on stage I non-small-cell lung cancer. Methodology. Prospective study of 52 patients operated on with stage I. Expression of VEGF-A and HIF-1α was performed through real-time quantitative polymerase chain reaction (qRT-PCR). Results. Mean age was 64.7 and 86.5% of patients were male. Stage IA represented 23.1% and stage IB 76.9%. Histology classification was 42.3% adenocarcinoma, 34.6% squamous cell carcinoma, and 23.1% others. Median survival was 81.0 months and 5-year survival 67.2%. There was correlation between HIF-1α and VEGF-A (P = 0.016). Patients with overexpression of HIF-1α had a tendency to better survival with marginal statistical significance (P = 0.062). Patients with overexpression of VEGF-A had worse survival, but not statistically significant (P = 0.133). Conclusion. The present study revealed that VEGF-A showed correlation with HIF-1α. HIF-1α had a tendency to protective effect with a P value close to statistical significance. VEGF-A showed a contrary effect but without statistical significance. PMID:26316946

  1. The relationship between microvessel count and the expression of vascular endothelial growth factor, p53, and K-ras in non-small cell lung cancer.

    PubMed Central

    Kang, Y. H.; Kim, K. S.; Yu, Y. K.; Lim, S. C.; Kim, Y. C.; Park, K. O.

    2001-01-01

    Using immunohistochemical staining, we studied the relationship between the microvessel count (MC) and the expression of K-ras, mutant p53 protein, and vascular endothelial growth factor (VEGF) in 61 surgically resected non-small cell lung cancers (NSCLC) (42 squamous cell carcinoma, 14 adenocarcinoma, 2 large cell carcinoma, 2 adenosquamous carcinoma, and 1 mucoepidermoid carcinoma). MC of the tumors with lymph node (LN) metastasis was significantly higher than that of tumors without LN metastasis (66.1+/-23.1 vs. 33.8+/-13.1, p<0.05). VEGF was positive in 54 patients (88.5%). MC was 58.1+/-25.2 (mean+/-S.D.) in a x200 field, and it was significantly higher in VEGF(+) tumors than in VEGF(-) tumors (61.4+/-23.7 vs. 32.9+/-23.8, p<0.05). VEGF expression was higher in K-ras-positive or mutant p53-positive tumors than in negative tumors (p<0.05). MC was significantly higher in K-ras(+) tumors than in K-ras(-) tumors, although it did not differ according to the level of mutant p53 protein expression. Survival did not differ with VEGF, mutant p53, or K-ras expression, or the level of MC. In conclusion, there is a flow of molecular alterations from K-ras and p53, to VEGF expression, leading to angiogenesis and ultimately lymph node metastasis. Correlations between variables in close approximation and the lack of prognostic significance of individual molecular alterations suggest that tumorigenesis and metastasis are multifactorial processes. PMID:11511786

  2. [The measurement of extra vascular lung water using a thermal-sodium double indicator dilution technique in patients undergoing surgery for esophageal cancer].

    PubMed

    Watanabe, A; Kusajima, K; Kawaharada, N; Komatsu, K; Sugimoto, S; Doi, H; Tanaka, A; Takeda, H; Mishina, H; Komatsu, S

    1990-11-01

    The Extra Vascular Lung Water (EVLW) was measured using the thermal sodium double indicator dilution technique in 21 patients undergoing surgery for esophageal cancer. This measurement is an important parameter in the control of the respiratory function. In the 16 cases without pulmonary complications, the preoperative EVLW was 5.3 +/- 0.2 (mean +/- SEM) ml/kg and the immediate postoperative EVLW was 4.8 +/- 0.4 ml/kg. This change was significant (p less than 0.05), but within 24 hours the EVLW returned to almost the same levels as those recorded before surgery. In only 3 cases, the EVLW were elevated beyond 7.5 ml/kg, but these high EVLW levels did not continue for more than 12 hours. Of the 5 patients with pulmonary complications, only two experienced pulmonary edema. Their preoperative EVLW levels were normal, but the immediate postoperative EVLW levels were significantly elevated beyond 10 ml/kg. These elevated levels were observed before the PaO2, the portable chest roentgenograms and the other test results changed following surgery. The high EVLW levels beyond 7.5 ml/kg continued for 72 hours after surgery. We found no correlation between the EVLW and measureable hemodynamic parameters (Cardiac Index, Pulmonary Wedge Pressure, Colloid Osmotic Pressure-Pulmonary Wedge Pressure gradient) during the observation period. In the other cases with pulmonary complications (2 cases were pneumonia, one was atelectasis with pneumonia), the changes in the EVLW levels were the same as for the cases without pulmonary complications. These results indicate that the EVLW is the optimum parameter for the control of the respiratory function and early diagnosis of pulmonary edema after surgery for esophageal cancer. PMID:2280095

  3. Efficacy evaluation of retrospectively applying the Varian normal breathing predictive filter for volume definition and artifact reduction in 4D CT lung patients.

    PubMed

    Malone, Ciaran; Rock, Luke; Skourou, Christina

    2014-01-01

    Phase-based sorting of four-dimensional computed tomography (4D CT) datasets is prone to image artifacts due to patient's breathing irregularities that occur during the image acquisition. The purpose of this study is to investigate the effect of the Varian normal breathing predictive filter (NBPF) as a retrospective phase-sorting parameter in 4D CT. Ten 4D CT lung cancer datasets were obtained. The volumes of all tumors present, as well as the total lung volume, were calculated on the maximum intensity projection (MIP) images as well as each individual phase image. The NBPF was varied retrospectively within the available range, and changes in volume and image quality were recorded. The patients' breathing trace was analysed and the magnitude and location of any breathing irregularities were correlated to the behavior of the NBPF. The NBPF was found to have a considerable effect on the quality of the images in MIP and single-phase datasets. When used appropriately, the NBPF is shown to have the ability to account for and correct image artifacts. However, when turned off (0%) or set above a critical level (approximately 40%), it resulted in erroneous volume reconstructions with variations in tumor volume up to 26.6%. Those phases associated with peak inspiration were found to be more susceptible to changes in the NBPF. The NBPF settings selected prior to exporting the breathing trace for patients evaluated using 4D CT directly affect the accuracy of the targeting and volume estimation of lung tumors. Recommendations are made to address potential errors in patient anatomy introduced by breathing irregularities, specifically deep breath or cough irregularities, by implementing the proper settings and use of this tool. PMID:24892327

  4. Stereotactic body radiation therapy (SBRT) for lung malignancies: preliminary toxicity results using a flattening filter-free linear accelerator operating at 2400 monitor units per minute

    PubMed Central

    2013-01-01

    Background Flattening filter-free (FFF) linear accelerators (linacs) are capable of delivering dose rates more than 4-times higher than conventional linacs during SBRT treatments, causing some to speculate whether the higher dose rate leads to increased toxicity owing to radiobiological dose rate effects. Despite wide clinical use of this emerging technology, clinical toxicity data for FFF SBRT are lacking. In this retrospective study, we report the acute and late toxicities observed in our lung radiosurgery experience using a FFF linac operating at 2400 MU/min. Methods We reviewed all flattening filter-free (FFF) lung SBRT cases treated at our institution from August 2010 through July 2012. Patients were eligible for inclusion if they had at least one clinical assessment at least 30 days following SBRT. Pulmonary, cardiac, dermatologic, neurologic, and gastrointestinal treatment related toxicities were scored according to CTCAE version 4.0. Toxicity observed within 90 days of SBRT was categorized as acute, whereas toxicity observed more than 90 days from SBRT was categorized as late. Factors thought to influence risk of toxicity were examined to assess relationship to grade > =2 toxicity. Results Sixty-four patients with >30 day follow up were eligible for inclusion. All patients were treated using 10 MV unflattened photons beams with intensity modulated radiation therapy (IMRT) inverse planning. Median SBRT dose was 48 Gy in 4 fractions (range: 30–60 Gy in 3–5 fractions). Six patients (9%) experienced > = grade 2 acute pulmonary toxicity; no non-pulmonary acute toxicities were observed. In a subset of 49 patients with greater than 90 day follow up (median 11.5 months), 11 pulmonary and three nerve related grade > =2 late toxicities were recorded. Pulmonary toxicities comprised six grade 2, three grade 3, and one each grade 4 and 5 events. Nerve related events were rare and included two cases of grade 2 chest wall pain and one grade 3

  5. Study of Stress Induced Failure of the Blood-gas Barrier and the Epithelial-epithelial Cells Connections of the Lung of the Domestic Fowl, Gallus gallus Variant Domesticus after Vascular Perfusion

    PubMed Central

    Maina, John N; Jimoh, Sikiru A

    2013-01-01

    Complete blood-gas barrier breaks (BGBBs) and epithelial-epithelial cells connections breaks (E-ECCBs) were enumerated in the lungs of free range chickens, Gallus gallus variant domesticus after vascular perfusion at different pressures. The E-ECCBs surpassed the BGBBs by a factor of ~2. This showed that the former parts of the gas exchange tissue were structurally weaker or more vulnerable to failure than the latter. The differences in the numbers of BGBBs and E-ECCBs in the different regions of the lung supplied with blood by the 4 main branches of the pulmonary artery (PA) corresponded with the diameters of the blood vessels, the angles at which they bifurcated from the PA, and the positions along the PA where they branched off. Most of the BGBBs and the E-ECCBs occurred in the regions supplied by the accessory- and the caudomedial branches: the former is the narrowest branch and the first blood vessel to separate from the PA while the latter is the most direct extension of the PA and is the widest. The E-ECCBs appeared to separate and fail from tensing of the blood capillary walls, as the perfusion- and intramural pressures increased. Compared to the mammalian lungs on which data are available, i.e., those of the rabbit, the dog, and the horse, the blood-gas barrier of the lung of free range chickens appears to be substantially stronger for its thinness. PMID:25288905

  6. SU-E-T-591: Optimizing the Flattening Filter Free Beam Selection in RapidArc-Based Stereotactic Body Radiotherapy for Stage I Lung Cancer

    SciTech Connect

    Huang, B-T; Lu, J-Y

    2015-06-15

    Purpose: To optimize the flattening filter free (FFF) beam energy selection in stereotactic body radiotherapy (SBRT) treatment for stage I lung cancer with different fraction schemes. Methods: Twelve patients suffering from stage I lung cancer were enrolled in this study. Plans were designed using 6XFFF and 10XFFF beams with the most widely used fraction schemes of 4*12 Gy, 3*18 Gy and 1*34 Gy, respectively. The plan quality was appraised in terms of planning target volume (PTV) coverage, conformity of the prescribed dose (CI100%), intermediate dose spillage (R50% and D2cm), organs at risk (OARs) sparing and beam-on time. Results: The 10XFFF beam predicted 1% higher maximum, mean dose to the PTV and 4–5% higher R50% compared with the 6XFFF beam in the three fraction schemes, whereas the CI100% and D2cm was similar. Most importantly, the 6XFFF beam exhibited 3–10% lower dose to all the OARs. However, the 10XFFF beam reduced the beam-on time by 31.9±7.2%, 38.7±2.8% and 43.6±4.0% compared with the 6XFFF beam in the 4*12 Gy, 3*18 Gy and 1*34 Gy schemes, respectively. Beam-on time was 2.2±0.2 vs 1.5±0.1, 3.3±0.9 vs 2.0±0.5 and 6.3±0.9 vs 3.5±0.4 minutes for the 6XFFF and 10XFFF one in the three fraction schemes. Conclusion: The 6XFFF beam obtains better OARs sparing in SBRT treatment for stage I lung cancer, but the 10XFFF one provides improved treatment efficiency. To balance the OARs sparing and intrafractional variation as a function of prolonged treatment time, the authors recommend to use the 6XFFF beam in the 4*12 Gy and 3*18 Gy schemes for better OARs sparing. However, for the 1*34 Gy scheme, the 10XFFF beam is recommended to achieve improved treatment efficiency.

  7. Vascular ring

    MedlinePlus

    ... with aberrant subclavian and left ligamentum ateriosus; Congenital heart defect - vascular ring; Birth defect heart - vascular ring ... accounts for less than 1% of all congenital heart problems. The condition occurs as often in males ...

  8. Vascular pressures and passage of gas emboli through the pulmonary circulation

    NASA Technical Reports Server (NTRS)

    Butler, B. D.; Katz, J.

    1988-01-01

    Doppler technique was used to measure the pulmonary vascular pressure gradients in dogs that received venous air emboli (VAE) at the rate of 0.35 ml/kg per min, at which the spillover of bubbles into the systemic arteries occur. It was found that, in 60 percent of dogs, venous bubbles spilled over into the arterial circulation at the pulmonary vascular pressure gradient of about 34.7 mm Hg. When the pulmonary vascular pressure gradient was raised to about 52 mm Hg, the spillover of venous bubbles occurred 100 percent of time. It is concluded that venous bubbles can cross the lungs of anesthetized dogs when the driving pressures are sufficient to overcome the normal filtering function.

  9. Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma.

    PubMed

    Wu, Xiao; Liu, Bao-Jun; Ji, Shumeng; Wu, Jing-Feng; Xu, Chang-Qing; Du, Yi-Jie; You, Xiao-Fang; Li, Bei; Le, Jing-Jing; Xu, Hai-Lin; Duan, Xiao-Hong; Dong, Jing-Cheng

    2015-07-01

    Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal-regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor-stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression. PMID:25824133

  10. Lung Circulation.

    PubMed

    Suresh, Karthik; Shimoda, Larissa A

    2016-01-01

    The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed. © 2016 American Physiological Society. Compr Physiol 6:897-943, 2016. PMID:27065170

  11. Bronchial and vascular effects of Paf in the rat isolated lung are completely blocked by WEB 2086, a novel specific Paf antagonist.

    PubMed Central

    Casals-Stenzel, J.; Franke, J.; Friedrich, T.; Lichey, J.

    1987-01-01

    1 The effect of the platelet-activating factor (Paf) antagonist, WEB 2086, on Paf-induced increase of pulmonary artery perfusion pressure (Pp), bronchial inflation pressure (Pi) and wet-to-dry lung weight ratios (W/D) was investigated in the rat isolated lung. 2 Lungs were perfused with Krebs-Ringer solution (KRS) as controls or with KRS containing WEB 2086 (0.1, 1.0, 10.0 or 100 micrograms ml-1) and then injected with a bolus of 20 micrograms Paf. 3 A dose-related inhibition of the Paf-induced increase of Pp, Pi and W/D was observed, being almost maximal for the 10.0 micrograms ml-1 and complete for the 100 micrograms ml-1 doses of WEB 2086 when compared to controls. 4 It is concluded that WEB 2086 is a highly effective and specific Paf antagonist in the pulmonary vasculature and bronchial tract. PMID:3664079

  12. Vascular rings.

    PubMed

    Backer, Carl L; Mongé, Michael C; Popescu, Andrada R; Eltayeb, Osama M; Rastatter, Jeffrey C; Rigsby, Cynthia K

    2016-06-01

    The term vascular ring refers to congenital vascular anomalies of the aortic arch system that compress the esophagus and trachea, causing symptoms related to those two structures. The most common vascular rings are double aortic arch and right aortic arch with left ligamentum. Pulmonary artery sling is rare and these patients need to be carefully evaluated for frequently associated tracheal stenosis. Another cause of tracheal compression occurring only in infants is the innominate artery compression syndrome. In the current era, the diagnosis of a vascular ring is best established by CT imaging that can accurately delineate the anatomy of the vascular ring and associated tracheal pathology. For patients with a right aortic arch there recently has been an increased recognition of a structure called a Kommerell diverticulum which may require resection and transfer of the left subclavian artery to the left carotid artery. A very rare vascular ring is the circumflex aorta that is now treated with the aortic uncrossing operation. Patients with vascular rings should all have an echocardiogram because of the incidence of associated congenital heart disease. We also recommend bronchoscopy to assess for additional tracheal pathology and provide an assessment of the degree of tracheomalacia and bronchomalacia. The outcomes of surgical intervention are excellent and most patients have complete resolution of symptoms over a period of time. PMID:27301603

  13. Vascular Tumors

    PubMed Central

    Sepulveda, Abel; Buchanan, Edward P.

    2014-01-01

    Vascular anomalies are divided into two main groups: tumors and malformations. Vascular tumors are a large and complex group of lesions, especially for clinicians with none or little experience in this field. In the past, these lesions caused a great deal of confusion because many appear analogous to the naked eye. Thankfully, recent advances in diagnostic techniques have helped the medical community to enhance our comprehension, accurately label, diagnose, and treat these lesions. In this article, we will review the most frequent vascular tumors and provide the reader with the tools to properly label, diagnose, and manage these complex lesions. PMID:25045329

  14. Vascular Diseases

    MedlinePlus

    ... heart and blood vessels, such as diabetes or high cholesterol Smoking Obesity Losing weight, eating healthy foods, being active and not smoking can help vascular disease. Other treatments include medicines and surgery.

  15. SU-E-T-131: Dosimetric Impact and Evaluation of Different Heterogenity Algorithm in Volumetric Modulated Arc Therapy Plan for Stereotactic Ablative Radiotherapy Lung Treatment with the Flattening Filter Free Beam

    SciTech Connect

    Chung, J; Kim, J; Lee, J; Kim, Y

    2014-06-01

    Purpose: The present study aimed to investigate the dosimetric impacts of the anisotropic analytic algorithm (AAA) and the Acuros XB (AXB) plan for lung stereotactic ablative radiation therapy using flattening filter-free (FFF) beam. We retrospectively analyzed 10 patients. Methods: We retrospectively analyzed 10 patients. The dosimetric parameters for the target and organs at risk (OARs) from the treatment plans calculated with these dose calculation algorithms were compared. The technical parameters, such as the computation times and the total monitor units (MUs), were also evaluated. Results: A comparison of DVHs from AXB and AAA showed that the AXB plan produced a high maximum PTV dose by average 4.40% with a statistical significance but slightly lower mean PTV dose by average 5.20% compared to the AAA plans. The maximum dose to the lung was slightly higher in the AXB compared to the AAA. For both algorithms, the values of V5, V10 and V20 for ipsilateral lung were higher in the AXB plan more than those of AAA. However, these parameters for contralateral lung were comparable. The differences of maximum dose for the spinal cord and heart were also small. The computation time of AXB was found fast with the relative difference of 13.7% than those of AAA. The average of monitor units (MUs) for all patients was higher in AXB plans than in the AAA plans. These results indicated that the difference between AXB and AAA are large in heterogeneous region with low density. Conclusion: The AXB provided the advantages such as the accuracy of calculations and the reduction of the computation time in lung stereotactic ablative radiotherapy (SABR) with using FFF beam, especially for VMAT planning. In dose calculation with the media of different density, therefore, the careful attention should be taken regarding the impacts of different heterogeneity correction algorithms. The authors report no conflicts of interest.

  16. Pulmonary blood volume indexed to lung volume is reduced in newly diagnosed systemic sclerosis compared to normals – a prospective clinical cardiovascular magnetic resonance study addressing pulmonary vascular changes

    PubMed Central

    2013-01-01

    Background Pulmonary involvement, manifested as pulmonary arterial hypertension or pulmonary fibrosis, is the most common cause of death in systemic sclerosis (SSc). We aimed to explore the feasibility of detecting early pulmonary involvement in SSc using recently developed non-invasive quantitative measures of pulmonary physiology using cardiovascular magnetic resonance (CMR). Methods Twenty-seven SSc patients (9 men, 57 ± 13 years) and 10 healthy controls (3 men, 54 ± 9 years) underwent CMR to determine the pulmonary blood volume (PBV) and the PBV variation (PBVV) throughout the cardiac cycle. Patients underwent Doppler echocardiography, high-resolution computed tomography (HRCT), and pulmonary function testing by spirometry. Comparisons were performed using the unpaired t-test and linear regression analysis was performed with Pearson’s correlation coefficient (r). Results Compared to healthy controls, the PBV indexed to lung volume (PBVI) was lower in patients (16 ± 4 vs 20 ± 5%, p < 0.05). There was no difference in PBV (466 ± 87 vs 471 ± 122 mL, p = 0.91) or PBVV/stroke volume (45 ± 10 vs 40 ± 6%, p = 0.09). There were no significant correlations between PBVI and pulmonary artery pressure estimated by Doppler (p = 0.08) the lung’s diffusion capacity for carbon monoxide (DLCO) (p = 0.09), vital capacity (p = 0.45), or pulmonary fibrosis by HRCT (p = 0.74). Conclusions This study is the first to measure the PBV in humans using CMR. Compared to healthy controls, newly diagnosed SSc patients have a reduced amount of blood in the pulmonary vasculature (PBVI) but unchanged pulmonary vascular distensibility (PBVV/stroke volume). PBVI is unrelated to DLCO, pulmonary artery pressure, vital capacity, and the presence of pulmonary fibrosis. PBVI may be a novel parameter reflecting vascular lung involvement in early-stage SSc, and these findings may be consistent with pathophysiological changes of

  17. Lung tissue engineering.

    PubMed

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

    2014-01-01

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

  18. Stack filters

    NASA Astrophysics Data System (ADS)

    Wendt, P. D.; Coyle, E. J.; Gallagher, N. C., Jr.

    1986-08-01

    A large class of easily implemented nonlinear filters called stack filters are discussed which includes the rank order operators in addition to the compositions of morphological operators. Techniques similar to those used to determine the root signal behavior of median filters are employed to study the convergence properties of the filters, and necessary conditions for a stack filter to preserve monotone regions or edges in signals, and the output distribution of the filters, are obtained. Among the stack filters of window width three are found asymmetric median filters in which one removes only positive going edges, the other removes only negative going edges, while the median filter removes impulses of both signs.

  19. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization.

    PubMed

    Downey, Charlene M; Aghaei, Mehrnoosh; Schwendener, Reto A; Jirik, Frank R

    2014-01-01

    The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2'3'-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a

  20. DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

    PubMed Central

    Downey, Charlene M.; Aghaei, Mehrnoosh; Schwendener, Reto A.; Jirik, Frank R.

    2014-01-01

    The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2′3′-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a

  1. Elevated SP-1 transcription factor expression and activity drives basal and hypoxia-induced vascular endothelial growth factor (VEGF) expression in non-small cell lung cancer.

    PubMed

    Deacon, Karl; Onion, David; Kumari, Rajendra; Watson, Susan A; Knox, Alan J

    2012-11-16

    VEGF plays a central role in angiogenesis in cancer. Non-small cell lung cancer (NSCLC) tumors have increased microvascular density, localized hypoxia, and high VEGF expression levels; however, there is a lack of understanding of how oncogenic and tumor microenvironment changes such as hypoxia lead to greater VEGF expression in lung and other cancers. We show that NSCLC cells secreted higher levels of VEGF than normal airway epithelial cells. Actinomycin D inhibited all NSCLC VEGF secretion, and VEGF minimal promoter-luciferase reporter constructs were constitutively active until the last 85 base pairs before the transcription start site containing three SP-1 transcription factor-binding sites; mutation of these VEGF promoter SP-1-binding sites eliminated VEGF promoter activity. Furthermore, dominant negative SP-1, mithramycin A, and SP-1 shRNA decreased VEGF promoter activity, whereas overexpression of SP-1 increased VEGF promoter activity. Chromatin immunoprecipitation assays demonstrated SP-1, p300, and PCA/F histone acetyltransferase binding and histone H4 hyperacetylation at the VEGF promoter in NSCLC cells. Cultured NSCLC cells expressed higher levels of SP-1 protein than normal airway epithelial cells, and double-fluorescence immunohistochemistry showed a strong correlation between SP-1 and VEGF in human NSCLC tumors. In addition, hypoxia-driven VEGF expression in NSCLC cells was SP-1-dependent, with hypoxia increasing SP-1 activity and binding to the VEGF promoter. These studies are the first to demonstrate that overexpression of SP-1 plays a central role in hypoxia-induced VEGF secretion. PMID:22992725

  2. Is 5 mm MMLC suitable for VMAT-based lung SBRT? A dosimetric comparison with 2.5 mm HDMLC using RTOG-0813 treatment planning criteria for both conventional and high-dose flattening filter-free photon beams.

    PubMed

    Subramanian, Shanmuga V; Subramani, Vellaiyan; Thirumalai Swamy, Shanmugam; Gandhi, Arun; Chilukuri, Srinivas; Kathirvel, Murugesan

    2015-01-01

    The aim of this study is to assess the suitability of 5 mm millennium multileaf collimator (MMLC) for volumetric-modulated arc therapy (VMAT)-based lung stereotactic body radiotherapy (SBRT). Thirty lung SBRT patient treatment plans along with their planning target volumes (ranging from 2.01 cc to 150.11 cc) were transferred to an inhomogeneous lung phantom and retrospectively planned using VMAT technique, along with the high definition multileaf collimator (HDMLC) and MMLC systems. The plans were evaluated using Radiation Therapy Oncology Group (RTOG-0813) treatment planning criteria for target coverage, normal tissue sparing, and treatment efficiency for both the MMLC and HDMLC systems using flat and flattening filter-free (FFF) photon beams. Irrespective of the target volumes, both the MLC systems were able to satisfy the RTOG-0813 treatment planning criteria without having any major deviation. Dose conformity was marginally better with HDMLC. The average conformity index (CI) value was found to be 1.069 ± 0.034 and 1.075 ± 0.0380 for HDMLC and MMLC plans, respectively. For the 6 MV FFF beams, the plan was slightly more conformal, with the average CI values of 1.063 ± 0.029 and 1.073 ± 0.033 for the HDMLC and MMLC plans, respectively. The high dose spillage was the maximum for 2 cc volume set (3% for HDMLC and 3.1% for MMLC). In the case of low dose spillage, both the MLCs were within the protocol of no deviation, except for the 2 cc volume set. The results from this study revealed that VMAT-based lung SBRT using 5 mm MMLC satisfies the RTOG-0813 treatment planning criteria for the studied target size and shapes. PMID:26219006

  3. Sci—Sat AM: Stereo — 06: Dosimetric Comparison of 3D Conformai, Flattened and Flattening Filter-Free TrueBeam RapidArc Planning for Lung SBRT

    SciTech Connect

    Jiang, Runqing; Zhan, Lixin; Osei, Ernest

    2014-08-15

    The major advantages of the VMAT SBRT plans compared to the conventional 3D conformai plan include faster delivery and improved target dose conformity. This study quantifies the dosimetric differences among 3D conformai plan; flattened beam and flattening filter-free (FFF) beam RapidArc Plans for lung SBRT. Five early stage lung cancer patients with various tumor positions and sizes previously treated with 3D non-coplanar SBRT were randomly selected. 4DCT was used for each patient to determine the internal target volume. Abdominal compression was applied to minimize respiratory motion for SBRT patients. For treatment planning, a 5 mm margin was given to the ITV to generate a planning target volume. The prescription dose was 48 Gy in 4 fractions and normalized to 95% of the PTV. Organs at risk (OAR) included spinal cord, esophagus, heart, trachea, bilateral lung, and great vessels. Optimization constraints were set to meet the criteria of the RTOG-0915 protocol. All VMAT plans were optimized with the RapidArc technique using two full arcs in Eclipse treatment planning system. The RapidArc SBRT plans with flattened 6MV beam and 6MV FFF beam were generated and dosimetric results were compared with the previous treated 3D non-coplanar plans. RapidArc plans demonstrated better conformity to target, sharper dose fall-off in normal tissues and lower dose to normal lung and other OARs than the 3D conformai plans. RapidArc SBRT for FFF beam showed comparable target conformity, adequate tumor dose, and clinically acceptable DVHs of OARs to flattened beams and significantly reduced treatment delivery time.

  4. Effects of an iron-based fuel-borne catalyst and a diesel particle filter on exhaust toxicity in lung cells in vitro.

    PubMed

    Steiner, Sandro; Czerwinski, Jan; Comte, Pierre; Heeb, Norbert V; Mayer, Andreas; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2015-08-01

    Metal-containing fuel additives catalyzing soot combustion in diesel particle filters are used in a widespread manner, and with the growing popularity of diesel vehicles, their application is expected to increase in the near future. Detailed investigation into how such additives affect exhaust toxicity is therefore necessary and has to be performed before epidemiological evidence points towards adverse effects of their application. The present study investigates how the addition of an iron-based fuel additive (Satacen®3, 40 ppm Fe) to low-sulfur diesel affects the in vitro cytotoxic, oxidative, (pro-)inflammatory, and mutagenic activity of the exhaust of a passenger car operated under constant, low-load conditions by exposing a three-dimensional model of the human airway epithelium to complete exhaust at the air-liquid interface. We could show that the use of the iron catalyst without and with filter technology has positive as well as negative effects on exhaust toxicity compared to exhaust with no additives: it decreases the oxidative and, compared to a non-catalyzed diesel particle filter, the mutagenic potential of diesel exhaust, but increases (pro-)inflammatory effects. The presence of a diesel particle filter also influences the impact of Satacen®3 on exhaust toxicity, and the proper choice of the filter type to be used is of importance with regards to exhaust toxicity. Figure ᅟ. PMID:24880869

  5. Effects of acute inhalation of aerosols generated during resistance spot welding with mild-steel on pulmonary, vascular and immune responses in rats

    PubMed Central

    Zeidler-Erdely, Patti C.; Meighan, Terence G.; Erdely, Aaron; Fedan, Jeffrey S.; Thompson, Janet A.; Bilgesu, Suzan; Waugh, Stacey; Anderson, Stacey; Marshall, Nikki B.; Afshari, Aliakbar; McKinney, Walter; Frazer, David G.; Antonini, James M.

    2015-01-01

    Spot welding is used in the automotive and aircraft industries, where high-speed, repetitive welding is needed to join thin sections of metal. Epoxy adhesives are applied as sealers to the metal seams. Pulmonary function abnormalities and airway irritation have been reported in spot welders, but no animal toxicology studies exist. Therefore, the goal of this study was to investigate vascular, immune and lung toxicity measures after exposure to these metal fumes in an animal model. Male Sprague-Dawley rats were exposed by inhalation to 25 mg/m3 to either mild-steel spot welding aerosols with sparking (high metal, HM) or without sparking (low metal, LM) for 4 h/d for 3, 8 and 13 d. Shams were exposed to filtered air. Bronchoalveolar lavage (BAL), lung gene expression and ex vivo BAL cell challenge were performed to assess lung toxicity. Lung resistance (RL) was evaluated before and after challenge with inhaled methacholine (MCh). Functional assessment of the vascular endothelium in isolated rat tail arteries and leukocyte differentiation in the spleen and lymph nodes via flow cytometry was also done. Immediately after exposure, baseline RL was significantly elevated in the LM spot welding aerosols, but returned to control level by 24 h postexposure. Airway reactivity to MCh was unaffected. Lung inflammation and cytotoxicity were mild and transient. Lung epithelial permeability was significantly increased after 3 and 8 d, but not after 13 d of exposure to the HM aerosol. HM aerosols also caused vascular endothelial dysfunction and increased CD4+, CD8+ and B cells in the spleen. Only LM aerosols caused increased IL-6 and MCP-1 levels compared with sham after ex vivo LPS stimulation in BAL macrophages. Acute inhalation of mild-steel spot welding fumes at occupationally relevant concentrations may act as an irritant as evidenced by the increased RL and result in endothelial dysfunction, but otherwise had minor effects on the lung. PMID:25140454

  6. Aquatic Plants Aid Sewage Filter

    NASA Technical Reports Server (NTRS)

    Wolverton, B. C.

    1985-01-01

    Method of wastewater treatment combines micro-organisms and aquatic plant roots in filter bed. Treatment occurs as liquid flows up through system. Micro-organisms, attached themselves to rocky base material of filter, act in several steps to decompose organic matter in wastewater. Vascular aquatic plants (typically, reeds, rushes, cattails, or water hyacinths) absorb nitrogen, phosphorus, other nutrients, and heavy metals from water through finely divided roots.

  7. Disk filter

    DOEpatents

    Bergman, Werner

    1986-01-01

    An electric disk filter provides a high efficiency at high temperature. A hollow outer filter of fibrous stainless steel forms the ground electrode. A refractory filter material is placed between the outer electrode and the inner electrically isolated high voltage electrode. Air flows through the outer filter surfaces through the electrified refractory filter media and between the high voltage electrodes and is removed from a space in the high voltage electrode.

  8. Disk filter

    DOEpatents

    Bergman, W.

    1985-01-09

    An electric disk filter provides a high efficiency at high temperature. A hollow outer filter of fibrous stainless steel forms the ground electrode. A refractory filter material is placed between the outer electrode and the inner electrically isolated high voltage electrode. Air flows through the outer filter surfaces through the electrified refractory filter media and between the high voltage electrodes and is removed from a space in the high voltage electrode.

  9. [Vascular parkinsonism].

    PubMed

    Yamanouchi, H

    1997-01-01

    Critchley speculated that multiple vascular lesions of the basal ganglia must have an etiological connection to the symptoms of so-called vascular parkinsonism (VP), but without neuropathological confirmation. Some had doubts about its existence because of the lack of the pathologically confirmed case with adequate clinical correlation. At present, VP is characterized clinically by the short-stepped or frozen gait, lead-pipe rigidity, the symmetry of findings, absence of resting tremor, and negative response to levodopa in elderly patients with cerebrovascular lesions on CT/MRI. Pseudobulbar palsies, pyramidal tract findings, and/or multi-infarct dementia coexist in some of the cases. Most of clinically suspected VP patients have cerebral white matter lesions as well as basal ganglia lesions. PMID:9014431

  10. Water Filters

    NASA Technical Reports Server (NTRS)

    1993-01-01

    The Aquaspace H2OME Guardian Water Filter, available through Western Water International, Inc., reduces lead in water supplies. The filter is mounted on the faucet and the filter cartridge is placed in the "dead space" between sink and wall. This filter is one of several new filtration devices using the Aquaspace compound filter media, which combines company developed and NASA technology. Aquaspace filters are used in industrial, commercial, residential, and recreational environments as well as by developing nations where water is highly contaminated.

  11. Lung Transplant

    MedlinePlus

    ... the NHLBI on Twitter. What Is a Lung Transplant? A lung transplant is surgery to remove a person's diseased lung ... a healthy lung from a deceased donor. Lung transplants are used for people who are likely to ...

  12. Biological Filters.

    ERIC Educational Resources Information Center

    Klemetson, S. L.

    1978-01-01

    Presents the 1978 literature review of wastewater treatment. The review is concerned with biological filters, and it covers: (1) trickling filters; (2) rotating biological contractors; and (3) miscellaneous reactors. A list of 14 references is also presented. (HM)

  13. Metallic Filters

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Filtration technology originated in a mid 1960's NASA study. The results were distributed to the filter industry, an HR Textron responded, using the study as a departure for the development of 421 Filter Media. The HR system is composed of ultrafine steel fibers metallurgically bonded and compressed so that the pore structure is locked in place. The filters are used to filter polyesters, plastics, to remove hydrocarbon streams, etc. Several major companies use the product in chemical applications, pollution control, etc.

  14. Vascular dementia

    PubMed Central

    Korczyn, Amos D; Vakhapova, Veronika; Grinberg, Lea T

    2012-01-01

    The epidemic grow of dementia causes great concern for the society. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown “vascular” risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD are similar, although the former is less effective. For prevention of dementia it is important to treat aggressively all factors, even in stroke survivors who do not show evidence of cognitive decline,. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss it interaction with AD. PMID:22575403

  15. FILTER TREATMENT

    DOEpatents

    Sutton, J.B.; Torrey, J.V.P.

    1958-08-26

    A process is described for reconditioning fused alumina filters which have become clogged by the accretion of bismuth phosphate in the filter pores, The method consists in contacting such filters with faming sulfuric acid, and maintaining such contact for a substantial period of time.

  16. Water Filters

    NASA Technical Reports Server (NTRS)

    1987-01-01

    A compact, lightweight electrolytic water filter generates silver ions in concentrations of 50 to 100 parts per billion in the water flow system. Silver ions serve as effective bactericide/deodorizers. Ray Ward requested and received from NASA a technical information package on the Shuttle filter, and used it as basis for his own initial development, a home use filter.

  17. Autophagy in vascular disease.

    PubMed

    Ryter, Stefan W; Lee, Seon-Jin; Smith, Akaya; Choi, Augustine M K

    2010-02-01

    Autophagy, or "self eating," refers to a regulated cellular process for the lysosomal-dependent turnover of organelles and proteins. During starvation or nutrient deficiency, autophagy promotes survival through the replenishment of metabolic precursors derived from the degradation of endogenous cellular components. Autophagy represents a general homeostatic and inducible adaptive response to environmental stress, including endoplasmic reticulum stress, hypoxia, oxidative stress, and exposure to pharmaceuticals and xenobiotics. Whereas elevated autophagy can be observed in dying cells, the functional relationships between autophagy and programmed cell death pathways remain incompletely understood. Preclinical studies have identified autophagy as a process that can be activated during vascular disorders, including ischemia-reperfusion injury of the heart and other organs, cardiomyopathy, myocardial injury, and atherosclerosis. The functional significance of autophagy in human cardiovascular disease pathogenesis remains incompletely understood, and potentially involves both adaptive and maladaptive outcomes, depending on model system. Although relatively few studies have been performed in the lung, our recent studies also implicate a role for autophagy in chronic lung disease. Manipulation of the signaling pathways that regulate autophagy could potentially provide a novel therapeutic strategy in the prevention or treatment of human disease. PMID:20160147

  18. DNA PURIFICATION BY POLYCARBONATE FILTERS

    EPA Science Inventory

    Organic solvent free procedure s are described for the purification of mammalian DNA from rat liver, kidney, spleen, lung and brain. he basis of the purification procedures are the use of the detergent sodium dodecyl sulfate (SDS) and inert polycarbonate filters with 2 um pores w...

  19. A novel spherical shell filter for reducing false positives in automatic detection of pulmonary nodules in thoracic CT scans

    NASA Astrophysics Data System (ADS)

    van de Leemput, Sil; Dorssers, Frank; Ehteshami Bejnordi, Babak

    2015-03-01

    Early detection of pulmonary nodules is crucial for improving prognosis of patients with lung cancer. Computer-aided detection of lung nodules in thoracic computed tomography (CT) scans has a great potential to enhance the performance of the radiologist in detecting nodules. In this paper we present a computer-aided lung nodule detection system for computed tomography (CT) scans that works in three steps. The system first segments the lung using thresholding and hole filling. From this segmentation the system extracts candidate nodules using Laplacian of Gaussian. To reject false positives among the detected candidate nodules, multiple established features are calculated. We propose a novel feature based on a spherical shell filter, which is specifically designed to distinguish between vascular structures and nodular structures. The performance of the proposed CAD system was evaluated by partaking in the ANODE09 challenge, which presents a platform for comparing automatic nodule detection programs. The results from the challenge show that our CAD system ranks third among the submitted works, demonstrating the efficacy of our proposed CAD system. The results also show that our proposed spherical shell filter in combination with conventional features can significantly reduce the number of false positives from the detected candidate nodules.

  20. Platelets in Lung Biology

    PubMed Central

    Weyrich, Andrew S.; Zimmerman, Guy A.

    2013-01-01

    Platelets and the lungs have an intimate relationship. Platelets are anucleate mammalian blood cells that continuously circulate through pulmonary vessels and that have major effector activities in hemostasis and inflammation. The lungs are reservoirs for megakaryocytes, the requisite precursor cell in thrombopoiesis, which is the intricate process by which platelets are generated. Platelets contribute to basal barrier integrity of the alveolar capillaries, which selectively restricts the transfer of water, proteins, and red blood cells out of the vessels. Platelets also contribute to pulmonary vascular repair. Although platelets bolster hemostatic and inflammatory defense of the healthy lung, experimental evidence and clinical evidence indicate that these blood cells are effectors of injury in a variety of pulmonary disorders and syndromes. Newly discovered biological capacities of platelets are being explored in the context of lung defense, disease, and remodeling. PMID:23043249

  1. Lung Emergencies

    MedlinePlus

    ... Emergencies Cardiac Emergencies Eye Emergencies Lung Emergencies Surgeries Lung Emergencies People with Marfan syndrome can be at ... should be considered an emergency. Symptoms of sudden lung collapse (pneumothorax) Symptoms of a sudden lung collapse ...

  2. Lung Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Lung Cancer What is Lung Cancer? How Tumors Form The body is made ... button on your keyboard.) Two Major Types of Lung Cancer There are two major types of lung ...

  3. Lung metastases

    MedlinePlus

    Metastases to the lung; Metastatic cancer to the lung ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs) and spread through the ...

  4. Filtering apparatus

    DOEpatents

    Haldipur, Gaurang B.; Dilmore, William J.

    1992-01-01

    A vertical vessel having a lower inlet and an upper outlet enclosure separated by a main horizontal tube sheet. The inlet enclosure receives the flue gas from a boiler of a power system and the outlet enclosure supplies cleaned gas to the turbines. The inlet enclosure contains a plurality of particulate-removing clusters, each having a plurality of filter units. Each filter unit includes a filter clean-gas chamber defined by a plate and a perforated auxiliary tube sheet with filter tubes suspended from each tube sheet and a tube connected to each chamber for passing cleaned gas to the outlet enclosure. The clusters are suspended from the main tube sheet with their filter units extending vertically and the filter tubes passing through the tube sheet and opening in the outlet enclosure. The flue gas is circulated about the outside surfaces of the filter tubes and the particulate is absorbed in the pores of the filter tubes. Pulses to clean the filter tubes are passed through their inner holes through tubes free of bends which are aligned with the tubes that pass the clean gas.

  5. Filtering apparatus

    DOEpatents

    Haldipur, G.B.; Dilmore, W.J.

    1992-09-01

    A vertical vessel is described having a lower inlet and an upper outlet enclosure separated by a main horizontal tube sheet. The inlet enclosure receives the flue gas from a boiler of a power system and the outlet enclosure supplies cleaned gas to the turbines. The inlet enclosure contains a plurality of particulate-removing clusters, each having a plurality of filter units. Each filter unit includes a filter clean-gas chamber defined by a plate and a perforated auxiliary tube sheet with filter tubes suspended from each tube sheet and a tube connected to each chamber for passing cleaned gas to the outlet enclosure. The clusters are suspended from the main tube sheet with their filter units extending vertically and the filter tubes passing through the tube sheet and opening in the outlet enclosure. The flue gas is circulated about the outside surfaces of the filter tubes and the particulate is absorbed in the pores of the filter tubes. Pulses to clean the filter tubes are passed through their inner holes through tubes free of bends which are aligned with the tubes that pass the clean gas. 18 figs.

  6. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

    Nagy, Janice A.; Benjamin, Laura; Zeng, Huiyan; Dvorak, Ann M.

    2008-01-01

    The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability. PMID:18293091

  7. Lung cancer

    SciTech Connect

    Aisner, J.

    1985-01-01

    This book contains 13 chapters. Some of the chapter titles are: The Pathology of Lung Cancer; Radiotherapy for Non-Small-Cell Cancer of the Lung; Chemotherapy for Non-Small-Cell Lung Cancer; Immunotherapy in the Management of Lung Cancer; Preoperative Staging and Surgery for Non-Small-Cell Lung Cancer; and Prognostic Factors in Lung Cancer.

  8. Perfusion and ventilation of isolated canine lungs

    PubMed Central

    Otto, T. J.; Trenkner, M.; Stopczyk, A.; Gawdziński, M.; Chełstowska, B.

    1968-01-01

    In order to evaluate methods of preserving lungs for use in transplantation, experiments on 28 mongrel dogs were carried out. Two methods were tried—first, mechanical respiration of isolated lungs under deep hypothermia, with the vascular bed filled with blood; and, secondly, the perfusion of isolated lungs with the aid of a modified DeWall's apparatus. Allogenic transplantations of lungs preserved in both ways were carried out. Gasometric and histological examinations of preserved lungs, before and after transplantation, were performed. The best results were obtained with perfusion under hypothermic conditions; ventilation without perfusion resulted in failure. Lung transplantation was successful when, after being preserved, the lung remained unchanged. Major discrepancies between the macroscopic and microscopic findings in preserved lungs were observed. An original classification of the changes occurring in preserved lungs is proposed. PMID:4886091

  9. Vascular Biomarkers in Asthma and COPD.

    PubMed

    Bakakos, Petros; Patentalakis, George; Papi, Alberto

    2016-01-01

    Bronchial asthma and chronic obstructive pulmonary disease (COPD) remain a global health problem with significant morbidity and mortality. The changes in bronchial microvasculature that occurin asthma and COPD contribute to airway wall remodeling. Angiogenesis seems to be more prevalent in asthma and vasodilatation seemsmore relevant in COPD while vascular leak is present in both diseases. Recently, there has been increased interest in the vascular component of airway remodeling in chronic bronchial inflammation of asthma and COPD although its role in the progression of the diseases has not been fully elucidated. Various cells andmediators are involved in the vascular remodeling in asthma and COPD while proinflammatory cytokines and growth factors exert angiogenic and antiangiogenic effects. Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel growth mainly in asthma but also in COPD. In asthmatic airways VEGF promotes proliferation and differentiation of endothelial cells and induces vascular leakage and permeability. It has also been involved in enhanced allergic sensitization, upregulated subsequent T-helper-2 type inflammatory responses, chemotaxis for monocytes and eosinophils, and airway oedema. Impaired VEGF signaling has been associated with emphysema in animal models. Studies on lung biopsies have shown a decreasing effect of anti-asthma drugs to the vascular component of airway remodeling. There is less available evidence on the effect of the currently used drugs on airway microvascular network in COPD. This review article explores the current knowledge regarding vascular biomarkers in asthma and COPD as well as the therapeutic implications of these mediators. PMID:26420364

  10. Angiosarcoma of the lung

    PubMed Central

    Grafino, Mónica; Alves, Paula; de Almeida, Margarida Mendes; Garrido, Patrícia; Hasmucrai, Direndra; Teixeira, Encarnação; Sotto-Mayor, Renato

    2016-01-01

    Angiosarcoma is a rare malignant vascular tumor. Pulmonary involvement is usually attributable to metastasis from other primary sites, primary pulmonary angiosarcoma therefore being quite uncommon. We report a case of angiosarcoma with pulmonary involvement, probably primary to the lung, which had gone untreated for more than two years. We describe this rare neoplasm and its growth, as well as the extensive local invasion and hematogenous metastasis at presentation. We also discuss its poor prognosis. PMID:26982044

  11. Accounting for regional background and population size in the detection of spatial clusters and outliers using geostatistical filtering and spatial neutral models: the case of lung cancer in Long Island, New York

    PubMed Central

    Goovaerts, Pierre; Jacquez, Geoffrey M

    2004-01-01

    Background Complete Spatial Randomness (CSR) is the null hypothesis employed by many statistical tests for spatial pattern, such as local cluster or boundary analysis. CSR is however not a relevant null hypothesis for highly complex and organized systems such as those encountered in the environmental and health sciences in which underlying spatial pattern is present. This paper presents a geostatistical approach to filter the noise caused by spatially varying population size and to generate spatially correlated neutral models that account for regional background obtained by geostatistical smoothing of observed mortality rates. These neutral models were used in conjunction with the local Moran statistics to identify spatial clusters and outliers in the geographical distribution of male and female lung cancer in Nassau, Queens, and Suffolk counties, New York, USA. Results We developed a typology of neutral models that progressively relaxes the assumptions of null hypotheses, allowing for the presence of spatial autocorrelation, non-uniform risk, and incorporation of spatially heterogeneous population sizes. Incorporation of spatial autocorrelation led to fewer significant ZIP codes than found in previous studies, confirming earlier claims that CSR can lead to over-identification of the number of significant spatial clusters or outliers. Accounting for population size through geostatistical filtering increased the size of clusters while removing most of the spatial outliers. Integration of regional background into the neutral models yielded substantially different spatial clusters and outliers, leading to the identification of ZIP codes where SMR values significantly depart from their regional background. Conclusion The approach presented in this paper enables researchers to assess geographic relationships using appropriate null hypotheses that account for the background variation extant in real-world systems. In particular, this new methodology allows one to identify

  12. Lung Diseases

    MedlinePlus

    ... many disorders affecting the lungs, such as asthma, COPD, infections like influenza, pneumonia and tuberculosis, lung cancer, and many other breathing problems. Some lung diseases can lead to respiratory failure. Dept. of Health and Human Services Office on Women's Health

  13. Collapsed Lung

    MedlinePlus

    A collapsed lung happens when air enters the pleural space, the area between the lung and the chest wall. If it is a ... is called pneumothorax. If only part of the lung is affected, it is called atelectasis. Causes of ...

  14. Lung surgery

    MedlinePlus

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

  15. Collapsed Lung

    MedlinePlus

    A collapsed lung happens when air enters the pleural space, the area between the lung and the chest wall. If it is a total collapse, it is called pneumothorax. If only part of the lung is affected, ...

  16. Lung disease

    MedlinePlus

    ... the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often ... the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An ...

  17. Heart and vascular services

    MedlinePlus

    ... branch of medicine that focuses on the cardiovascular system. ... Circulatory system; Vascular system; Cardiovascular system ... to diagnose, monitor or treat diseases of the circulatory and vascular system include: Cardiac CT for calcium scoring Cardiac MRI ...

  18. Society for Vascular Medicine

    MedlinePlus

    ... Annual Meeting Events Calendar Vascular Medicine Events Job Bank Professional Practice Position Statements PAD Awareness Vascular Related ... for a new job? Try the SVM Job Bank . Browse the jobs or sign up for job ...

  19. Collagen vascular disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001223.htm Collagen vascular disease To use the sharing features on ... were previously said to have "connective tissue" or "collagen vascular" disease. We now have names for many ...

  20. Heart and vascular services

    MedlinePlus

    ... gov/ency/article/007459.htm Heart and vascular services To use the sharing features on this page, ... blood vessels (arteries and veins). Heart and vascular services refers to the branch of medicine that focuses ...

  1. Lymphangiosarcoma complicating extensive congenital mixed vascular malformations.

    PubMed

    Al Dhaybi, Rola; Agoumi, Mehdi; Powell, Julie; Dubois, Josée; Kokta, Victor

    2010-09-01

    Pediatric hepatic angiosarcoma is a very rare malignant vascular tumor. A few cases have shown pediatric hepatic angiosarcoma occurring on a background of preexisting vascular lesions. We report the case of a newborn girl who presented extensive limbs and upper trunk cutaneous mixed vascular malformations at birth. These malformations were associated with thrombocytopenia. Cutaneous biopsies revealed complex vascular malformations with a significant lymphatic component. Compressive body suit therapy led to regression of the limbs' cutaneous vascular malformations. At the age of 9 months, the patient presented multiple heterogeneous hepatosplenic nodules. Aggressive treatment with prednisone, vincristine, and hepatosplenic embolizations resulted in initial improvement of the hepatosplenic lesions for few months, followed by an increase of the lesions with failure of response to treatment despite adding alpha-interferon-2b to treatment. The patient died at the age of 19 months. The autopsy's pathological examination revealed a hepatic-based angiosarcoma with plurimetastatic dissemination to the spleen, lungs, peritoneum, pleura, mesenteric linings as well as the serosa of the stomach and small intestine. Multiple cutaneous and visceral complex capillaro-lymphatico-venous malformations were also identified. We hypothesize that these multiple extensive mixed vascular malformations were associated with chronic lymphedema which probably predisposed to the development of the angiosarcoma in our patient. PMID:20863270

  2. Airway vascular damage in elite swimmers.

    PubMed

    Moreira, André; Palmares, Carmo; Lopes, Cristina; Delgado, Luís

    2011-11-01

    We postulated that high level swimming can promote airway inflammation and thus asthma by enhancing local vascular permeability. We aimed to test this hypothesis by a cross-sectional study comparing swimmers (n = 13, 17 ± 3 years, competing 7 ± 4 years, training 18 ± 3 h per week), asthmatic-swimmers (n = 6, 17 ± 2 years, competing 8 ± 3 years, training 16 ± 4 h per week), and asthmatics (n = 19, 14 ± 3 years). Subjects performed induced sputum and had exhaled nitric oxide, lung volumes, and airway responsiveness determined. Airway vascular permeability index was defined as the ratio of albumin in sputum and serum. Results from the multiple linear regression showed each unit change in airway vascular permeability index was associated with an increase of 0.97% (95%CI: 0.02 to 1.92; p = 0.047) in sputum eosinophilis, and of 2.64% (95%CI:0.96 to 4.31; p = 0.006) in sputum neutrophils after adjustment for confounders. In a general linear model no significant differences between airway vascular permeability between index study groups existed, after controlling for sputum eosinophilis and neutrophils. In conclusion, competitive swimmers training in chlorine-rich pools have similar levels of airway vascular permeability than asthmatics. Although competitive swimming has been associated with asthma, airway inflammation and airway hyperesponsiveness do not seem to be dependent on increased airway vascular permeability. PMID:21669516

  3. 78 FR 7792 - National Heart, Lung, and Blood Institute; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-04

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of... Sleep Disorders Research, Division of Lung Diseases, National Heart, Lung, and Blood Institute, National..., Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood Diseases...

  4. Water Filters

    NASA Technical Reports Server (NTRS)

    1988-01-01

    Seeking to find a more effective method of filtering potable water that was highly contaminated, Mike Pedersen, founder of Western Water International, learned that NASA had conducted extensive research in methods of purifying water on board manned spacecraft. The key is Aquaspace Compound, a proprietary WWI formula that scientifically blends various types of glandular activated charcoal with other active and inert ingredients. Aquaspace systems remove some substances; chlorine, by atomic adsorption, other types of organic chemicals by mechanical filtration and still others by catalytic reaction. Aquaspace filters are finding wide acceptance in industrial, commercial, residential and recreational applications in the U.S. and abroad.

  5. An Innovative Ultrasound Technique for Evaluation of Tumor Vascularity in Breast Cancers: Superb Micro-Vascular Imaging

    PubMed Central

    Park, Ah Young; Cha, Sang Hoon; Yeom, Suk Keu; Lee, Seung Wha; Chung, Hwan Hoon

    2016-01-01

    Tumor vascularity is an important indicator for differential diagnosis, tumor growth, and prognosis. Superb micro-vascular imaging (SMI) is an innovative ultrasound technique for vascular examination that uses a multidimensional filter to eliminate clutter and preserve extremely low-velocity flows. Theoretically, SMI could depict more vessels and more detailed vascular morphology, due to the increased sensitivity of slow blood flow. Here, we report the early experience of using SMI in 21 breast cancer patients. We evaluated tumor vascular features in breast cancer and compared SMI and conventional color or power Doppler imaging. SMI was superior to color or power Doppler imaging in detecting tumor vessels, the details of vessel morphology, and both peripheral and central vascular distribution. In conclusion, SMI is a promising ultrasound technique for evaluating microvascular information of breast cancers.

  6. Vascular restoration therapy and bioresorbable vascular scaffold

    PubMed Central

    Wang, Yunbing; Zhang, Xingdong

    2014-01-01

    This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s, metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s, to bioresorbable vascular scaffold (BVS) technology in large-scale development in recent years. The history, the current stage, the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy. The criteria of materials selection, design and processing principles of BVS, and the corresponding clinical trial results are also summarized in this article. PMID:26816624

  7. Vascular Precursor Cells

    PubMed Central

    Chaudhury, Hera; Goldie, Lauren C.

    2011-01-01

    Understanding the mechanisms that regulate the proliferation and differentiation of human stem and progenitor cells is critically important for the development and optimization of regenerative medicine strategies. For vascular regeneration studies, specifically, a true “vascular stem cell” population has not yet been identified. However, a number of cell types that exist endogenously, or can be generated or propagated ex vivo, function as vascular precursor cells and can participate in and/or promote vascular regeneration. Herein, we provide an overview of what is known about the regulation of their differentiation specifically toward a vascular endothelial cell phenotype. PMID:22866199

  8. Lung cancer

    PubMed Central

    Dong, Jie; Kislinger, Thomas; Jurisica, Igor; Wigle, Dennis A.

    2010-01-01

    High-throughput genomic data for both lung development and lung cancer continue to accumulate. Significant molecular intersection between these two processes has been hypothesized due to overlap in phenotypes and genomic variation. Examining the network biology of both cancer and development of the lung may shed functional light on the individual signaling modules involved. Stem cell biology may explain a portion of this network intersection and consequently studying lung organogenesis may have relevance for understanding lung cancer. This review summarizes our understanding of the potential overlapping mechanisms involved in lung development and lung tumorigenesis. PMID:19202349

  9. Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

    PubMed Central

    Alvira, Cristina M.

    2016-01-01

    In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized. PMID:27243014

  10. Angiogenesis in the mouse lung.

    PubMed

    Mitzner, W; Lee, W; Georgakopoulos, D; Wagner, E

    2000-07-01

    When pulmonary arterial blood flow is obstructed in all mammals studied, there is a compensatory growth of the bronchial vasculature. This angiogenesis normally occurs through a proliferation of the systemic circulation to the intraparenchymal airways. It is an important pathophysiological process, not only in pulmonary vascular disease, but also in lung cancer, because the blood flow that supplies primary lung tumors arises from the systemic circulation. In the mouse, however, the systemic blood vessels that supply the trachea and mainstem bronchi do not penetrate into the intraparenchymal airways, as they do in all other larger species. In this study, we attempted to generate a new functional bronchial circulation in the mouse by permanently obstructing 40% of the pulmonary circulation. We quantified the systemic blood flow to the lung with fluorescent microspheres for 3 months after left pulmonary artery ligation. Results demonstrated that a substantial systemic blood flow to the lung that can eventually supply up to 15% of the normal pulmonary flow can be generated beginning 5-6 days after ligation. These new angiogenic vessels do not arise from the extraparenchymal bronchial circulation. Rather they enter the lung directly via a totally new vasculature that develops between the visceral and parietal pleuras, supplied by several intercostal arteries. This unique model of angiogenesis occurs in the absence of any hypoxic stimulus and mimics the vascular source of many lung tumors. PMID:10880380

  11. Effects of acute inhalation of aerosols generated during resistance spot welding with mild-steel on pulmonary, vascular and immune responses in rats.

    PubMed

    Zeidler-Erdely, Patti C; Meighan, Terence G; Erdely, Aaron; Fedan, Jeffrey S; Thompson, Janet A; Bilgesu, Suzan; Waugh, Stacey; Anderson, Stacey; Marshall, Nikki B; Afshari, Aliakbar; McKinney, Walter; Frazer, David G; Antonini, James M

    2014-10-01

    Spot welding is used in the automotive and aircraft industries, where high-speed, repetitive welding is needed to join thin sections of metal. Epoxy adhesives are applied as sealers to the metal seams. Pulmonary function abnormalities and airway irritation have been reported in spot welders, but no animal toxicology studies exist. Therefore, the goal of this study was to investigate vascular, immune and lung toxicity measures after exposure to these metal fumes in an animal model. Male Sprague-Dawley rats were exposed by inhalation to 25 mg/m³ to either mild-steel spot welding aerosols with sparking (high metal, HM) or without sparking (low metal, LM) for 4 h/d for 3, 8 and 13 d. Shams were exposed to filtered air. Bronchoalveolar lavage (BAL), lung gene expression and ex vivo BAL cell challenge were performed to assess lung toxicity. Lung resistance (R(L)) was evaluated before and after challenge with inhaled methacholine (MCh). Functional assessment of the vascular endothelium in isolated rat tail arteries and leukocyte differentiation in the spleen and lymph nodes via flow cytometry was also done. Immediately after exposure, baseline R(L) was significantly elevated in the LM spot welding aerosols, but returned to control level by 24 h postexposure. Airway reactivity to MCh was unaffected. Lung inflammation and cytotoxicity were mild and transient. Lung epithelial permeability was significantly increased after 3 and 8 d, but not after 13 d of exposure to the HM aerosol. HM aerosols also caused vascular endothelial dysfunction and increased CD4+, CD8+ and B cells in the spleen. Only LM aerosols caused increased IL-6 and MCP-1 levels compared with sham after ex vivo LPS stimulation in BAL macrophages. Acute inhalation of mild-steel spot welding fumes at occupationally relevant concentrations may act as an irritant as evidenced by the increased R(L) and result in endothelial dysfunction, but otherwise had minor effects on the lung. PMID:25140454

  12. Tobacco Smoking and Lung Cancer

    PubMed Central

    Furrukh, Muhammad

    2013-01-01

    Tobacco smoking remains the most established cause of lung carcinogenesis and other disease processes. Over the last 50 years, tobacco refinement and the introduction of filters have brought a change in histology, and now adenocarcinoma has become the most prevalent subtype. Over the last decade, smoking also has emerged as a strong prognostic and predictive patient characteristic along with other variables. This article briefly reviews scientific facts about tobacco, and the process and molecular pathways involved in lung carcinogenesis in smokers and never-smokers. The evidence from randomised trials about tobacco smoking’s impact on lung cancer outcomes is also reviewed. PMID:23984018

  13. Abdominal Distension and Vascular Collapse.

    PubMed

    Cosentino, Gina; Uwaifo, Gabriel I

    2016-04-01

    We present the case of a 43-year-old gentleman who presented to the emergency room with acute abdominal distension, confusion and vascular collapse. The emergent radiologic imaging obtained showed massive bilateral adrenal enlargement, but despite the initial clinical suspicion of possible overwhelming sepsis and/or massive abdominal/intralesional hemorrhage, lab tests based obtained rapidly confirmed the diagnosis of acute Addisonian crisis which responded dramatically to adrenocorticoid hormone replacement therapy and aggressive fluid resuscitation. The patient's established history of metastatic lung cancer confirmed this as a case of metastatic massive bilateral adrenal metastases with an initial presentation of acute adrenal insufficiency which is uncommon in the setting of metastatic carcinomatosis but more typically associated with lymphomas. Recognition of this clinical possibility is vital to enable rapid diagnosis and consequent life saving therapy. PMID:27328473

  14. Water Filter

    NASA Technical Reports Server (NTRS)

    1982-01-01

    A compact, lightweight electrolytic water sterilizer available through Ambassador Marketing, generates silver ions in concentrations of 50 to 100 parts per billion in water flow system. The silver ions serve as an effective bactericide/deodorizer. Tap water passes through filtering element of silver that has been chemically plated onto activated carbon. The silver inhibits bacterial growth and the activated carbon removes objectionable tastes and odors caused by addition of chlorine and other chemicals in municipal water supply. The three models available are a kitchen unit, a "Tourister" unit for portable use while traveling and a refrigerator unit that attaches to the ice cube water line. A filter will treat 5,000 to 10,000 gallons of water.

  15. Eyeglass Filters

    NASA Technical Reports Server (NTRS)

    1987-01-01

    Biomedical Optical Company of America's suntiger lenses eliminate more than 99% of harmful light wavelengths. NASA derived lenses make scenes more vivid in color and also increase the wearer's visual acuity. Distant objects, even on hazy days, appear crisp and clear; mountains seem closer, glare is greatly reduced, clouds stand out. Daytime use protects the retina from bleaching in bright light, thus improving night vision. Filtering helps prevent a variety of eye disorders, in particular cataracts and age related macular degeneration.

  16. Imaging Pediatric Vascular Lesions.

    PubMed

    Nguyen, Tuyet A; Krakowski, Andrew C; Naheedy, John H; Kruk, Peter G; Friedlander, Sheila Fallon

    2015-12-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  17. Imaging Pediatric Vascular Lesions

    PubMed Central

    Nguyen, Tuyet A.; Krakowski, Andrew C.; Naheedy, John H.; Kruk, Peter G.

    2015-01-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  18. Lung Involvement in Systemic Sclerosis

    PubMed Central

    Hassoun, Paul M.

    2011-01-01

    Summary Scleroderma is a multisystem disease characterized by a severe inflammatory process and exuberant fibrosis. Lung involvement is a frequent complication and a leading cause of morbidity and mortality in this syndrome. Two major pulmonary syndromes are associated with scleroderma; a pulmonary vascular disorder evolving over time into relatively isolated pulmonary arterial hypertension (PAH), and interstitial lung disease (ILD). Each syndrome, when present, is a cause of morbidity and significantly reduces survival of scleroderma patients when compared to patients free of lung complication. When pulmonary hypertension and ILD are combined, survival is further reduced. Current therapy appears to have no meaningful effect on either condition and, thus, there is a need for better understanding of underlying pathogenic mechanisms. This review focuses on clinical, diagnostic, and therapeutic features of PAH and ILD as well as other frequent but less debilitating lung complications of scleroderma. PMID:21195581

  19. Acute Lung Failure

    PubMed Central

    Mac Sweeney, Rob; McAuley, Daniel F.; Matthay, Michael A.

    2013-01-01

    Lung failure is the most common organ failure seen in the intensive care unit. The pathogenesis of acute respiratory failure (ARF) can be classified as (1) neuromuscular in origin, (2) secondary to acute and chronic obstructive airway diseases, (3) alveolar processes such as cardiogenic and noncardiogenic pulmonary edema and pneumonia, and (4) vascular diseases such as acute or chronic pulmonary embolism. This article reviews the more common causes of ARF from each group, including the pathological mechanisms and the principles of critical care management, focusing on the supportive, specific, and adjunctive therapies for each condition. PMID:21989697

  20. Improving performance of computer-aided detection of pulmonary embolisms by incorporating a new pulmonary vascular-tree segmentation algorithm

    NASA Astrophysics Data System (ADS)

    Wang, Xingwei; Song, XiaoFei; Chapman, Brian E.; Zheng, Bin

    2012-03-01

    We developed a new pulmonary vascular tree segmentation/extraction algorithm. The purpose of this study was to assess whether adding this new algorithm to our previously developed computer-aided detection (CAD) scheme of pulmonary embolism (PE) could improve the CAD performance (in particular reducing false positive detection rates). A dataset containing 12 CT examinations with 384 verified pulmonary embolism regions associated with 24 threedimensional (3-D) PE lesions was selected in this study. Our new CAD scheme includes the following image processing and feature classification steps. (1) A 3-D based region growing process followed by a rolling-ball algorithm was utilized to segment lung areas. (2) The complete pulmonary vascular trees were extracted by combining two approaches of using an intensity-based region growing to extract the larger vessels and a vessel enhancement filtering to extract the smaller vessel structures. (3) A toboggan algorithm was implemented to identify suspicious PE candidates in segmented lung or vessel area. (4) A three layer artificial neural network (ANN) with the topology 27-10-1 was developed to reduce false positive detections. (5) A k-nearest neighbor (KNN) classifier optimized by a genetic algorithm was used to compute detection scores for the PE candidates. (6) A grouping scoring method was designed to detect the final PE lesions in three dimensions. The study showed that integrating the pulmonary vascular tree extraction algorithm into the CAD scheme reduced false positive rates by 16.2%. For the case based 3D PE lesion detecting results, the integrated CAD scheme achieved 62.5% detection sensitivity with 17.1 false-positive lesions per examination.

  1. Ceramic filters

    SciTech Connect

    Holmes, B.L.; Janney, M.A.

    1995-12-31

    Filters were formed from ceramic fibers, organic fibers, and a ceramic bond phase using a papermaking technique. The distribution of particulate ceramic bond phase was determined using a model silicon carbide system. As the ceramic fiber increased in length and diameter the distance between particles decreased. The calculated number of particles per area showed good agreement with the observed value. After firing, the papers were characterized using a biaxial load test. The strength of papers was proportional to the amount of bond phase included in the paper. All samples exhibited strain-tolerant behavior.

  2. Lung transplant

    MedlinePlus

    ... nih.gov/pubmed/20675678 . Kotloff RM, Keshavjee S. Lung transplantation. In: Broaddus VC, Mason RJ, Ernst MD, et ... 58. Solomon M, Grasemann H, Keshavjee S. Pediatric lung transplantation. Pediatr Clin North Am . 2010; 57(2):375- ...

  3. Lung Cancer

    MedlinePlus

    Lung cancer is one of the most common cancers in the world. It is a leading cause of ... in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

  4. Lung transplant

    MedlinePlus

    ... diseases that may require a lung transplant are: Cystic fibrosis Damage to the arteries of the lung because ... BC; Clinical Practice Guidelines for Pulmonary Therapies Committee; ... Therapies Committee. Cystic fibrosis pulmonary guidelines: ...

  5. Lung surgery

    MedlinePlus

    ... Pneumonectomy; Lobectomy; Lung biopsy; Thoracoscopy; Video-assisted thoracoscopic surgery; VATS ... You will have general anesthesia before surgery. You will be asleep and unable to feel pain. Two common ways to do surgery on your lungs are thoracotomy and video- ...

  6. Caveolins and lung function.

    PubMed

    Maniatis, Nikolaos A; Chernaya, Olga; Shinin, Vasily; Minshall, Richard D

    2012-01-01

    The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood and to ventilate carbon dioxide produced by catabolic reactions within cells. However, it is also responsible for a variety of other important functions, including host defense and production of vasoactive agents to regulate not only systemic blood pressure, but also water, electrolyte and acid-base balance. Caveolin-1 is highly expressed in the majority of cell types in the lung, including epithelial, endothelial, smooth muscle, connective tissue cells, and alveolar macrophages. Deletion of caveolin-1 in these cells results in major functional aberrations, suggesting that caveolin-1 may be crucial to lung homeostasis and development. Furthermore, generation of mutant mice that under-express caveolin-1 results in severe functional distortion with phenotypes covering practically the entire spectrum of known lung diseases, including pulmonary hypertension, fibrosis, increased endothelial permeability, and immune defects. In this Chapter, we outline the current state of knowledge regarding caveolin-1-dependent regulation of pulmonary cell functions and discuss recent research findings on the role of caveolin-1 in various pulmonary disease states, including obstructive and fibrotic pulmonary vascular and inflammatory diseases. PMID:22411320

  7. CAVEOLINS AND LUNG FUNCTION

    PubMed Central

    Maniatis, Nikolaos A.; Chernaya, Olga; Shinin, Vasily; Minshall, Richard D.

    2012-01-01

    The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood and to ventilate carbon dioxide produced by catabolic reactions within cells. However, it is also responsible for a variety of other important functions, including host defense and production of vasoactive agents to regulate not only systemic blood pressure, but also water, electrolyte and acid-base balance. Caveolin-1 is highly expressed in the majority of cell types in the lung, including epithelial, endothelial, smooth muscle, connective tissue cells, and alveolar macrophages. Deletion of caveolin-1 in these cells results in major functional aberrations, suggesting that caveolin-1 may be crucial to lung homeostasis and development. Furthermore, generation of mutant mice that under-express caveolin-1 results in severe functional distortion with phenotypes covering practically the entire spectrum of known lung diseases, including pulmonary hypertension, fibrosis, increased endothelial permeability, and immune defects. In this Chapter, we outline the current state of knowledge regarding caveolin-1-dependent regulation of pulmonary cell functions and discuss recent research findings on the role of caveolin-1 in various pulmonary disease states, including obstructive and fibrotic pulmonary vascular and inflammatory diseases. PMID:22411320

  8. Improving Outcomes for Pulmonary Vascular Disease

    PubMed Central

    Robbins, Ivan M.; Blaisdell, Carol J.; Abman, Steven H.

    2012-01-01

    Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would be expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trials; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs. PMID:22335936

  9. Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

    PubMed

    Hilgendorff, Anne; Apitz, Christian; Bonnet, Damien; Hansmann, Georg

    2016-05-01

    Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof. PMID:27053698

  10. [Vascular factors in glaucoma].

    PubMed

    Mottet, B; Aptel, F; Geiser, M; Romanet, J P; Chiquet, C

    2015-12-01

    The exact pathophysiology of glaucoma is not fully understood. Understanding of the vascular pathophysiology of glaucoma requires: knowing the techniques for measuring ocular blood flow and characterizing the topography of vascular disease and the mechanisms involved in this neuropathy. A decreased mean ocular perfusion pressure and a loss of vascular autoregulation are implicated in glaucomatous disease. Early decrease in ocular blood flow has been identified in primary open-angle glaucoma and normal pressure glaucoma, contributing to the progression of optic neuropathy. The vascular damage associated with glaucoma is present in various vascular territories within the eye (from the ophthalmic artery to the retina) and is characterized by a decrease in basal blood flow associated with a dysfunction of vasoregulation. PMID:26597554

  11. What Is Lung Cancer?

    MedlinePlus

    ... starts in the lungs, it is called lung cancer. Lung cancer begins in the lungs and may spread ... lung cancer. For more information, visit the National Cancer Institute’s Lung Cancer. Previous Basic Information Basic Information Basic Information ...

  12. Lung Organogenesis

    PubMed Central

    Warburton, David; El-Hashash, Ahmed; Carraro, Gianni; Tiozzo, Caterina; Sala, Frederic; Rogers, Orquidea; De Langhe, Stijn; Kemp, Paul J.; Riccardi, Daniela; Torday, John; Bellusci, Saverio; Shi, Wei; Lubkin, Sharon R; Jesudason, Edwin

    2011-01-01

    Developmental lung biology is a field that has the potential for significant human impact: lung disease at the extremes of age continues to cause major morbidity and mortality worldwide. Understanding how the lung develops holds the promise that investigators can use this knowledge to aid lung repair and regeneration. In the decade since the “molecular embryology” of the lung was first comprehensively reviewed, new challenges have emerged—and it is on these that we focus the current review. Firstly, there is a critical need to understand the progenitor cell biology of the lung in order to exploit the potential of stem cells for the treatment of lung disease. Secondly, the current familiar descriptions of lung morphogenesis governed by growth and transcription factors need to be elaborated upon with the reinclusion and reconsideration of other factors, such as mechanics, in lung growth. Thirdly, efforts to parse the finer detail of lung bud signaling may need to be combined with broader consideration of overarching mechanisms that may be therapeutically easier to target: in this arena, we advance the proposal that looking at the lung in general (and branching in particular) in terms of clocks may yield unexpected benefits. PMID:20691848

  13. Strategies for Whole Lung Tissue Engineering

    PubMed Central

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

    2014-01-01

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

  14. Strategies for whole lung tissue engineering.

    PubMed

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

    2014-05-01

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

  15. Vascular Access in Children

    SciTech Connect

    Krishnamurthy, Ganesh Keller, Marc S.

    2011-02-15

    Establishment of stable vascular access is one of the essential and most challenging procedures in a pediatric hospital. Many clinical specialties provide vascular service in a pediatric hospital. At the top of the 'expert procedural pyramid' is the pediatric interventional radiologist, who is best suited and trained to deliver this service. Growing awareness regarding the safety and high success rate of vascular access using image guidance has led to increased demand from clinicians to provide around-the-clock vascular access service by pediatric interventional radiologists. Hence, the success of a vascular access program, with the pediatric interventional radiologist as the key provider, is challenging, and a coordinated multidisciplinary team effort is essential for success. However, there are few dedicated pediatric interventional radiologists across the globe, and also only a couple of training programs exist for pediatric interventions. This article gives an overview of the technical aspects of pediatric vascular access and provides useful tips for obtaining vascular access in children safely and successfully using image guidance.

  16. Arginase and vascular aging

    PubMed Central

    Santhanam, Lakshmi; Christianson, David W.; Nyhan, Daniel; Berkowitz, Dan E.

    2008-01-01

    Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (l-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including polyamine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality. PMID:18719233

  17. A protocol for a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Petersen, Bodil; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    By providing insight into the cellular events of vascular injury and repair, experimental model systems seek to promote timely therapeutic strategies for human disease. The goal of many current studies of neovascularization is to identify cells critical to the process and their role in vascular channel assembly. We propose here a protocol to analyze, in an in vivo rodent model, vessel and capillary remodeling (reorganization and growth) in the injured lung. Sequential analyses of stages in the assembly of vascular structures, and of relevant cell types, provide further opportunities to study the molecular and cellular determinants of lung neovascularization. PMID:18323809

  18. Women and Vascular Disease

    MedlinePlus

    ... Search Patient information Membership Directory (SIR login) Interventional Radiology Women and Vascular Disease Early Warning Symptom for ... major public health issue, the Society of Interventional Radiology recommends greater screening efforts by the medical community ...

  19. Diversity in vascular surgery.

    PubMed

    Woo, Karen; Kalata, Emily A; Hingorani, Anil P

    2012-12-01

    A growing body of literature in vascular surgery demonstrates disparities in the type of health care that racial/ethnic minorities receive in the United States. Numerous recommendations, including those of the Institute of Medicine, have been set forth, which identify increasing the number of minority health professionals as a key strategy to eliminating health disparities. The purpose of this study is to compare the racial/ethnic distribution of the Society for Vascular Surgery (SVS) membership, the SVS leadership, vascular surgery trainees, and medical students. The results demonstrate that the racial/ethnic distribution of the SVS membership reflects a considerable lack of diversity with a paucity of diversity among the SVS leadership. An increasing rate of racial/ethnic diversity among vascular surgery trainees may indicate that the SVS will see an improvement in diversity in the future. PMID:23182481

  20. Uterine Vascular Lesions

    PubMed Central

    Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

    2013-01-01

    Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID:24340126

  1. What Is Vascular Disease?

    MedlinePlus

    ... or 911 immediately. @ 2016 Vascular Cures is a tax-exempt, nonprofit organization tax ID#: 94-2825216 as described in the Section ... 3) of the Internal Revenue Code. Donations are tax deductible. 555 Price Ave., Suite 180, Redwood City, ...

  2. Implications of Vascular Aging

    PubMed Central

    Barodka, Viachaslau M.; Joshi, Brijen L.; Berkowitz, Dan E.; Hogue, Charles W.; Nyhan, Daniel

    2011-01-01

    Chronological age is a well established risk factor for the development of cardiovascular diseases. The changes that accumulate in the vasculature with age, though, are highly variable. It is now increasingly recognized that indices of vascular health are more reliable than age per se in predicting adverse cardiovascular outcomes. The variation in the accrual of these age-related vascular changes is a function of multiple genetic and environmental factors. In this review, we highlight some of the pathophysiological mechanisms that characterize the vascular aging phenotype. Furthermore, we provide an overview of the key outcome studies that address the value of these vascular health indices in general and discuss potential effects on perioperative cardiovascular outcomes. PMID:21474663

  3. Vascular Access for Hemodialysis

    MedlinePlus

    ... short-term use. [ Top ] What is an arteriovenous fistula? An AV fistula is a connection, made by a vascular surgeon, ... vessel surgery. The surgeon usually places an AV fistula in the forearm or upper arm. An AV ...

  4. 75 FR 9912 - National Heart, Lung, and Blood Institute; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-04

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of..., National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Suite 9030, Bethesda, MD 20892, 301-435... Center for Sleep Disorders Research; 93.837, Heart and Vascular Diseases Research; 93.838, Lung...

  5. 76 FR 57066 - National Heart, Lung, and Blood Institute; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-15

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of Closed... and projects conducted by the National Heart, Lung, and Blood Institute, including consideration of...; 93.837, Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood...

  6. 76 FR 40923 - National Heart, Lung, and Blood Institute Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-12

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute Notice of Closed... of Committee: National Heart, Lung, and Blood Institute Special Emphasis Panel; Reducing Emergency..., Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood Diseases...

  7. 76 FR 57061 - National Heart, Lung, and Blood Institute; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-15

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of..., National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Suite 9030, Bethesda, MD 20892, 301-435... Center for Sleep Disorders Research; 93.837, Heart and Vascular Diseases Research; 93.838, Lung...

  8. 76 FR 19106 - National Heart, Lung, and Blood Institute; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-06

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of... Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Suite 9030, Bethesda, MD 20892, 301-435-0080... Center for Sleep Disorders Research; 93.837, Heart and Vascular Diseases Research; 93.838, Lung...

  9. 77 FR 58402 - National Heart, Lung, and Blood Institute; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-20

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of Closed... programs and projects conducted by the National Heart, Lung, and Blood Institute, including consideration... Disorders Research; 93.837, Heart and Vascular Diseases Research; 93.838, Lung Diseases Research;...

  10. 75 FR 61508 - National Heart, Lung, and Blood Institute; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-05

    ... HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute; Notice of Closed... and projects conducted by the National Heart, Lung, and Blood Institute, including consideration of....837, Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood Diseases...