443 results on '"Voelkel NF"'
Search Results
2. Transforming Growth Factor-β1 Induces Endothelin-1 in a Bovine Pulmonary Artery Endothelial Cell Line and Rat Lungs via cAMP
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Lee, SD, Lee, DS, Chun, YG, Paik, SH, Kim, WS, Kim, DS, Kim, WD, Tuder, RM, and Voelkel, NF
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- 2000
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3. Hypothyroidism Worsens Pressure Overload Induced Maladaptive Right Ventricular Remodeling in Rats.
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Natarajan, R, primary, Sweeney, LB, additional, Smithson, L, additional, Bogaard, HJ, additional, and Voelkel, NF, additional
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- 2009
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4. Are Histone Deacetylases Part of the Lung Structure Maintenance Program?.
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Mizuno, S, primary, Yasuo, M, additional, Kraskauskas, D, additional, Bogaard, HJ, additional, and Voelkel, NF, additional
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- 2009
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5. Endocrine Factors in a Cohort of Pulmonary Arterial Hypertension Patients.
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Sweeney, LB, primary and Voelkel, NF, additional
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- 2009
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6. Role of Vascular Endothelial Growth Factor (VEGF) in the Phagocytosis of Apoptotic Cells by Macrophages: Implications in Obstructive Airways Disease.
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Dalal, SA, primary, Tuder, RM, additional, Voelkel, NF, additional, Lee, CG, additional, Elias, JA, additional, Henson, PM, additional, and Vandivier, RW, additional
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- 2009
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7. Proactive Integrated Care Reduces Critical Care & Improves Quality-of-Life in COPD.
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Koff, PB, primary, Min, S, additional, Freitag, TJ, additional, James, SS, additional, Keith, RL, additional, Kveton, C, additional, Carwin, S, additional, Stelzner, TJ, additional, Brand, DW, additional, Ritzwoller, DP, additional, Beck, AL, additional, Voelkel, NF, additional, and Vandivier, RW, additional
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- 2009
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8. β-Adrenergic Blockade with Carvedilol Mitigates Maladaptive Right Ventricular Remodeling in Rats with Experimentally-Induced Pulmonary Hypertension.
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Bogaard, HJ, primary, Natarajan, R, additional, Kraskauskas, D, additional, Kraskauskienne, V, additional, and Voelkel, NF, additional
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- 2009
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9. Bosentan Fails To Prevent Right Ventricular Hypertrophy and Heart Failure in Immune Impaired Animals Exposed to Chronic Hypoxia.
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Taraseviciene-Stewart, L, primary, Slepikas, L, additional, Parr, J, additional, Kraskauskiene, V, additional, Kraskauskas, D, additional, Bogart, HJ, additional, and Voelkel, NF, additional
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- 2009
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10. Suppression of Histone Deacetylases Worsens Right Ventricular Hypertrophy and Induces Failure after Pulmonary Artery Banding in Rats.
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Bogaard, HJ, primary, Natarajan, R, additional, Kraskauskas, D, additional, Smithson, L, additional, and Voelkel, NF, additional
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- 2009
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11. Right Ventricular (RV) Failure in Pulmonary Arterial Hypertension (PAH): It's Not Just the Pressure.
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Natarajan, R, primary, Bogaard, HJ, additional, Smithson, L, additional, Kraskauskas, D, additional, and Voelkel, NF, additional
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- 2009
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12. Estrogen Exposure in Women with Pulmonary Arterial Hypertension.
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Sweeney, LB, primary and Voelkel, NF, additional
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- 2009
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13. Female Gender Protects Against Angioproliferative Pulmonary Hypertension Induced by VEGF Receptor Inhibition and Hypoxic Exposure.
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Sweeney, LB, primary, Bogaard, HJ, additional, Natarajan, R, additional, Kraskauskas, D, additional, and Voelkel, NF, additional
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- 2009
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14. Quasi-Neoplastic Potential of Myofibroblasts Detected in Endarterectomized Clots from Patients with Chronic Thromboembolic Pulmonary Hypertension.
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Sakao, S, primary, Maruoka, M, additional, Tanabe, N, additional, Kantake, S, additional, Kasahara, Y, additional, Tada, Y, additional, Kurosu, K, additional, Takiguchi, Y, additional, Kuriyama, T, additional, Voelkel, NF, additional, and Tatsumi, K, additional
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- 2009
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15. Severe pulmonary hypertensive diseases: a perspective
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Voelkel, NF, primary and Tuder, RM, additional
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- 1999
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16. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension
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Voelkel, NF, primary and Tuder, RM, additional
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- 1995
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17. MicroRNA-199a-5p is associated with hypoxia-inducible factor-1α expression in lungs from patients with COPD.
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Mizuno S, Bogaard HJ, Gomez-Arroyo J, Alhussaini A, Kraskauskas D, Cool CD, Voelkel NF, Mizuno, Shiro, Bogaard, Harm J, Gomez-Arroyo, Jose, Alhussaini, Aysar, Kraskauskas, Donatas, Cool, Carlyne D, and Voelkel, Norbert F
- Abstract
Background: MicroRNAs (miRNAs) are small noncoding RNAs that silence target gene expression posttranscriptionally, and their impact on gene expression has been reported in various diseases. It has been reported that the expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced and that of p53 is increased in lungs from patients with COPD. However, the role of miRNAs associated with these genes in lungs from patients with COPD is unknown.Methods: Lung tissue samples from 55 patients were included in this study. Total RNA, miRNA, and protein were extracted from lung tissues and used for reverse transcriptase polymerase chain reaction and Western blot analysis. Cell culture experiments were performed using cultured human pulmonary microvascular endothelial cells (HPMVECs).Results: miR-34a and miR-199a-5p expressions were increased, and the phosphorylation of AKT was decreased in the lung tissue samples of patients with COPD. The miR-199a-5p expression was correlated with HIF-1α protein expression in the lungs of patients with COPD. Transfection of HPMVECs with the miR-199a-5p precursor gene decreased HIF-1α protein expression, and transfection with the miR-34a precursor gene increased miR-199a-5p expression.Conclusions: These data suggest that miR-34a and miR-199a-5p contribute to the pathogenesis of COPD, and these miRNAs may also affect the HIF-1α-dependent lung structure maintenance program. [ABSTRACT FROM AUTHOR]- Published
- 2012
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18. Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats.
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Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, Kasper M, Natarajan R, Voelkel NF, Bogaard, Harm J, Mizuno, Shiro, Hussaini, Ayser A Al, Toldo, Stefano, Abbate, Antonio, Kraskauskas, Donatas, Kasper, Michael, Natarajan, Ramesh, and Voelkel, Norbert F
- Abstract
Rationale: Inhibitors of histone deacetylases (HDACs) reduce pressure-overload-induced left ventricular hypertrophy and dysfunction, but their effects on right ventricular (RV) adaptation to pressure overload are unknown.Objectives: Determine the effect of the broad-spectrum HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) on RV function and remodeling after pulmonary artery banding (PAB) in rats.Methods: Chronic progressive RV pressure-overload was induced in rats by PAB. After establishment of adaptive RV hypertrophy 4 weeks after surgery, rats were treated for 2 weeks with vehicle, TSA, or VPA. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurements, immunohistochemistry, and molecular analyses after 2 weeks of HDAC inhibition. The effects of TSA were determined on the expression of proangiogenic and prohypertrophic genes in human myocardial fibroblasts and microvascular endothelial cells.Measurements and Main Results: TSA treatment did not prevent the development of RV hypertrophy and was associated with RV dysfunction, capillary rarefaction, fibrosis, and increased rates of myocardial cell death. Similar results were obtained with the structurally unrelated HDAC inhibitor VPA. With TSA treatment, a reduction was found in expression of vascular endothelial growth factor and angiopoietin-1, which proteins are involved in vascular adaptation to pressure-overload. TSA dose-dependently suppressed vascular endothelial growth factor, endothelial nitric oxide synthase, and angiopoietin-1 expression in cultured myocardial endothelial cells, which effects were mimicked by selective gene silencing of several class I and II HDACs.Conclusions: HDAC inhibition is associated with dysfunction and worsened remodeling of the pressure-overloaded RV. The detrimental effects of HDAC inhibition on the pressure-overloaded RV may come about via antiangiogenic or proapoptotic effects. [ABSTRACT FROM AUTHOR]- Published
- 2011
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19. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.
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Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF, Bogaard, Harm J, Natarajan, Ramesh, Henderson, Scott C, Long, Carlin S, Kraskauskas, Donatas, Smithson, Lisa, Ockaili, Ramzi, McCord, Joe M, and Voelkel, Norbert F
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- 2009
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20. THE INDUCTION OF CYCLOOXYGENASE-2 (COX-2) IN PULMONARY INTRAVASCULAR PMNs ACCOUNTS FOR THROMBOXANE SYNTHESIS IN ENDOTOXIN-PRIMED RAT LUNGS
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T. Tanita, Voelkel Nf, S. Fujimura, Westcott Jy, M. Chida, and S. Ono
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biology ,business.industry ,Thromboxane ,Emergency Medicine ,biology.protein ,Medicine ,Cyclooxygenase ,Pharmacology ,Critical Care and Intensive Care Medicine ,business - Published
- 1995
21. Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke.
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Nana-Sinkam SP, Lee JD, Sotto-Santiago S, Stearman RS, Keith RL, Choudhury Q, Cool C, Parr J, Moore MD, Bull TM, Voelkel NF, Geraci MW, Nana-Sinkam, S Patrick, Lee, Jong Deog, Sotto-Santiago, Sylk, Stearman, Robert S, Keith, Robert L, Choudhury, Qamrul, Cool, Carlyne, and Parr, Jane
- Abstract
Rationale: Impaired endothelial cell-dependent vasodilation, inflammation, apoptosis, and proliferation are manifestations of endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Prostacyclin (PGI(2)) is a major product of the cyclooxygenase pathway with potent vasodilatory and antimitogenic properties and may be relevant to endothelial dysfunction in COPD.Objectives: To determine if PGI(2) expression is altered in smoking-related lung disease and if it may be protective in COPD-associated endothelial dysfunction.Methods: We evaluated, by immunohistochemistry, Western blotting, and polymerase chain reaction, human emphysema tissue compared with normal tissue for expression of prostacyclin synthase (PGI(2)S). We examined the effects of cigarette smoke extract (CSE) and aldehyde components on eicosanoid expression in primary human pulmonary microvascular endothelial cells. Finally, we used a murine model of lung-specific PGI(2)S overexpression and in vitro studies to determine if PGI(2) expression has protective effects on cigarette smoke-induced endothelial apoptosis.Measurements and Main Results: Human emphysema lung tissue exhibited lower PGI(2)S expression within the pulmonary endothelium than in normal lung. In vitro studies demonstrated that CSE, and in particular the alpha,beta unsaturated aldehyde acrolein, suppressed PGI(2)S gene expression, whereas CSE significantly induced the upstream mediators COX-2 and cytosolic phospholipase A2 in human pulmonary microvascular endothelial cells. Mice with lung-specific PGI(2)S overexpression exhibited less endothelial apoptosis after chronic smoke exposure. In vitro, iloprost exhibited protective effects on CSE-induced apoptosis.Conclusions: PGI(2) has protective effects in the pulmonary vasculature after acute and chronic cigarette smoke exposure. An imbalance in eicosanoid expression may be important to COPD-associated endothelial dysfunction. [ABSTRACT FROM AUTHOR]- Published
- 2007
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22. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure.
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Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB, and US National Heart, Lung, and Blood Institute. Working Group on Cellular and Molecular Mechanisms of Right Heart Failure
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- 2006
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23. HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques.
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Marecki JC, Cool CD, Parr JE, Beckey VE, Luciw P, Tarantal AF, Carville A, Shannon RP, Cota-Gomez A, Tuder RM, Voelkel NF, Flores SC, Marecki, John C, Cool, Carlyne D, Parr, Jane E, Beckey, Virginia E, Luciw, Paul A, Tarantal, Alice F, Carville, Angela, and Shannon, Richard P
- Abstract
Rationale: HIV-infected patients with pulmonary arterial hypertension have histologic manifestations that are indistinguishable from those found in patients with idiopathic pulmonary arterial hypertension. In addition, the role of pleiotropic viral proteins in the development of plexiform lesions in HIV-related pulmonary hypertension (HRPH) has not been explored. Simian immunodeficiency virus (SIV) infection of macaques has been found to closely recapitulate many of the characteristic features of HIV infection, and thus hallmarks of pulmonary arterial hypertension should also be found in this nonhuman primate model of HIV.Objectives: To determine whether pulmonary arterial lesions were present in archived SIV-infected macaque lung tissues from Johns Hopkins University and two National Primate Research Centers.Methods: Archived macaque and human lung sections were examined via immunohistochemistry for evidence of complex vascular lesions.Results: Complex plexiform-like lesions characterized by lumenal obliteration, intimal disruption, medial hypertrophy, thrombosis, and recanalized lumena were found exclusively in animals infected with SHIV-nef (a chimeric viral construct containing the HIV nef gene in an SIV backbone), but not in animals infected with SIV. The mass of cells in the lesions were factor VIII positive, and contained cells positive for muscle-specific and smooth muscle actins. Lung mononuclear cells were positive for HIV Nef, suggesting viral replication. Endothelial cells in both the SHIV-nef macaques and patients with HRPH, but not in patients with idiopathic pulmonary arterial hypertension, were also Nef positive.Conclusions: The discovery of complex vascular lesions in SHIV-nef- but not SIV-infected animals, and the presence of Nef in the vascular cells of patients with HRPH, suggest that Nef plays a key role in the development of severe pulmonary arterial disease. [ABSTRACT FROM AUTHOR]- Published
- 2006
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24. A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema.
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Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, Choe K, Taraseviciene-Stewart L, Scerbavicius R, Shapiro L, Zhang B, Song S, Hicklin D, Voelkel NF, Flotte T, Tuder RM, Petrache, Irina, Fijalkowska, Iwona, Zhen, Lijie, and Medler, Terry R
- Abstract
Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of alpha1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema.Objectives: We propose that, in addition to its antielastolytic effects, alpha1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. METHODS, MEASUREMENTS, AND MAIN RESULTS: Transduction of human alpha1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human alpha1-antitrypsin intravenously.Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by alpha1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of alpha1-antitrypsin. [ABSTRACT FROM AUTHOR]- Published
- 2006
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25. Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema.
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Sullivan AK, Simonian PL, Falta MT, Mitchell JD, Cosgrove GP, Brown KB, Kotzin BL, Voelkel NF, Fontenot AP, Sullivan, Andrew K, Simonian, Philip L, Falta, Michael T, Mitchell, John D, Cosgrove, Gregory P, Brown, Kevin K, Kotzin, Brian L, Voelkel, Norbert F, and Fontenot, Andrew P
- Abstract
Rationale: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an important role in this continued inflammatory response is unknown.Objective: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli.Methods: Lung T-cell receptor (TCR) Vbeta repertoire from eight patients with severe emphysema and six control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotide sequencing of expanded TCR-Vbeta subsets was performed.Results: No significantly expanded TCR-Vbeta subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n = 8) but from only one of the control lung samples (n = 6) when exposed to interleukin 2 (p = 0.0013). Within the cultured cells, seven major CD4-expressing TCR-Vbeta subset expansions were identified from five of the patients with emphysema. These expansions were composed of oligoclonal populations of T cells that had already been expanded in vivo.Conclusion: Severe emphysema is associated with inflammation involving T lymphocytes that are composed of oligoclonal CD4+ T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema. [ABSTRACT FROM AUTHOR]- Published
- 2005
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26. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension.
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Bull TM, Coldren CD, Moore M, Sotto-Santiago SM, Pham DV, Nana-Sinkam SP, Voelkel NF, and Geraci MW
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The importance of genetic predisposition, inflammation, and autoimmune mechanisms in the development of pulmonary arterial hypertension (PAH) is becoming increasingly clear. We hypothesized that the analysis of gene expression profiles from peripheral blood mononuclear cells would distinguish patients with PAH from normal volunteers. We also hypothesized that a subset of genes would discriminate between patients with idiopathic PAH and pulmonary hypertension related to secondary causes. Mononuclear cells were isolated from 15 patients diagnosed with PAH and 6 normal control subjects. Microarray expression was performed, and the expression profiles were analyzed for consistent and predictive differences in gene expression. We identified a signature set of 106 genes that discriminated with high certainty (p < or = 0.002) between patients with PAH and normal individuals. The results of the microarray analysis were retrospectively and prospectively confirmed by quantitative polymerase chain reaction for 2 of the 106 genes. Supervised clustering analysis generated a list of differentially expressed genes between patients with idiopathic and secondary causes of pulmonary hypertension. Microarray expression profiling of peripheral blood cells can discriminate between patients with PAH and normal volunteers. These findings may have important implications toward diagnosis, screening, and pathogenesis of this disease. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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27. Pulmonary arterial hypertension: future directions. Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases workshop.
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Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JGN, Kao PN, Knowles JA, Loyd JE, McGoon MD, Morse JH, Nichols WC, Rabinovitch M, Rodman DM, Stevens T, Tuder RM, Voelkel NF, and Gail DB
- Published
- 2004
28. Acute hypoxia, but not chronic hypoxia, induces cyclooxygenase-2 (COX-2)gene expression in the lung
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Fujimura S, Voelkel Nf, and M. Chida
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Lung ,biology ,business.industry ,Chronic hypoxia ,Pathology and Forensic Medicine ,Acute hypoxia ,medicine.anatomical_structure ,Physiology (medical) ,Gene expression ,biology.protein ,Cancer research ,Medicine ,Cyclooxygenase ,business - Published
- 1994
29. Perspective: high-altitude pulmonary edema.
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Voelkel NF
- Published
- 2002
30. Hypoxia regulates human lung fibroblast proliferation via p53-dependent and -independent pathways.
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Mizuno S, Bogaard HJ, Voelkel NF, Umeda Y, Kadowaki M, Ameshima S, Miyamori I, Ishizaki T, Mizuno, Shiro, Bogaard, Herman J, Voelkel, Norbert F, Umeda, Yukihiro, Kadowaki, Maiko, Ameshima, Shingo, Miyamori, Isamu, and Ishizaki, Takeshi
- Abstract
Background: Hypoxia induces the proliferation of lung fibroblasts in vivo and in vitro. However, the subcellular interactions between hypoxia and expression of tumor suppressor p53 and cyclin-dependent kinase inhibitors p21 and p27 remain unclear.Methods: Normal human lung fibroblasts (NHLF) were cultured in a hypoxic chamber or exposed to desferroxamine (DFX). DNA synthesis was measured using bromodeoxyuridine incorporation, and expression of p53, p21 and p27 was measured using real-time RT-PCR and Western blot analysis.Results: DNA synthesis was increased by moderate hypoxia (2% oxygen) but was decreased by severe hypoxia (0.1% oxygen) and DFX. Moderate hypoxia decreased p21 synthesis without affecting p53 synthesis, whereas severe hypoxia and DFX increased synthesis of both p21 and p53. p27 protein expression was decreased by severe hypoxia and DFX. Gene silencing of p21 and p27 promoted DNA synthesis at ambient oxygen concentrations. p21 and p53 gene silencing lessened the decrease in DNA synthesis due to severe hypoxia or DFX exposure. p21 gene silencing prevented increased DNA synthesis in moderate hypoxia. p27 protein expression was significantly increased by p53 gene silencing, and was decreased by wild-type p53 gene transfection.Conclusion: These results indicate that in NHLF, severe hypoxia leads to cell cycle arrest via the p53-p21 pathway, but that moderate hypoxia enhances cell proliferation via the p21 pathway in a p53-independent manner. In addition, our results suggest that p27 may be involved in compensating for p53 in cultured NHLF proliferation. [ABSTRACT FROM AUTHOR]- Published
- 2009
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31. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation.
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Sakao S, Tatsumi K, Voelkel NF, Sakao, Seiichiro, Tatsumi, Koichiro, and Voelkel, Norbert F
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Severe pulmonary arterial hypertension, whether idiopathic or secondary, is characterized by structural alterations of microscopically small pulmonary arterioles. The vascular lesions in this group of pulmonary hypertensive diseases show actively proliferating endothelial cells without evidence of apoptosis. In this article, we review pathogenetic concepts of severe pulmonary arterial hypertension and explain the term "complex vascular lesion ", commonly named "plexiform lesion", with endothelial cell dysfunction, i.e., apoptosis, proliferation, interaction with smooth muscle cells and transdifferentiation. [ABSTRACT FROM AUTHOR]
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- 2009
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32. Expression of human herpesvirus 8 in primary pulmonary hypertension.
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Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, and Voelkel NF
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- 2003
33. HHV-8 in pulmonary hypertension.
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Henke-Gendo C, Schulz TF, Hoeper MM, Cool CD, Rai PR, and Voelkel NF
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- 2004
34. Lung Fibrosis Is Linked to Increased Endothelial Cell Activation and Dysfunctional Vascular Barrier Integrity.
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Fließer E, Jandl K, Lins T, Birnhuber A, Valzano F, Kolb D, Foris V, Heinemann A, Olschewski H, Evermann M, Hoetzenecker K, Kreuter M, Voelkel NF, Marsh LM, Wygrecka M, and Kwapiszewska G
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- Humans, Male, Female, Middle Aged, von Willebrand Factor metabolism, Aged, Cadherins metabolism, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Cell Adhesion, Thrombomodulin metabolism, Antigens, CD metabolism, Endothelial Cells metabolism, Endothelial Cells pathology, Lung pathology, Lung metabolism, Lung blood supply, Pulmonary Fibrosis pathology, Pulmonary Fibrosis metabolism
- Abstract
Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro . Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.
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- 2024
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35. The vascular perspective on acute and chronic lung disease.
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Borek I, Birnhuber A, Voelkel NF, Marsh LM, and Kwapiszewska G
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- Humans, Lung pathology, Endothelial Cells, Endothelium, Vascular, Pulmonary Disease, Chronic Obstructive pathology, Respiratory Distress Syndrome therapy, Respiratory Distress Syndrome pathology, Pulmonary Fibrosis pathology
- Abstract
The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), and chronic obstructive pulmonary disease (COPD). The primary emphasis in the management of these parenchymal disorders has largely revolved around the injury and aberrant repair of epithelial cells. However, there is increasing evidence that the vascular endothelium plays an active role in the development of acute and chronic lung diseases. The endothelial cell network in the capillary bed and the arterial and venous vessels provides a metabolically highly active barrier that controls the migration of immune cells, regulates vascular tone and permeability, and participates in the remodeling processes. Phenotypically and functionally altered endothelial cells, and remodeled vessels, can be found in acute and chronic lung diseases, although to different degrees, likely because of disease-specific mechanisms. Since vascular remodeling is associated with pulmonary hypertension, which worsens patient outcomes and survival, it is crucial to understand the underlying vascular alterations. In this Review, we describe the current knowledge regarding the role of the pulmonary vasculature in the development and progression of ARDS, PF, and COPD; we also outline future research directions with the hope of facilitating the development of mechanism-based therapies.
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- 2023
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36. ARDS in the time of corona: context and perspective.
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Voelkel NF, Bogaard HJ, and Kuebler WM
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- Humans, SARS-CoV-2, COVID-19, Respiratory Distress Syndrome
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For more than 2 years, COVID-19 has been holding the world at awe with new waves of infections, novel mutants, and still limited (albeit improved) means to combat SARS-CoV-2-induced respiratory failure, the most common and fatal presentation of severe COVID-19. In the present perspective, we draw from the successes and-mostly-failures in previous acute respiratory distress syndrome (ARDS) work and the experiences from COVID-19 to define conceptual barriers that have so far hindered therapeutic breakthroughs in this deadly disease, and to open up new avenues of thinking and thus, ultimately of therapy.
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- 2022
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37. Sugen, hypoxia and the lung circulation.
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Voelkel NF and Bogaard HJ
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- 2021
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38. The Role of Regulatory T Cells in Pulmonary Arterial Hypertension.
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Tian W, Jiang SY, Jiang X, Tamosiuniene R, Kim D, Guan T, Arsalane S, Pasupneti S, Voelkel NF, Tang Q, and Nicolls MR
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- Animals, Autoimmunity, Endothelium, Vascular immunology, Endothelium, Vascular pathology, Humans, Indoles adverse effects, Pulmonary Arterial Hypertension pathology, Pyrroles adverse effects, Rats, Sex Characteristics, Vascular System Injuries pathology, Pulmonary Arterial Hypertension immunology, Pulmonary Arterial Hypertension prevention & control, T-Lymphocytes, Regulatory immunology, Vascular System Injuries immunology, Vascular System Injuries prevention & control
- Abstract
Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4
+ CD25high FOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tian, Jiang, Jiang, Tamosiuniene, Kim, Guan, Arsalane, Pasupneti, Voelkel, Tang and Nicolls.)- Published
- 2021
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39. Impact of Proactive Integrated Care on Chronic Obstructive Pulmonary Disease.
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Koff PB, Min SJ, Freitag TJ, Diaz DLP, James SS, Voelkel NF, Linderman DJ, Diaz Del Valle F, Zakrajsek JK, Albert RK, Bull TM, Beck A, Stelzner TJ, Ritzwoller DP, Kveton CM, Carwin S, Ghosh M, Keith RL, Westfall JM, and Vandivier RW
- Abstract
Background: Up to 50% of chronic obstructive pulmonary disease (COPD) patients do not receive recommended care for COPD. To address this issue, we developed Proactive Integrated Care (Proactive iCare), a health care delivery model that couples integrated care with remote monitoring., Methods: We conducted a prospective, quasi-randomized clinical trial in 511 patients with advanced COPD or a recent COPD exacerbation, to test whether Proactive iCare impacts patient-centered outcomes and health care utilization. Patients were allocated to Proactive iCare (n=352) or Usual Care ( =159) and were examined for changes in quality of life using the St George's Respiratory Questionnaire (SGRQ), symptoms, guideline-based care, and health care utilization., Findings: Proactive iCare improved total SGRQ by 7-9 units ( p < 0.0001), symptom SGRQ by 9 units ( p <0.0001), activity SGRQ by 6-7 units (p <0.001) and impact SGRQ by 7-11 units ( p <0.0001) at 3, 6 and 9 months compared with Usual Care. Proactive iCare increased the 6-minute walk distance by 40 m ( p <0.001), reduced annual COPD-related urgent office visits by 76 visits per 100 participants (p <0.0001), identified unreported exacerbations, and decreased smoking ( p =0.01). Proactive iCare also improved symptoms, the b ody mass index-airway o bstruction- d yspnea- e xercise tolerance (BODE) index and oxygen titration ( p <0.05). Mortality in the Proactive iCare group (1.1%) was not significantly different than mortality in the Usual Care group (3.8%; p =0.08)., Interpretation: Linking integrated care with remote monitoring improves the lives of people with advanced COPD, findings that may have been made more relevant by the coronavirus 2019 (COVID-19) pandemic., Competing Interests: RWV, PBK, SJM, DLPD, TJF, SSJ, NFV, DJL, AB, TJS, DPR, CMK, SC, RLK and JMW received funding from the Colorado Cancer, Cardiovascular Disease and Chronic Pulmonary Disease Prevention, Early Detection and Treatment Program (CCPD). RWV and MG received funding from the National Institutes of Health. PBK worked for Robert Bosch Healthcare from 2010 to 2015 and for Philips Healthcare from 2015 to 2017, after the study was completed. RKA, FDV, JKZ and TMB had no conflicts of interest., (JCOPDF © 2021.)
- Published
- 2021
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40. SCUBE Diving: Biomarker Discovery for Pulmonary Hypertension From Bench to Bedside.
- Author
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Gomez-Arroyo J, Voelkel NF, and Abbate A
- Abstract
Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Published
- 2020
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41. Angiotensin converting enzyme 2 and angiotensin (1-7) axis in pulmonary arterial hypertension.
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Sandoval J, Del Valle-Mondragón L, Masso F, Zayas N, Pulido T, Teijeiro R, Gonzalez-Pacheco H, Olmedo-Ocampo R, Sisniega C, Paez-Arenas A, Pastelin-Hernandez G, Gomez-Arroyo J, and Voelkel NF
- Subjects
- Angiotensin I, Animals, Humans, Peptide Fragments, Peptidyl-Dipeptidase A, Angiotensin-Converting Enzyme 2, Pulmonary Arterial Hypertension
- Abstract
Background: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood., Methods: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically., Results: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL
-1 versus 0.19, 0.10-0.37 pmol·mL-1 ; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL-1 versus 12.9, 9.55-19.9 ng·dL-1 ; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL-1 versus 4.07, 2.82-6.73 pmol·mL-1 ; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL-1 versus 4.53, 1.47-14.3 ng·mL-1 ; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL-1 versus 5.97, 3.1-17.8 nmol·mL-1 ; p<0.001). No significant differences were found among the three different aetiological forms of PAH., Conclusions: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted., Competing Interests: Conflict of interest: J. Sandoval has nothing to disclose. Conflict of interest: L. Del Valle-Mondragón has nothing to disclose. Conflict of interest: F. Masso has nothing to disclose. Conflict of interest: N. Zayas has nothing to disclose. Conflict of interest: T. Pulido reports grants from and personal fees for advisory board work and lectures from Actelion and Bayer, grants from Lilly, Reata Pharmaceuticals and United Therapeutics, personal fees for advisory board work from Pfizer and Akros Pharma, outside the submitted work. Conflict of interest: R. Teijeiro reports grants from CONACYT (FOSISS project 2015-1-262511), during the conduct of the study. Conflict of interest: H. González-Pacheco has nothing to disclose. Conflict of interest: R. Olmedo-Ocampo has nothing to disclose. Conflict of interest: C. Sisniega has nothing to disclose. Conflict of interest: A. Paez-Arenas has nothing to disclose. Conflict of interest: G. Pastelin-Hernandez has nothing to disclose. Conflict of interest: J. Gómez-Arroyo has nothing to disclose. Conflict of interest: N.F. Voelkel has nothing to disclose., (Copyright ©ERS 2020.)- Published
- 2020
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42. The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis-ten years later.
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Cool CD, Kuebler WM, Bogaard HJ, Spiekerkoetter E, Nicolls MR, and Voelkel NF
- Subjects
- Animals, Apoptosis, Autoimmunity, Humans, Neoplasm Proteins metabolism, Lung Neoplasms pathology, Models, Biological, Pulmonary Arterial Hypertension pathology
- Abstract
Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the "quasi-malignancy concept" of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.
- Published
- 2020
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43. A new treatment for severe pulmonary arterial hypertension based on an old idea: inhibition of 5-lipoxygenase.
- Author
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Voelkel NF and Peters-Golden M
- Abstract
It has been generally accepted that severe forms of pulmonary arterial hypertension are associated with inflammation. Plasma levels in patients with severe pulmonary arterial hypertension show elevated levels of interleukins and mediators of inflammation and histologically the diseased small pulmonary arterioles show infiltrates of inflammatory and immune cells. Here, we review the literature that connects pulmonary hypertension with the arachidonic acid/5-lipoxygenase-derived leukotriens. This mostly preclinical background data together with the availability of 5-lipoxygenase inhibitors and leukotriene receptor blockers provide the rationale for testing the hypothesis that 5-lipoxygenase products contribute to the pathobiology of severe pulmonary arterial hypertension in a subgroup of patients., (© The Author(s) 2020.)
- Published
- 2020
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44. Sugen-morphine model of pulmonary arterial hypertension.
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Agarwal S, Harter ZJ, Krishnamachary B, Chen L, Nguyen T, Voelkel NF, and Dhillon NK
- Abstract
Pulmonary arterial hypertension is a fatal disease associated with pulmonary vascular remodeling and right ventricular hypertrophy. Pre-clinical animal models that reproduce the human pulmonary arterial hypertension process and pharmacological response to available therapies are critical for future drug development. The most prevalent animal model reproducing many aspects of angioobliterative forms of pulmonary arterial hypertension is the rat Sugen/hypoxia model in which Sugen, a vascular endothelial growth factor receptor antagonist, primarily causes initiation of endothelial injury and later in the presence of hypoxia promotes proliferation of apoptosis-resistant endothelial cells. We previously demonstrated that exposure of human pulmonary microvascular endothelium to morphine and HIV-proteins results in initial apoptosis followed by increased proliferation. Here, we demonstrate that the double-hit of morphine and Sugen 5416 (Sugen-morphine) in rats leads to the development of pulmonary arterial hypertension with significant medial hypertrophy of pre-acinar pulmonary arteries along with neo-intimal thickening of intra-acinar vessels. In addition, the pulmonary smooth muscle and endothelial cells isolated from Sugen-morphine rats showed hyperproliferation and apoptotic resistance, respectively, in response to serum starvation. Our findings support that the dual hit model of Sugen 5416 and morphine provides another experimental strategy to induce significant pulmonary vascular remodeling and development of severe pulmonary arterial hypertension pathology in rats without exposure to hypoxia., (© The Author(s) 2020.)
- Published
- 2020
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45. Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.
- Author
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Tian W, Jiang X, Sung YK, Shuffle E, Wu TH, Kao PN, Tu AB, Dorfmüller P, Cao A, Wang L, Peng G, Kim Y, Zhang P, Chappell J, Pasupneti S, Dahms P, Maguire P, Chaib H, Zamanian R, Peters-Golden M, Snyder MP, Voelkel NF, Humbert M, Rabinovitch M, and Nicolls MR
- Subjects
- Animals, Endothelial Cells metabolism, Hypertension, Pulmonary physiopathology, Myocytes, Smooth Muscle metabolism, Pulmonary Arterial Hypertension genetics, Pulmonary Artery pathology, Pulmonary Artery physiopathology, Rats, Transgenic, Signal Transduction physiology, Bone Morphogenetic Protein Receptors, Type II genetics, Inflammation metabolism, Neointima metabolism, Pulmonary Arterial Hypertension physiopathology
- Abstract
Background: Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2
+/ - mice. Accordingly, 5-LO and its metabolite, leukotriene B4 , are candidates for the second hit. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats., Methods: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2 -mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes., Results: Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-β) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 -mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-β) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation., Conclusions: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.- Published
- 2019
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46. Role of the Aryl Hydrocarbon Receptor/ARNT/Cytochrome P450 System in Pulmonary Vascular Diseases.
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Kwapiszewska G, Johansen AKZ, Gomez-Arroyo J, and Voelkel NF
- Subjects
- Animals, Environmental Pollutants toxicity, Enzyme Activation, Estrogens metabolism, Female, Genetic Predisposition to Disease, Humans, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary genetics, Hypoxia complications, Inflammation, Male, Mice, Polymorphism, Genetic, Sex Factors, Vasoconstriction, Aryl Hydrocarbon Receptor Nuclear Translocator physiology, Basic Helix-Loop-Helix Transcription Factors physiology, Cytochrome P-450 Enzyme System physiology, Hypertension, Pulmonary metabolism, Receptors, Aryl Hydrocarbon physiology
- Abstract
Rationale: CYPs (cytochrome p450) are critically involved in the metabolism of xenobiotics and toxins. Given that pulmonary hypertension is strongly associated with environmental exposure, we hypothesize that CYPs play a role in the development and maintenance of pathological vascular remodeling., Objective: We sought to identify key CYPs that could link drug or hormone metabolism to the development of pulmonary hypertension., Methods and Results: We searched in Medline (PubMed) database, as well as http://www.clinicaltrials.gov, for CYPs associated with many key aspects of pulmonary arterial hypertension including, but not limited to, severe pulmonary hypertension, estrogen metabolism, inflammation mechanisms, quasi-malignant cell growth, drug susceptibility, and metabolism of the pulmonary arterial hypertension-specific drugs., Conclusions: We postulate a hypothesis where the AhR (aryl hydrocarbon receptor) mediates aberrant cell growth via expression of different CYPs associated with estrogen metabolism and inflammation.
- Published
- 2019
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47. Is Myocardial Fibrosis Impairing Right Heart Function?
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Bogaard HJ and Voelkel NF
- Subjects
- Fibrosis, Heart, Humans, Cardiomyopathies, Ventricular Dysfunction, Right
- Published
- 2019
- Full Text
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48. Restrictive atrial communication in right and left heart failure.
- Author
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Bauer A, Esmaeili A, deRosa R, Voelkel NF, and Schranz D
- Abstract
Heart failure (HF) is usually defined by the dominantly affected heart chamber; therefore, termed right or left HF (RHF or LHF). Pulmonologists understand RHF as a complex syndrome characterized by insufficient delivery of blood from the right ventricle associated with elevated systemic venous pressure at rest or exercise. Cardiologists specify LHF by its clinical functional class and the relation to a reduced (HFrEF), preserved (HFpEF) or mid-range ejection fraction (HFmrEF). Pediatric cardiologist, dealing also with patients with a failing single ventricle, define HF as a condition of insufficient systemic oxygen delivery (DO
2 ). Certainly, pediatricians do not think of the right and left heart, or even a single ventricle as an isolated, independently acting entity. Because of the importance of cardiac interactions, the creation of a restrictive atrial communication aims at a palliative approach with the goal to diminish the congestive consequences of a dysfunctional ventricle; further to serve as a pop-off valve in order to prevent syncope and cardiovascular collapse. This review covers the background, the particular indications, the techniques and preliminary results achieved following the creation of a restrictive atrial septum defect (rASD) in different pathophysiological settings. Based on the institutional experience, percutaneous trans-catheter perforation of the atrial septum, followed by gradual balloon dilatation can be performed at any age and location worldwide. Medical institutions in low resource countries can make use of such palliating procedures in the setting of right as well as LHF independent of their pharmacological facilities., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.- Published
- 2019
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49. Endothelial cells from pulmonary endarterectomy specimens possess a high angiogenic potential and express high levels of hepatocyte growth factor.
- Author
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Naito A, Sakao S, Lang IM, Voelkel NF, Jujo T, Ishida K, Sugiura T, Matsumiya G, Yoshino I, Tanabe N, and Tatsumi K
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, Cells, Cultured, Chronic Disease, Endarterectomy, Endothelial Cells metabolism, Female, Gene Expression, Hepatocyte Growth Factor antagonists & inhibitors, Hepatocyte Growth Factor blood, Hepatocyte Growth Factor genetics, Humans, Hypertension, Pulmonary blood, Hypertension, Pulmonary complications, Hypertension, Pulmonary surgery, Male, Middle Aged, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met metabolism, Pulmonary Artery pathology, Pulmonary Artery surgery, Pulmonary Embolism blood, Pulmonary Embolism complications, Pyrrolidinones pharmacology, Quinolines pharmacology, Endothelial Cells physiology, Hepatocyte Growth Factor metabolism, Hypertension, Pulmonary physiopathology, Lung Neoplasms pathology, Neovascularization, Pathologic genetics, Pulmonary Artery physiopathology, Pulmonary Embolism physiopathology
- Abstract
Background: Impaired angiogenesis is assumed to be an important factor in the development of chronic thromboembolic pulmonary hypertension (CTEPH). However, the role of endothelial cells (ECs) in CTEPH remains unclear. The aim of this study was to investigate the angiogenic potential of ECs from pulmonary endarterectomy (PEA) specimens., Methods: We isolated ECs from PEA specimens (CTEPH-ECs) and control EC lines from the intact pulmonary arteries of patients with peripheral lung cancers, using a MACS system. These cells were analyzed in vitro including PCR-array analysis, and the PEA specimens were analyzed with immunohistochemistry. Additionally, the serum HGF levels were determined in CTEPH patients., Results: A three-dimensional culture assay revealed that CTEPH-ECs were highly angiogenic. An angiogenesis-focused gene PCR array revealed a high expression of hepatocyte growth factor (HGF) in CTEPH-ECs. The high expression of HGF was also confirmed in the supernatant extracted from PEA specimens. The immunohistochemical analysis showed expression of HGF on the surface of the thrombus vessels. The serum HGF levels in CTEPH patients were higher than those in pulmonary thromboembolism survivors., Conclusion: Our study suggests that there are ECs with pro-angiogenetic character and high expression of HGF in PEA specimens. It remains unknown how these results are attributable to the etiology. However, further investigation focused on the HGF pathway may provide novel diagnostic and therapeutic tools for patients with CTEPH.
- Published
- 2018
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50. Drug abuse and HIV-related pulmonary hypertension: double hit injury.
- Author
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Harter ZJ, Agarwal S, Dalvi P, Voelkel NF, and Dhillon NK
- Subjects
- Humans, Hypertension, Pulmonary pathology, HIV Infections complications, Hypertension, Pulmonary physiopathology, Substance-Related Disorders complications
- Abstract
: Improved survival among HIV-1-infected individuals with the advent of antiretroviral therapy has clearly led to a greater prevalence of noninfectious complications. One of the most devastating sequelae in these individuals is the development of pulmonary arterial hypertension (PAH). Various epidemiological studies suggest worse survival of HIV-PAH patients when compared with other forms of PAH. Given that only a subset and not all HIV-infected individuals develop HIV-PAH, it is suggested that an additional second-hit of genetic or environmental trigger is needed for the development of PAH. In this context, it has been well documented that HIV patients who abuse illicit drugs such as stimulants, opioids, and the like, are more susceptible to develop PAH. In this review, we highlight the studies that support the significance of a double hit of HIV and drug abuse in the incidence of PAH and focus on the research that has been undertaken to unravel the pathobiology and vascular remodeling mechanisms underlying the deleterious synergy between HIV infection and drugs of abuse in orchestrating the development of PAH.
- Published
- 2018
- Full Text
- View/download PDF
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