Development of chronic pulmonary hypertension (CPH) may be associated with long standing inflammation of the lung. Under such circumstances, the hypertension not only complicates effective treatment of the disorder but may also become the principal problem. To develop effective treatment of this disease, we must first understand its pathogenesis at physiologic, biochemical, structural, cellular, and molecular levels. In this application, we propose to test the hypothesis that acute inflammation of the lung causes microvascular endothelial injury, granulocyte sequestration, vasoconstriction and decreased peripheral vascular volume. These inflammation mediated changes lead to increased pulmonary vascular pressures and, eventually, to the onset of sustained pulmonary hypertension and the characteristic structural remodelling of large and small pulmonary arteries. We further propose that neutrophil elastase and endothelin-1 (ET-1) contribute to the development of CPH, elastase playing a role in the early inflammatory changes and ET-1, by acting as an early and a sustained vasoconstrictor, as well as one of several growth factors responsible for structural remodelling of the arteries. To test these hypotheses, we will conduct studies mainly in a large animal model of CPH, the chronically catheterized sheep receiving continuous air embolization. We propose experiments to test the following: 1) Determine whether administration of the elastase inhibitor, recombinant secretory leukocyte proteinase inhibitor, rSLPI, alters the functional and structural changes of CPH; 2) Determine whether rSLPI alters elastin homeostasis in the lung during the development of CPH; 3) Explore the effects of rSLPI on the cellular localization of elastin mRNA in large and small pulmonary arteries, and alveolar walls; 4) Determine the localization of aerosolized rSLPI in the normal lung and assess its site of action during the onset of CPH; 5) Determine whether endothelin plays a role in the pulmonary vasoconstriction and vascular remodelling of CPH; 6) Determine whether ET-1 regulates pulmonary vascular cell growth in vitro and stimulates elastin synthesis; 7) Initiate studies, in rats, to determine whether hyperexpression of ET-1 in the lung's vasculature leads to the functional and structural changes of CPH. Such information will contribute to our understanding of the pathogenesis of CPH and ultimately to development of novel therapies for treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048536-03
Application #
2224606
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-06-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Fratz, Sohrab; Meyrick, Barbara; Ovadia, Boaz et al. (2004) Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure. Am J Physiol Lung Cell Mol Physiol 287:L592-7
Chen, Daohong; Balyakina, Elena V; Lawrence, Mayme et al. (2003) Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 284:L614-21
Balyakina, Elena V; Chen, Daohong; Lawrence, Mayme L et al. (2002) ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery. Am J Physiol Lung Cell Mol Physiol 283:L42-51
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Johnson, J E; Perkett, E A; Meyrick, B (1997) Pulmonary veins and bronchial vessels undergo remodeling in sustained pulmonary hypertension induced by continuous air embolization into sheep. Exp Lung Res 23:459-73
Michel, R P; Hu, F; Meyrick, B O (1995) Myoendothelial junctional complexes in postobstructive pulmonary vasculopathy: a quantitative electron microscopic study. Exp Lung Res 21:437-52

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