Led by a bench scientist with expertise in structural biochemistry and a physician neonatologist-researcher, our pulmonology group has a focus on three areas of lung development and lung disease in premature infants. The first of these is the study of lung surfactant associated proteins that are essential for normal lung function and preventing collapse of the air spaces in the lung. Most premature infants born six or more weeks early are deficient or lacking the most essential surfactant protein, referred to as Surfactant Protein B, or SP-B, and must be given surfactant mixtures derived from cow or pig lungs to improve survival and long term lung health. The goal of this area of research is to establish alternative approaches that would allow the infant to produce and secrete its own surfactant and make use of animal derived products unnecessary.
A second area of research involves the study of oxygen sensing proteins and pathways in alveolar cells and responses to low oxygen tensions observed during lung development or lung collapse. A very unique discovery by our lab is that pulmonary alveolar cells that are responsible for production of surfactant produce hemoglobin when exposed to conditions of low oxygen. Low oxygen tensions occur in several situations, including during lung development, as a result of specific lung diseases, and lung collapse. We aim to determine the role of hemoglobin in surfactant production by these cells. The third area of research focuses on the production of bioengineered scaffolds for culture of isolated primary cells in single or multi-cell type culture to mimic regeneration of lung tissue. This approach also allows very specialized studies required for the projects mentioned above. Most experiments designed to study lung health require the use of animal models or cell models that approximate human disease or development. To overcome this obstacle, we have developed a novel human lung tissue cryopreservation method that yields viable lung tissue and viable primary cells after thawing. This technique will allow us to expand our research beyond animal and cell culture models, thereby permitting specific examination of human lung development or disease.
Neuroprotection and Monitoring: Led by Dr. Dorothea Jenkins, an academic neonatologist with almost 20 years’ experience at MUSC, with close collaboration from a team of physicians, bench researchers, and physical therapists, the primary research interest of this group is the pathophysiology of brain injury and neuroprotective strategies to mitigate such injury in vulnerable infants. Our research ranges from bench research using animal models of disease to translation research designed to bring bench advances to clinical fruition. After applying hypothermia to a baby boy with birth asphyxia in 1999 and having a good neonatal outcome, we conducted a seminal clinical trial investigating the use of hypothermia in prevention of secondary neuronal injury after brain injury in neonates. As a result of this clinical research study, and later, larger multicenter trials, the clinical use of hypothermia as a neuroprotective therapy was established as a national standard of care.
We are now investigating complex cytokine and chemokine interactions over time with hypothermia treatment after hypoxic ischemic injury in neonates. This work has led to interesting observations not only of increased inflammatory cytokines, but important modulatory actions of those cytokines at 24-36 hours after birth in the hypothermic group and resultant continued immunosuppression in those patients with worse outcomes. Through observations like these, we hope to improve the efficacy of current modalities of brain protection through adjunct therapies.
We have also been investigating neuroprotective interventions to add to the clinical effectiveness of hypothermia in neonatal animal models. We have extensive volumetric and behavioral data showing improved outcomes, including improved learning and working memory, in animals treated with hypothermia plus N-acetylcysteine and vitamin D.
Based on such pre-clinical data in an animal model of chorioamnionitis, the group is investigating the effectiveness of an existing pharmaceutical, N-Acetylcysteine, in chorioamnionitis. The study “Safety of N-Acetylcysteine in Maternal Chorioamnionitis” is an NINDS-funded pharmacokinetic study to determine the best dose of NAC administered to mothers with intrauterine infection, to protect the fetal brain against inflammatory injury. This work is been presented at national meetings and manuscripts addressing safety and pharmacokinetic data are ongoing. In addition, we have investigated MRS and DTI as MRI biomarkers in infants exposed to chorioamnionitis with Dr. Lakshmi Katikaneni, the Director of the Neonatal Follow-up Program, Dr. Denise Mulvihill, a pediatric radiologist, and biophysicists Drs. Helpern and Brown. With the collaboration of these individuals, we have demonstrated changes in myoInositol and N-acetyl aspartate in infants of women with chorioamnionitis which correlated with degree of fetal inflammatory response and neurodevelopmental outcome at one year of age in term infants who appear healthy in the nursery. As chorioamnionitis is a significant risk factor for developmental delay and cerebral palsy, these clinical investigations provide important new data indicating metabolic changes in the brain as a result of inflammation can be detected shortly after birth in otherwise healthy infants. We anticipate that these findings will ultimately allow us to identify otherwise well-appearing infants who require specialized follow-up developmental screening intervention.
Investigations of early neuromuscular biomarkers with the collaboration of Dr. Mulvihill (Pediatric Radiology), Dr. Moreau (Physical Therapy), Dr. Poon (Developmental Pediatrics) and Dr. Coker-Bolt (Occupational Therapy) are aimed at obtaining innovative neuromotor kinematic assessments as early measures of later motor and behavioral impairment after preterm birth or brain injury in young infants. Development of such quantifiable outcome measures benefits everyone involved in neuroprotective and behavioral outcomes research. In this pilot study, we followed high-risk infants through development, developed a novel scale for rapid assessment of motor deficits, and correlated this novel scale of 10 motor items with neuroimaging to obtain reliable, early predictive measures for future neurodevelopmental consequences in several domains. We have obtained SCOR funding, completed enrollment of 22 preterm infants, and presented data on MRS, kinematics at 12 weeks corrected gestational age indicating ability to predict outcome at 12 months. This work spans several disciplines and resulted in presentations at NIH (invitational SCOR conference-2011), as well as at national meetings of the Pediatric Academic Society (three abstracts), American Occupational Therapy Association (one abstract), and the American Academy for Cerebral Palsy and Developmental Medicine (two free papers) in 2012. Two publications are in preparation, one case report is accepted and another publication is in revision from this work. In addition, eight occupational therapy students have won first or second place in the student research day presentations two years in a row exploring the many aspects of this data.
In these clinical and basic science research projects we aim to develop therapeutics at the same time that we try to better define the timeline of injury and recovery with biomarkers.
