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Am. J. Respir. Crit. Care Med., Volume 159, Number 6, June 1999, 1925-1932

Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension

RUBIN M. TUDER, CARLYNE D. COOL, MARK W. GERACI, JUN WANG, STEVEN H. ABMAN, LAUREL WRIGHT, DAVID BADESCH, and NORBERT F. VOELKEL

Departments of Pathology, Medicine (Division of Pulmonary Sciences and Critical Care Medicine), and Pediatrics (Divisions of Pediatric Oncology and Pulmonary Medicine), and Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colorado

Prostacyclin is a powerful vasodilator and inhibits platelet adhesion and cell growth. We hypothesized that a decrease in expression of the critical enzyme PGI2 synthase (PGI2-S) in the lung may represent an important manifestation of pulmonary endothelial dysfunction in severe pulmonary hypertension (PH). Immunohistochemistry and Western blot analysis were used to assess lung PGI2-S protein expression, and in situ hybridization was used to assess PGI2-S mRNA expression. In the normal pulmonary circulation (n = 7), PGI2-S was expressed in 48% of small, 67% of medium, and 76% of large pulmonary arteries as assessed by immunohistochemistry. PPH (n = 12), cirrhosis-associated (n = 4) and HIV-associated PH (n = 2) lungs exhibited a marked reduction in PGI2-S expression, involving all size ranges of pulmonary arteries. Vessels with concentric lesions showed complete lack of PGI2-S expression. Congenital heart (n = 4) and CREST (n = 2) cases exhibited a more variable immunohistological pattern of PGI2-S expression. These results were complemented by in situ hybridization and Western blots of representative lung samples. We conclude that the different sizes of the pulmonary arteries express PGI2-S differently and that the loss of expression of PGI2-S represents one of the phenotypic alterations present in the pulmonary endothelial cells in severe PH.




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C. D. Fike, M. R. Kaplowitz, and S. L. Pfister
Arachidonic acid metabolites and an early stage of pulmonary hypertension in chronically hypoxic newborn pigs
Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L316 - L323.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
A. Widlitz and R.J. Barst
Pulmonary arterial hypertension in children
Eur. Respir. J., January 1, 2003; 21(1): 155 - 176.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot
Pathobiology of pulmonary arterial hypertension
Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
L. J. Rubin
Therapy of Pulmonary Hypertension: The Evolution from Vasodilators to Antiproliferative Agents
Am. J. Respir. Crit. Care Med., November 15, 2002; 166(10): 1308 - 1309.
[Full Text] [PDF]

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 CirculationHome page
C. Yokoyama, T. Yabuki, M. Shimonishi, M. Wada, T. Hatae, S. Ohkawara, J. Takeda, T. Kinoshita, M. Okabe, and T. Tanabe
Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction
Circulation, October 29, 2002; 106(18): 2397 - 2403.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
N. Galie, A. Manes, and A. Branzi
The new clinical trials on pharmacological treatment in pulmonary arterial hypertension
Eur. Respir. J., October 1, 2002; 20(4): 1037 - 1049.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
Y. Coe, S. J. Haleen, K. M. Welch, Y.-A. Liu, and F. Coceani
The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb
J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 672 - 680.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
F. C Blumberg, C. Lorenz, K. Wolf, P. Sandner, G. A.J Riegger, and M. Pfeifer
Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension
Cardiovasc Res, July 1, 2002; 55(1): 171 - 177.
[Abstract] [Full Text] [PDF]

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 ChestHome page
K. L. Swanson and M. J. Krowka
Arterial Oxygenation Associated With Portopulmonary Hypertension*
Chest, June 1, 2002; 121(6): 1869 - 1875.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
N. Galie, M. Humbert, J.-L. Vachiery, C. Vizza, M. Kneussl, A. Manes, O. Sitbon, A. Torbicki, M. Delcroix, R. Naeije, et al.
Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial
J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1496 - 1502.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin
New Treatments for Pulmonary Arterial Hypertension
Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216.
[Full Text] [PDF]

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 Eur Respir JHome page
M. Beghetti, G. Reber, P. de Moerloose, L. Vadas, A. Chiappe, I. Spahr-Schopfer, and P.C. Rimensberger
Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation
Eur. Respir. J., March 1, 2002; 19(3): 518 - 524.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
P. DORFMULLER, V. ZARKA, I. DURAND-GASSELIN, G. MONTI, K. BALABANIAN, G. GARCIA, F. CAPRON, A. COULOMB-LHERMINE, A. MARFAING-KOKA, G. SIMONNEAU, et al.
Chemokine RANTES in Severe Pulmonary Arterial Hypertension
Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 534 - 539.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
R. M. Tuder and A. L. Zaiman
Prostacyclin Analogs as the Brakes for Pulmonary Artery Smooth Muscle Cell Proliferation . Is It Sufficient to Treat Severe Pulmonary Hypertension?
Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 171 - 174.
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 Am. J. Respir. Cell Mol. Bio.Home page
L. H. Clapp, P. Finney, S. Turcato, S. Tran, L. J. Rubin, and A. Tinker
Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle Proliferation and Cyclic AMP Generation in Human Pulmonary Artery
Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 194 - 201.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
R. L. Keith, Y. E. Miller, Y. Hoshikawa, M. D. Moore, T. L. Gesell, B. Gao, A. M. Malkinson, H. A. Golpon, R. A. Nemenoff, and M. W. Geraci
Manipulation of Pulmonary Prostacyclin Synthase Expression Prevents Murine Lung Cancer
Cancer Res., February 1, 2002; 62(3): 734 - 740.
[Abstract] [Full Text] [PDF]

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 ChestHome page
D. H. Roberts, J. J. Lepore, A. Maroo, M. J. Semigran, and L. C. Ginns
Oxygen Therapy Improves Cardiac Index and Pulmonary Vascular Resistance in Patients With Pulmonary Hypertension
Chest, November 1, 2001; 120(5): 1547 - 1555.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. D. Fike, M. R. Kaplowitz, and M. Bousamra II
eNOS and prostanoid enzymes in lungs of newborn piglets with chronic aortopulmonary shunts
Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L475 - L482.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
R. M. F. BERGER, R. GEIGER, J. HESS, A. J. J. C. BOGERS, and W. J. MOOI
Altered Arterial Expression Patterns of Inducible and Endothelial Nitric Oxide Synthase in Pulmonary Plexogenic Arteriopathy Caused by Congenital Heart Disease
Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1493 - 1499.
[Abstract] [Full Text]

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 Circ. Res.Home page
M. W. Geraci, M. Moore, T. Gesell, M. E. Yeager, L. Alger, H. Golpon, B. Gao, J. E. Loyd, R. M. Tuder, and N. F. Voelkel
Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension : A Gene Microarray Analysis
Circ. Res., March 30, 2001; 88(6): 555 - 562.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
J. Wharton, N. Davie, P. D. Upton, M. H. Yacoub, J. M. Polak, and N. W. Morrell
Prostacyclin Analogues Differentially Inhibit Growth of Distal and Proximal Human Pulmonary Artery Smooth Muscle Cells
Circulation, December 19, 2000; 102(25): 3130 - 3136.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
N. Nagaya, C. Yokoyama, S. Kyotani, M. Shimonishi, R. Morishita, M. Uematsu, T. Nishikimi, N. Nakanishi, T. Ogihara, M. Yamagishi, et al.
Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats
Circulation, October 17, 2000; 102(16): 2005 - 2010.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
E. S. YI, H. KIM, H. AHN, J. STROTHER, T. MORRIS, E. MASLIAH, L. A. HANSEN, K. PARK, and P. J. FRIEDMAN
Distribution of Obstructive Intimal Lesions and Their Cellular Phenotypes in Chronic Pulmonary Hypertension . A Morphometric and Immunohistochemical Study
Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1577 - 1586.
[Abstract] [Full Text] [PDF]

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 Physiol. Rev.Home page
V. Hampl and J. Herget
Role of Nitric Oxide in the Pathogenesis of Chronic Pulmonary Hypertension
Physiol Rev, October 1, 2000; 80(4): 1337 - 1372.
[Abstract] [Full Text] [PDF]

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 GutHome page
M J KROWKA
Hepatopulmonary syndromes
Gut, January 1, 2000; 46(1): 1 - 4.
[Full Text] [PDF]

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 Am. J. Pathol.Home page
C. D. Cool, J. S. Stewart, P. Werahera, G. J. Miller, R. L. Williams, N. F. Voelkel, and R. M. Tuder
Three-Dimensional Reconstruction of Pulmonary Arteries in Plexiform Pulmonary Hypertension Using Cell-Specific Markers : Evidence for a Dynamic and Heterogeneous Process of PulmonaryEndothelial Cell Growth
Am. J. Pathol., August 1, 1999; 155(2): 411 - 419.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
D. Langleben, R. J. Barst, D. Badesch, B. M. Groves, V. F. Tapson, S. Murali, R. C. Bourge, N. Ettinger, E. Shalit, L. M. Clayton, et al.
Continuous Infusion of Epoprostenol Improves the Net Balance Between Pulmonary Endothelin-1 Clearance and Release in Primary Pulmonary Hypertension
Circulation, June 29, 1999; 99(25): 3266 - 3271.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
D. D. Ivy, M. Yanagisawa, C. E. Gariepy, S. A. Gebb, K. L. Colvin, and I. F. McMurtry
Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats
Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L703 - L712.
[Abstract] [Full Text] [PDF]


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