Neonatal & Dev Medicine in the department of pediatrics

Laboratory Research

Bland's Laboratory

Dr. Bland's research program focuses on lung growth and development, and the adverse impact of prolonged mechanical ventilation on the incompletely formed lung, which in very premature infants often leads to a life-threatening condition that was first described as bronchopulmonary dysplasia (Northway WH Jr et al, Stanford University, New Engl J Med 276: 357-368, 1967). This form of neonatal chronic lung disease is the leading cause of long-term hospitalization and recurrent respiratory disorders seen in tiny infants who have been born at less than 28 weeks of gestation. Failed alveolar formation and excess disordered lung elastin are prominent histological features of this disease, which in some ways resembles adult emphysema. Bland's group studies the effects of mechanical ventilation with either air or 40% O2 on genes and proteins that regulate lung growth and development in newborn mice, whose alveoli and pulmonary capillaries form mainly after birth at term gestation. As elastin plays a crucial role in lung growth and development (elastin-null mice die soon after birth from cardiorespiratory failure related to defective alveolar and lung vascular formation), studies are done to examine the effects of prolonged mechanical ventilation (cyclic lung stretch) with O2-rich gas (which is often needed to sustain life of extremely premature infants) on genes that regulate elastin synthesis and assembly, which in turn can affect lung septation and angiogenesis. The lab group is currently studying the effects of mechanical ventilation on lungs of mutant newborn mice that have defects in elastin assembly and associated abnormalities of lung structure. Because mechanical ventilation of the developing lung can induce release of proteolytic enzymes that break down elastin, a new project examines the effects of mechanical ventilation with O2-rich gas in a transgenic mouse that over-expresses elafin, a potent inhibitor of serine elastase activity. It is anticipated that these studies will pave the way for novel and effective strategies to treat or prevent neonatal chronic lung disease, and perhaps other respiratory disorders that exhibit similar pathological features in older children and adults.

Images of Hart's-stained lung tissue from 5 day old mice after breathing 40% O2 for 24 hours either with (right) or without (left) mechanical ventilation at 180 breaths/min. Lung elastin accumulation (arrows, pointing to dark elastic fiber stain) was significantly greater in mice that had mechanical ventilation. Elastin was expressed mainly at the tips of septa in the unventilated control lung, whereas elastic fibers were prominent throughout the walls of distal air spaces in the lung that was exposed to mechanical ventilation for 24 hours.

Recent Relevant Publications

Bland, RD, Ertsey R, Mokres LM, Xu L, Jacobson BE, Jiang S, Alvira CM, Rabinovitch M, Shinwell ES and Dixit A. Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice. Am J Physiol Lung Cell Mol Physiol 294: L3-L14, 2008

Bland RD, Mokres LM, Ertsey R, Jacobson BE, Jiang S, Rabinovitch M, Xu L, Shinwell ES, Zhang F and Beasley MA. Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: L1099-L1110, 2007

Bland RD, Xu L, Ertsey R, Rabinovitch M, Albertine KH, Kumar VH. Ryan RM, Swartz DD, Wynn KA. Csiszar K and Fong KSK. Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic  lung disease. Am J Physiol Lung Cell Mol Physiol 292: L1370-L1384, 2007

Bland RD, Albertine KH, Carlton DP and MacRitchie AJ. Inhaled nitric oxide effects on lung structure and  function in chronically ventilated preterm lambs. Am J Respir Crit Care Med 172: 899-906, 2005

Bland RD. Neonatal chronic lung disease in the post-surfactant era. Lessons learned from authentic animal models. Biol Neonate 88: 181-191, 2005

Bland/Rabinovitch Lab Website


Lab

Contag’s Laboratory

HO-1 has pleiotrophic effects on many systems in the body. It is an antioxidant, an immune modulator, and vasoregulator; HO-1 may play a role in host responses to infection, autoimmunity, solid organ transplantation, and hematopoiesis. Understanding how this enzyme is regulated from transcription to enzyme activation will be key to revealing and controlling its activity in these biological processes. Modulating gene expression using various transcriptional activators and controlling enzymatic activity using Mps may allow us to control the effects of HO-1 in several clinically relevant scenarios. We have been investigating HO-1 and its gene, hmox-1, using molecular imaging tools that have been developed in our laboratory at Stanford, and some clinical imaging tools that have been modified for use in small laboratory animals. Using bioluminescent reporters and low light imaging systems we have been able to noninvasively reveal regulatory patterns of HO-1 in intact living animals. Using genetic knockouts and pharmaceutical knockdown approaches we are studying the role of HO-1 in stem cell biology—hematopoiesis, and as an immunomodulator in infectious diseases. Some bacterial pathogens have HO analogs and the role of these proteins in the mechanisms of pathogenesis and host-pathogen interactions are also being investigated in our group. The interface of basic biology in animal models of human disease and clinical investigation has proven to be a tremendous strength in our Division. Pushing the envelope of basic science and using these insights to drive clinical investigation, and then taking what we learn in the clinic back to the lab to address key issues in medicine is a strength of our research program.

Contag Lab Website


Lab

Penn’s Laboratory

The Penn lab studies the role of placental factors in brain development. Given that 10% of all infants in the US are born preterm and more extremely preterm infants are being saved, there is a pressing need to understand the factors contributing to brain damage in these infants. A key contributor to this damage may be loss of placental hormones. To understand this hormonal contribution, we are pursing investigations that range from the development of novel mouse models to use of human infant data obtained at Packard Children's Hospital. Our overall goal is to understanding the hormonal factors that contribute to normal neurodevelopment and the effects of their loss following premature birth. The placenta has long been underappreciated and understudied, and its role in protecting and shaping the normal development of the fetal brain has only very recently started to be investigated. The placenta is an endocrine organ that produces a wide array of hormones that can shape the developing brain. In premature birth, these placental hormones are abruptly and inappropriately lost. We hypothesize that preterm birth is just one example in which disruption of placental function leads to long-term neurological dysfunction or damage. Many events, such as infection, malnutrition and genetic abnormalities, can disrupt placental function. Our goal is to understand the normal role of placental hormones, the effects of their disruption and ultimately to provide the basis for replacement with an individually tailored placental hormone "cocktail" to improve development. Our experiments can provide fundamental new insights in placental physiology and brain development and help redefine disorders such as cerebral palsy and autism as disorders of the placenta. We hope to open new avenues for therapeutic treatments to improve neurological outcome in preterm infants and in others at high risk of developmental brain damage due to placental injury or failure.

Penn Lab Website


Lab

Stevenson’s Laboratory

Neonatal jaundice is a condition that affects children throughout the world. Pathologic jaundice becomes a serious threat to the well-being of neonates in the context of increased bilirubin production. For the last 20 years, we have studied the ontogeny and control of heme catabolism and bilirubin production and have developed novel methods to measure carbon monoxide (CO) production in newborn infants as an indicator of risk for severe neonatal hyperbilirubinemia. In addition, we have actively investigated a more targeted, preventive approach to the treatment of newborns, who are high producers of the pigment and/or are unable to efficiently eliminate bilirubin; thus, leading to an accumulation of the pigment in circulation and tissues which may lead to irreversible neurologic injury. Control of bilirubin production is a logical strategy and can be accomplished through the use of metalloporphyrins (Mps), competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in the heme catabolic pathway. Because heme degradation leads to the formation of the biologically active compounds, CO, ferrous iron, and bilirubin, inhibition of HO may result in unexplored consequences for the immature mammal. Thus, an increasing emphasis on studies to further explore the pivotal role of HO in developmental heme metabolism is necessary. A better understanding of the role of increased bilirubin production in neonatal jaundice, the prevention of hemolytic jaundice, and the transcriptional regulation of HO has remained an overall objective of our program. Recently, we have defined, established, and evaluated a transgenic (Tg) mouse (HO-1-luc) model to study the in vivo regulation of HO-1 gene expression patterns and bilirubin production, as well as assess the efficacy of potential therapeutic agents that inhibit the activity of HO using noninvasive bioluminescence imaging (BLI) as a method to rapidly assess gene expression both spatially and temporally. We have extended these studies to not only investigate the role of heme catabolism in jaundiced infants with infection or hypoxic-ischemic brain injury, but also evaluate the efficacy and safety of Mps, especially in these clinical circumstances. Our research program also includes the development of new bedside treatment strategies for detection and measurement of neonatal jaundice and involves the development and evaluation of safe and efficacious new phototherapy devices based on blue light emitting diode technology.

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