Nitric Oxide in Pulmonary Hypertension

Summary

Principal Investigator: Serpil Erzurum
Abstract: DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure (PAP) and abnormalities in blood vessel growth. The excessive growth of the vascular endothelial cells is the focus of our research. Four years ago, we established methods for culture of pulmonary artery endothelial cells (PAEC) from PAH and donor lungs. The PAEC in culture reflect abnormalities found in PAH lungs and patients in vivo, and made it possible to test our hypotheses in translational mechanistic studies. We found that PAH PAEC have enhanced proliferation &survival, which is dependent on activation of signal transducer and activator of transcription-3 (STAT3), a fundamental regulator of cell survival and angiogenesis. The PAH cells have impaired production of the vasodilator nitric oxide (NO) due to post- translational mechanisms that include phosphorylation/inhibition of endothelial NO synthase (eNOS). In association with low NO, the cells have reduced mitochondria numbers &respiration, which is accompanied by ~3-fold increase in glycolysis for energy production. The shift to anaerobic glycolytic metabolism is related to expression of the pro-survival and pro-angiogenic signal transducer, hypoxia-inducible factor -1a (HIF-1a). Physiologic effects classically ascribed to HIF-expression [increased lung glucose uptake by 18F- fluoro-deoxy-glucose analogue - positron emission tomography (FDG-PET), high-levels of plasma erythropoietin (Epo) and mobilization of bone marrow progenitors] are present in patients and quantitatively associated with PAP. The HIF-expression is mechanistically linked to the alterations in STAT3, NO and Mn superoxide dismutase (MnSOD). Preliminary data show that the PAH PAEC secrete the potent growth- stimulatory &bone marrow-mobilizing hepatocyte growth factor (HGF). Present at high-levels in patient plasma and PAH cell cultures, HGF signals through STAT3 and induces HIF-1a, and is itself induced by STAT3 and increased by hypoxia, which endows the cells with autocrine and paracrine proliferative and pro-angiogenic effects. Here, we hypothesize that PAH endothelial cells have decreased NO production by eNOS and activation of survival pathways STAT3 and HIF-1a. These biochemical mechanisms account for the proliferative, glycolytic, and strongly pro-angiogenic phenotype of the cells. We identify mechanisms of reduced eNOS activity in aim 1, and focus on HIF-expression and mechanisms accounting for its expression in aim 2. In aim 3, we test if HIF-expression is mechanistically important in PAH pathophysiology using the primary cell culture model, a xenograft model of PAH cells in immunodeficient mice and a longitudinal clinical study, in which we test whether experimental outcomes of HIF-effects are associated with clinical outcomes in patients over time. Overall our goals are to define the pathophysiology of the abnormal vascular growth in PAH, and in so doing, apply the knowledge to improve the care of patients. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure and abnormalities in blood vessel growth. The excessive growth of the endothelial cells that line the blood vessels in the lungs of patients afflicted with PAH is the focus of our research. Our studies provide evidence for biochemical and metabolic abnormalities in vascular endothelial cells in PAH, and identify the causal molecular mechanisms. We have found that the PAH endothelial cells have lower than normal production of the vasoregulatory gaseous molecule nitric oxide (NO), and use more than 3-fold greater amounts of glucose for energy production than normal cells. On the basis of our findings, we propose basic biochemical studies, and also test whether measures of glucose uptake in the lung using intravenously injected glucose analogues and positron emission tomography (FDG-PET) are useful to assess lung vascular disease in patients over time. Our goals in this competitive renewal are to define the pathophysiology of the abnormal vascular growth, and in so doing, apply the knowledge to improve the care of patients.
Funding Period: 1999-04-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungs
    Ana Fernandez-Bustamante
    From the Department of Anesthesiology and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado A F B Department of Anesthesiology and iC42 Integrated Solutions in Systems Biology, University of Colorado School of Medicine, Aurora, Colorado J K, U C Department of Medicine and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado J E R Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado A A, T S Department of Pathobiology and Lerner Research Institute NC22, the Cleveland Clinic Foundation and Case Western Reserve University School of Medicine, Cleveland, Ohio A J J, S C E Case Western Reserve University School of Medicine, Cleveland, Ohio C S Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado M M, I S D and Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado Z V T
    Anesthesiology 121:469-81. 2014
  2. ncbi Deficiency of lung antioxidants in idiopathic pulmonary arterial hypertension
    Fares A Masri
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA
    Clin Transl Sci 1:99-106. 2008
  3. pmc Nitric oxide in adaptation to altitude
    Cynthia M Beall
    Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106, USA
    Free Radic Biol Med 52:1123-34. 2012
  4. pmc Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension
    Jun Yu
    Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Cell Physiol 228:322-9. 2013
  5. pmc Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension
    Kewal Asosingh
    Pathobiology, Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Blood 120:1218-27. 2012
  6. pmc High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4
    Eileen M Bauer
    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, United States of America
    Mol Med 18:1509-18. 2012
  7. pmc Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension
    Samar Farha
    Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Respir Res 14:6. 2013
  8. pmc Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year
    Erika L Lundgrin
    Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
    Ann Am Thorac Soc 10:1-9. 2013
  9. pmc A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension
    Monal Patel
    Department of Pharmacology, Rush University Medical Center, Chicago, Illinois 60612, USA
    J Biol Chem 288:25701-16. 2013
  10. pmc Relevant issues in the pathology and pathobiology of pulmonary hypertension
    Rubin M Tuder
    Program in Translational Lung Research, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado Electronic address
    J Am Coll Cardiol 62:D4-12. 2013

Scientific Experts

  • Kewal Asosingh
  • Samar Farha
  • Suzy A A Comhair
  • T Peikert
  • Brian D Hoit
  • Weiling Xu
  • Jean Pierre Yared
  • Cynthia M Beall
  • Steven B Cannady
  • Serpil C Erzurum
  • Eileen M Bauer
  • Fares A Masri
  • Rubin M Tuder
  • Arnaud Chambellan
  • Serpil Erzurum
  • Philip M Bauer
  • Raed A Dweik
  • Sudakshina Ghosh
  • Ana Fernandez-Bustamante
  • Mark E Lauer
  • Monal Patel
  • Erika L Lundgrin
  • Jun Yu
  • Allison J Janocha
  • Timothy R Billiar
  • W H Wilson Tang
  • Jacqueline Sharp
  • Han Zheng
  • James D Thomas
  • Archana Gangopahyay
  • Heng T Duong
  • Kylie M Drake
  • Ilka Decker
  • Margaret Park
  • Iwona Fijalkowska
  • Sarinya Puwanant
  • Katalin Szabo
  • Paul J Cruickshank
  • David E Nethery
  • S C Erzurum
  • Allison Janocha
  • Vincent C Hascall
  • Metin Aytekin
  • Marc Moss
  • Uwe Christians
  • Amanda Agazio
  • Liping Tian
  • Chirag Shah
  • Tamas Seres
  • Carol F Farver
  • Jacqueline Loftis
  • John E Repine
  • Ivor S Douglas
  • Zung Vu Tran
  • Jelena Klawitter
  • Minhua Wang
  • Iva Dostanic
  • Stephen L Archer
  • Peter Polgar
  • Ralph Schermuly
  • Aliya Husain
  • Sangeeta Bhorade
  • Anna Ryan-Hemnes
  • Peter Dorfmuller
  • Evangelos Michelakis
  • Jiwang Chen
  • Dan Predescu
  • Laura Davis
  • Marlene Rabinovitch
  • Christophe Guignabert
  • Brian B Graham
  • Donald R Neumann
  • Sanda Predescu
  • Margaret M Park
  • Rajive Tandon
  • Kurt R Stenmark
  • Jennifer Pogoriler
  • Cristina Bardita
  • Roberto Machado
  • Anna Ryan Hemnes
  • Jamie Wilson
  • Frank P DiFilippo
  • Nicholas W Morrell
  • Linda Taylor
  • David Ishizawar
  • Ferhaan Ahmad
  • Richard Shapiro
  • Phyllis Harbor
  • Jeffrey W Wertz
  • Wai Hong Wilson Tang

Detail Information

Publications43

  1. ncbi Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungs
    Ana Fernandez-Bustamante
    From the Department of Anesthesiology and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado A F B Department of Anesthesiology and iC42 Integrated Solutions in Systems Biology, University of Colorado School of Medicine, Aurora, Colorado J K, U C Department of Medicine and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado J E R Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado A A, T S Department of Pathobiology and Lerner Research Institute NC22, the Cleveland Clinic Foundation and Case Western Reserve University School of Medicine, Cleveland, Ohio A J J, S C E Case Western Reserve University School of Medicine, Cleveland, Ohio C S Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado M M, I S D and Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado Z V T
    Anesthesiology 121:469-81. 2014
    ..The authors aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications...
  2. ncbi Deficiency of lung antioxidants in idiopathic pulmonary arterial hypertension
    Fares A Masri
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA
    Clin Transl Sci 1:99-106. 2008
    ..04). Pulmonary artery pressure (PAP) could be predicted by a regression model incorporating SOD, GPx, and NO(3) values (R(2)= 0.96, p= 0.01). These findings suggest that SOD and GPx are associated with alterations in NO and PAP in IPAH...
  3. pmc Nitric oxide in adaptation to altitude
    Cynthia M Beall
    Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106, USA
    Free Radic Biol Med 52:1123-34. 2012
    ..Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress...
  4. pmc Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension
    Jun Yu
    Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Cell Physiol 228:322-9. 2013
    ..Importantly, the data suggest that caution must be taken when applying ET-1 receptor antagonist therapy to PAH patients...
  5. pmc Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension
    Kewal Asosingh
    Pathobiology, Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Blood 120:1218-27. 2012
    ..The results of the present study suggest a causal role for hematopoietic stem cell abnormalities in vascular injury, right ventricular hypertrophy, and morbidity associated with PAH...
  6. pmc High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4
    Eileen M Bauer
    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, United States of America
    Mol Med 18:1509-18. 2012
    ..These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH...
  7. pmc Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension
    Samar Farha
    Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Respir Res 14:6. 2013
    ....
  8. pmc Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year
    Erika L Lundgrin
    Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
    Ann Am Thorac Soc 10:1-9. 2013
    ....
  9. pmc A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension
    Monal Patel
    Department of Pharmacology, Rush University Medical Center, Chicago, Illinois 60612, USA
    J Biol Chem 288:25701-16. 2013
    ..Our findings identify a novel GrB-EH(ITSN)-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH...
  10. pmc Relevant issues in the pathology and pathobiology of pulmonary hypertension
    Rubin M Tuder
    Program in Translational Lung Research, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado Electronic address
    J Am Coll Cardiol 62:D4-12. 2013
    ..Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. ..
  11. pmc Modification of hyaluronan by heavy chains of inter-α-inhibitor in idiopathic pulmonary arterial hypertension
    Mark E Lauer
    From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195
    J Biol Chem 289:6791-8. 2014
    ..CD45-positive leukocytes were identified within these HC-HA matrices. Elevated mRNA levels of the enzyme that transfers HCs to HA, known as tumor necrosis factor-stimulated gene 6, were detected in IPAH lung tissue. ..
  12. pmc Allergen-induced, eotaxin-rich, proangiogenic bone marrow progenitors: a blood-borne cellular envoy for lung eosinophilia
    Kewal Asosingh
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA and
    J Allergy Clin Immunol 125:918-25. 2010
    ....
  13. pmc Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities
    Samar Farha
    Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Blood 117:3485-93. 2011
    ....
  14. pmc Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation
    Heng T Duong
    Department of Pathobiology, NC22, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Angiogenesis 14:411-22. 2011
    ..This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH...
  15. pmc Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation
    Archana Gangopahyay
    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 286:33134-40. 2011
    ..These data demonstrate a new action of BMPs/BMPRII in the pulmonary endothelium and provide novel mechanistic insight into the pathogenesis of PAH...
  16. pmc High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertension
    Ilka Decker
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
    Clin Transl Sci 4:253-8. 2011
    ..This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients...
  17. pmc Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8
    Kylie M Drake
    Genomic Medicine Institute, Cleveland Clinic, OH 44195, USA
    Am J Respir Crit Care Med 184:1400-8. 2011
    ..We therefore hypothesized that noncanonical pathways may play an important role in PAH...
  18. pmc Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice
    Eileen M Bauer
    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 6:e28578. 2011
    ..The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension...
  19. pmc Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells
    Iwona Fijalkowska
    Department of Pathology, Johns Hopkins Univesity School of Medicine, Baltimore, MD, USA
    Am J Pathol 176:1130-8. 2010
    ..These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1alpha expression and account for lower numbers of mitochondria in IPAH-ECs...
  20. pmc Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension
    Sarinya Puwanant
    Department of Cardiovascular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Circulation 121:259-66. 2010
    ..We tested the hypothesis that right ventricular (RV) pressure overload affects RV function and further influences left ventricular (LV) geometry, which adversely affects LV twist mechanics and segmental function...
  21. pmc Pivotal role of c-Fos in nitric oxide synthase 2 expression in airway epithelial cells
    Arnaud Chambellan
    INSERM, UMR915, l institut du thorax, Nantes F 44000, France
    Nitric Oxide 20:143-9. 2009
    ..Overall, these studies indicate that c-Fos is a requisite and specific component for inducible NOS2 expression...
  22. pmc Elevated pulmonary artery pressure among Amhara highlanders in Ethiopia
    Brian D Hoit
    Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 7125, USA
    Am J Hum Biol 23:168-76. 2011
    ..The objective of this study was to identify the consequences of lifelong hypoxia exposure for the pulmonary vasculature among Amhara high-altitude natives from Ethiopia...
  23. ncbi Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders
    Brian D Hoit
    Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106 5038, USA
    J Appl Physiol (1985) 99:1796-801. 2005
    ....
  24. pmc Abnormalities in nitric oxide and its derivatives in lung cancer
    Fares A Masri
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Am J Respir Crit Care Med 172:597-605. 2005
    ..Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer...
  25. ncbi Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis
    Tobias Peikert
    Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Cancer Res 66:4693-700. 2006
    ..028) in 293/MAGE-A4 cells. These findings suggest that MAGE-A4 expression may promote tumor cell death, sensitize malignancies to apoptotic stimuli, such as chemotherapeutic agents, and therefore may represent a tumor suppressor protein...
  26. pmc Gene expression profile of human airway epithelium induced by hyperoxia in vivo
    Arnaud Chambellan
    Institut du Thorax, INSERM U533, Faculte de Medecine, Nantes, France
    Am J Respir Cell Mol Biol 35:424-35. 2006
    ..Thus, the human airway early response to hyperoxia relies predominantly upon induction of cytoprotective chaperones and the ubiquitin-proteasome-dependent protein degradation system to maintain airway homeostatic integrity...
  27. ncbi Role of epithelial nitric oxide in airway viral infection
    Weiling Xu
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, NC 20, Cleveland, OH 44195, USA
    Free Radic Biol Med 41:19-28. 2006
    ..Hosts deficient in NO synthesis, such as those patients with cystic fibrosis, have impaired antiviral defense and may benefit from therapies to augment NO levels in the airways...
  28. ncbi Inactivation of neuregulin-1 by nitration
    David E Nethery
    Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals of Cleveland, Wearn 610, 11100 Euclid Avenue, Cleveland, OH 44106, USA
    Am J Physiol Lung Cell Mol Physiol 292:L287-93. 2007
    ..Posttranslational nitration of growth factors in states where reactive nitrogen species are increased may be an important means of regulating growth factor receptor effects in the lung...
  29. ncbi Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trial
    Jean Pierre Yared
    Department of Cardiothoracic Anesthesiology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Cardiothorac Vasc Anesth 21:68-75. 2007
    ..The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occurrence of postoperative atrial fibrillation (AF)...
  30. ncbi Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthma
    Kewal Asosingh
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Immunol 178:6482-94. 2007
    ..Thus, a Th1- and Th2-dependent angiogenic switch with EPC mobilization, recruitment, and increased lung vessel formation occurs early but becomes a sustained and cumulative component of the allergen-induced asthmatic response...
  31. pmc Two routes to functional adaptation: Tibetan and Andean high-altitude natives
    Cynthia M Beall
    Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106, USA
    Proc Natl Acad Sci U S A 104:8655-60. 2007
    ..Identifying the genetic bases of these traits is crucial to discovering the steps along the Tibetan and Andean routes to functional adaptation...
  32. ncbi Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension
    Fares A Masri
    Department of Pathobiology, Allergy and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Am J Physiol Lung Cell Mol Physiol 293:L548-54. 2007
    ..Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs...
  33. pmc Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle
    Samar Farha
    Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, Cleveland, OH, USA
    J Appl Physiol 103:1789-95. 2007
    ..These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle...
  34. ncbi Signal transduction and oxidative processes in sinonasal polyposis
    Steven B Cannady
    Head and Neck Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Allergy Clin Immunol 120:1346-53. 2007
    ..Based on its critical role in mediating cell growth and antimicrobial function, decrease of NO levels has been implicated in the pathogenesis of nasal polyposis...
  35. pmc Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans
    S C Erzurum
    Department of Pathobiology, Allergy, and Critical Care, Cleveland Clinic, Cleveland, OH 44195, USA
    Proc Natl Acad Sci U S A 104:17593-8. 2007
    ..These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia...
  36. pmc Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension
    Kewal Asosingh
    Cleveland Clinic, Department of Pathobiology, NC22, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Am J Pathol 172:615-27. 2008
    ..Thus, mobilization of high levels of proliferative bone marrow-derived proangiogenic precursors is a characteristic of IPAH and may participate in the pulmonary vascular remodeling process...
  37. pmc Effects of the menstrual cycle on lung function variables in women with asthma
    Samar Farha
    Respiratory Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Am J Respir Crit Care Med 180:304-10. 2009
    ..One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed...
  38. pmc Angioplasticity in asthma
    Kewal Asosingh
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Biochem Soc Trans 37:805-10. 2009
    ..This mini review provides a concise synopsis of our present knowledge about vascular plasticity in adult lungs, summarizes our current view of angioplasticity in asthma and highlights yet unresolved areas of potential interest...
  39. ncbi The regulation and role of extracellular glutathione peroxidase
    Suzy A A Comhair
    Department of Pulmonary and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
    Antioxid Redox Signal 7:72-9. 2005
    ..Induction of extracellular glutathione peroxidase occurs in airway inflammation and undoubtedly plays an important defense against oxidative injury to the airway surface...