Abstract

Prostacyclin has potent vasodilatory, antiaggregatory, antiinflammatory, and antiproliferative properties. In severe human pulmonary hypertension, the lung is deficient in PGI2-synthase. The overall goal of the planned research is to gather critical information required to understand the etiology of the PGI2 synthase impairment of pulmonary hypertensive vessels. The knowledge gained may lead to new, rational treatment strategies for severely hypertensive patients. The current proposal will examine strategies leading to increased PGI2 synthesis via gene therapy. The idea will be tested that mice which overexpress PGI2 synthase in a lung specific manner develop less pulmonary hypertension after exposure to hypoxia than their wild-type counterparts. Lung endothelial cells and airway cells of rats also will be transfected with the PGI2 synthase gene and their response to hypoxia examined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL043180-04A2
Application #
2486027
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1992-07-13
Project End
2002-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Hoshikawa, Yasushi; Nana-Sinkam, Patrick; Moore, Mark D et al. (2003) Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 12:209-19
Keith, Robert L; Miller, York E; Hoshikawa, Yasushi et al. (2002) Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res 62:734-40
Hoshikawa, Y; Voelkel, N F; Gesell, T L et al. (2001) Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med 164:314-8
Tuder, R M; Cool, C D; Yeager, M et al. (2001) The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 22:405-18
Geraci, M W; Gao, B; Shepherd, D C et al. (1999) Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 103:1509-15
Tuder, R M; Cool, C D; Geraci, M W et al. (1999) Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159:1925-32
Silliman, C C; Voelkel, N F; Allard, J D et al. (1998) Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 101:1458-67
Kaminsky, D A; Jones, K; Schoene, R B et al. (1996) Urinary leukotriene E4 levels in high-altitude pulmonary edema. A possible role for inflammation. Chest 110:939-45
Wade, M L; Voelkel, N F; Fitzpatrick, F A (1995) ""Suicide"" inactivation of prostaglandin I2 synthase: characterization of mechanism-based inactivation with isolated enzyme and endothelial cells. Arch Biochem Biophys 321:453-8
Voelkel, N F; Lobel, K; Westcott, J Y et al. (1995) Nitric oxide-related vasoconstriction in lungs perfused with red cell lysate. FASEB J 9:379-86

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