Premature birth is a major health care problem, affecting approximately 12% of all births and contributing to more than 85% of all perinatal complications and deaths. Survival of very low birth weight (VLBW) infants has increased, however, these infants remain at risk for long-term medical problems including neurocognitive impairment and bronchopulmonary dysplasia (BPD). Each year 15,000 newborns develop BPD, a chronic lung disease that affects VLBW infants (<1500 grams) who need long-term mechanical ventilation and oxygen therapy. The subsequent lung injuries impair the growth and development of the airways and pulmonary vasculature, leading to a decrease in the air exchanging units of the lung and fewer blood vessels that can participate in exchanging CO2 and O2. Unfortunately, little is known about the long-term cardiopulmonary consequences of BPD. We postulate that a compromised lung vasculature, present in newborns with BPD, will persist to some extent as these patients age. We expect that children and adults with a history of BPD will have abnormal pulmonary vascular function, particularly when the lungs are challenged, which will place excess stress on the right heart. We anticipate that abnormal pulmonary vascular-right heart interactions in BPD will cause right heart dysfunction and increase the potential for right heart failure in adults with a history of BPD. In this grant we am to determine the impact of BPD on 1) the pulmonary vasculature, 2) right heart function, and 3) the efficiency with which the right heart and pulmonary vasculature interact. To accomplish these aims, we will study humans with and without a history of BPD as well as a rat BPD model. We have access to two unique human cohorts (born in 1988-1991 and 2003) of serially followed VLBW infants, which will allow us to assess the impact of prematurity and early life events on the progression of right heart and pulmonary vascular dysfunction into childhood and early adulthood. To answer our questions, we propose to use a combination of state-of-the-art MR imaging, right heart catheterization, 3D echocardiography and exercise to reveal any abnormalities in the pulmonary vasculature, right heart, and their interactions in our BPD cohort compared to healthy, controls. In our animal model, we will assess the hemodynamic impact of BPD in both intact rats and isolated rat lungs. Furthermore, we will determine at cellular and molecular levels how BPD affects the contractility of the right heart, through length- tension experiments and protein analysis. We expect that our findings will be exciting to clinicians who care for the growing population of those with BPD, biomedical engineers interested in novel diagnostic and prognostic indicators based on cardiopulmonary hemodynamics, and scientists investigating the causes and consequences of right ventricular failure in chronic lung diseases.
A too frequent consequence of premature birth is a chronic lung disease known as bronchopulmonary dysplasia (BPD). A group of well-studied very low birth weight infants (1-3 pounds), including those who did and did not develop BPD, are now reaching adulthood. We have a unique and important opportunity to investigate the consequences of BPD on lung and right heart function in this population, which will inform treatment strategies and predictions of disease progression in the future.
|Braun, Rudolf K; Broytman, Oleg; Braun, Felix M et al. (2018) Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats. Respir Physiol Neurobiol 256:97-108|
|Braun, Rudolf K; Chetty, Chandramu; Balasubramaniam, Vivek et al. (2018) Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia. Biochem Biophys Res Commun 503:2653-2658|
|Bates, Melissa L; Anagnostopoulos, Petros V; Nygard, Cole et al. (2018) Consequences of an early catheter-based intervention on pulmonary artery growth and right ventricular myocardial function in a pig model of pulmonary artery stenosis. Catheter Cardiovasc Interv :|
|Patel, Jitandrakumar R; Barton, Gregory P; Braun, Rudolf K et al. (2017) Altered Right Ventricular Mechanical Properties Are Afterload Dependent in a Rodent Model of Bronchopulmonary Dysplasia. Front Physiol 8:840|
|Goss, Kara N; Kumari, Santosh; Tetri, Laura H et al. (2017) Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis. Am J Respir Cell Mol Biol 56:609-619|
|Fain, Sean B; Eldridge, Marlowe W (2017) Exploring new heights with pulmonary functional imaging: insights into high-altitude pulmonary edema. J Appl Physiol (1985) 122:853-854|
|Bates, Melissa L; Farrell, Emily T; Eldridge, Marlowe W (2014) Abnormal ventilatory responses in adults born prematurely. N Engl J Med 370:584-5|
|Bates, Melissa L; Pillers, De-Ann M; Palta, Mari et al. (2013) Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia. Respir Physiol Neurobiol 189:329-37|