Pulmonary hypertension which occurs in newborn infants is a serious disorder of unknown cause. Treatment is unsatisfactory because the mortality is high and survivors often have disabling reactive airway disease. Because the manifestations of the disease, i.e., pulmonary hypertension, bronchoconstriction, and pulmonary edema, are reminiscent of the actions of certain lipids, the leukotrienes, it is possible that leukotrienes and/or related lipids such as prostanoids and platelet activating factor (PAF) are involved in the pathogenesis. Some of these substances (PAF, leukotrienes, thromboxane) constrict airways and vessels, while others (prostacyclin) act as dilators. The working hypothesis for this proposal is that an excess of constrictor substances and/or a deficiency of dilator substances cause the disease process. The approach is, first, to determine in animal models of pulmonary hypertension whether the appearance (or disappearance) of these lipids are related to the pulmonary hypertension, and whether inhibitors will block both the lipid substances and the hypertension. This approach will be followed in newborn calves made hypertensive at high altitude (our hypoxia model) and in rats given the pyrrolizidine alkaloid, monocrotaline (our lung injury model). Also if the lipids under consideration cause persistence of hypertension after birth they could be involved in maintaining high pulmonary vascular resistance in the calf at high altitude prior to birth. The approach, second, is to determine whether an analysis of lung lavage from affected infants yield values appropriate for the course of the illness. If the study suggested possible mechanisms of the hypertension and perhaps indicated better modes of therapy, it would make a contribution to the care of newborns with persistent pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001503-04
Application #
3081873
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Inscore, S C; Stenmark, K R; Orton, C et al. (1991) Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia. J Appl Physiol 70:384-90
Durmowicz, A G; St Cyr, J A; Clarke, D R et al. (1990) Unilateral pulmonary hypertension as a result of chronic high flow to one lung. Am Rev Respir Dis 142:230-3
Graham, L M; Vasil, A; Vasil, M L et al. (1990) Decreased pulmonary vasoreactivity in an animal model of chronic Pseudomonas pneumonia. Am Rev Respir Dis 142:221-9
Bakerman, P R; Stenmark, K R; Fisher, J H (1990) Alpha-skeletal actin messenger RNA increases in acute right ventricular hypertrophy. Am J Physiol 258:L173-8
Dempsey, E C; Stenmark, K R; McMurtry, I F et al. (1990) Insulin-like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways. J Cell Physiol 144:159-65
Orton, E C; Reeves, J T; Stenmark, K R (1988) Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension. J Appl Physiol 65:2459-67