Persistent pulmonary hypertension of the newborn is poorly understood although gestational long term hypoxia is a significant risk factor in its development as infants born at high altitude have as much as 100-fold increased risk of developing disease. Recent studies illustrate that high altitude newborn lambs have elevated baseline pulmonary artery pressures and greater increases in pulmonary artery pressure in response to acute hypoxia. Even though the underlying mechanisms remain largely unknown, high altitude fetal and newborn sheep have cardio-pulmonary problems that are similar to human infants and consistent with the development of pulmonary hypertension including right heart cardiomyopathy and reduced pulmonary vasodilation. High altitude exposure can enhance anaerobic glycolysis, depress aerobic metabolism as well as induce oxidative stress and promote inflammation. These fundamental changes in cellular metabolism, and underlying changes in protein expression may provide unique metabolic signatures and contribute in novel ways to the development of pulmonary hypertension in the newborn.
In Specific Aim 1 the proposed study will test the hypothesis that LTH results in discernable differences in primary metabolism, oxidative stress and inflammation that will be detected in the metabolic profile and proteins found in the plasma of the fetus and newborn.
Specific Aim 2 will then test the hypothesis that LTH modifies pulmonary vascular development impacting primary metabolism and augmenting oxidative stress and inflammation. Plasma and pulmonary arterial samples isolated from near term fetal, two-week -old newborn lambs, and adult sheep maintained near sea level (300 m) or at high altitude (3,801 m) will be used to test these hypotheses. Proteomic analysis and metabolomics profiling will then be performed, including untargeted metabolic profiling of energy metabolism and targeted analysis for endocannabinoids and oxylipins, which markers of oxidative stress and inflammation. The findings of these studies will provide groundwork to advance our knowledge of the biomarkers associated with gestational hypoxia-induced pulmonary hypertension in the newborn and improve our understanding of pathophysiological mechanisms underlying the development of disease. These studies will provide new insights and a proof of concept regarding the development of new diagnostic biomarkers for detection of pulmonary hypertension in the newborn. The studies will also bring to light potential therapeutic strategies that may be beneficial for the treatment of infants with pulmonary hypertension. This is of critical importance given the extreme limit of effective therapeutic intervention currently available for this important clinical problem in newborns.
The investigations we propose help provide a mechanistic basis for the role of long-term intrauterine hypoxia in the development of pulmonary hypertension in the newborn. The goal of these studies is to relate changes in metabolism due to hypoxic stress to disease pathogenesis. Such results will provide an important positive impact as ryanodine receptors provide novel targets for therapeutic interventions.
