The environment for research in neonatal lung development and repair is also excellent. Research opportunities include: alterations in gas transport and sepsis-associated lung injury, pulmonary and cardiovascular physiology, gas transport, and coagulation-mediated lung injury, nitric oxide and reactive oxygen species biology and biochemistry, surfactant, cell biological and organ explant methods of manipulating lung development with state-of-the-art morphometric reconstruction of the developing lung. A particular strength of this program is the opportunity for a fellow to use an acute lung injury model in the adult baboon

Richard L. Auten, M.D., Associate Professor of Pediatrics

Dr. Auten's laboratory focuses on the oxidative and inflammatory disruption of postnatal lung development. Transgenic and knockout mice lacking key inflammatory functions, as well as the use of chemokine and leukocyte function inhibitors are used to determine the dominant mechanisms responsible for disrupted alveolar and airway development. Perinatal exposure to oxidative stressors like ozone and other inhaled pollutants is being studied to determine the effects of multiple, combined exposures on disrupted airway development in collaboration with investigators in the Nicholas School of the Environment.


Thomas M. Murphy, M.D., Associate Professor of Pediatrics

Dr. Murphy 's laboratory is studying the following topics related to airway smooth muscle responsiveness: 1) Early Origins of Airway Hyperresponsiveness-- the Smooth Muscle Contribution; 2) Ontogenic Changes in Airway Smooth Muscle Relaxation; 3) Maturational Changes in ASM Plasticity; and 4) Role of a Putative NAD(P)H Oxidase in ASM Proliferation and Contractility.

Claude A. Piantadosi, M.D., Professor of Medicine

Dr. Piantadosi's research focuses on regulation of oxidative metabolism, oxidative stress, and nitric oxide biology in the lung and other organs. A portion of the work is devoted to understanding the roles of oxidative and nitrosative stress during acute lung injury. Acute lung injury is produced experimentally by exposure to oxygen, ischemia, endotoxin, or endogenous inflammatory mediators. The physiological, biochemical and molecular responses of the lung are measured during the evolution of oxidative stress in order to understand the injury mechanisms and thereby be able to prevent it with specific interventions. Another part of the work is devoted to understanding the responses of non-pulmonary organs to acute lung injury and to severe sepsis. This work focuses on the central role of the mitochondrion in energy provision, signaling of programmed cell death (apoptosis) and the role of mitochondrial biogenesis in cell survival. The laboratory has a special expertise recognized on a national level in mechanisms of acute lung injury and multiple organ failure, especially the roles of oxygen, reactive oxygen species, and nitric oxide in the physiological and pathogenic responses to such injuries.

Jonathan S. Stamler, M.D., Professor of Medicine and Biochemistry, Associate Investigator of the Howard Hughes Medical Institute

Dr. Stamler is a member of the new Translational Medicine Initiative (TMI) at Duke. He is internationally recognized for his study of NO and its role in normal and pathophysiological conditions. The impact of his studies is emphasized by his multiple publications in Nature, Science, Cell, and The Proceedings of the National Academy of Sciences, USA. Dr. Stamler is a member of the American Association of Physicians and has received many awards for his research. In 2000, he was an ASCI prize finalist, and in 2001 the AFMR prize winner. Dr. Stamler’s research focuses on the regulation of redox systems as they relate to complex physiological responses, focusing specifically on nitric oxide (NO). By studying the molecular details of the interactions of NO with thiol and transition metal-containing proteins, insights are gained into the molecular basis of redox sensitivity in biological systems, and new molecules can be generated with therapeutic applications. The role of redox systems in organ damage, for example hyperoxia, hypoxia, and pulmonary hypertension, make studies of this system very relevant to the training of the pediatric investigator.

Mary Sunday, M.D., Professor of Pathology

Dr. Sunday's laboratory is focused on understanding early lung embryogenesis and early origins of lung injury. With regard to lung development, her lab is investigating the role of novel transcription factors (TRs) in regulating cell migrating and cell fate determination. Lung formation begins as an outpouching of ventral foregut on murine gestational day 0.5 (E9.5), followed by branching morphogenesis and cell differentiation. The central hypotheses are that specific TFs direct mammalian lung embryogenesis and pulmonary effects are due to downstream molecular and/or cellular events. Dr. Sunday's laboratory is testing these hypotheses using genetically deficient mice. These models are used to determine whether abnormal lung development might be linked to abnormal mesenchymal cell migration and/or cell differentiation. Additionally, the overall hypothesis is that bombesin-like peptide (BLP) is an early mediator of lung injury in bronchopulmonary dysplasia (BPD). Human infants with BPD have increased numbers of pulmonary neuroendocrine cells (PNECs) containing BLP. Elevated BLP could mediate lung injury in BPD, including interstitial fibrosis and reactive airway disease. New data indicates that premature infants with elevated urine BLP levels at days 2-5 of age have a 10-fold increased risk of BPD even when normalized for all other variables including prematurity. Elevated urine BLP levels also occur shortly after birth in 2 baboon models of BPD in which BLP levels correlate with severity of subsequent chronic lung disease (CLD). Postnatal therapy with anti-BLP monoclonal antibody 2A11 protects against BPD in both models. The lab is beginning to address hypotheses using hyperoxic newborn mice, validating this as a model of CLD with similarities to human BPD. It is being determined whether intratracheal BLP triggers specific pro-inflammatory cascades that also characterize hyperoxic CLD. Using both murine and baboon models, evaluations are being made whether BLP blocking antibody (SA11 and a human anti-BLP antibody) can function as prophylactic agents for CLD using a minimum dosage schedule. Furthermore, determining which BLP receptors might be involved in mediating hyperoxic CLD using mice deficient in one or more of the 3 cloned BLP receptors (GRP-R, BRS-3, and/or NMB-R). These studies will help to clarify cellular and molecular mechanisms by which BLP could contribute to the pathophysiology of BPD and facilitate the development of novel prophylactic treatments for infants at risk.

Judith Voynow, M.D., Associate Professor of Pediatrics

Our laboratory has been studying the regulation of the major respiratory tract mucins and their functions in the lung. Recently, her work has focused on the regulation of mucins by neutrophile lastase (NE), a major inflammatory mediator in CF. She has found that NE increases expression of two major respiratory tract mucins, MUC5AC and MUC4, and this effect is mediated by oxidant stress. Furthermore, she found that NE regulates these mucins by a post-transcriptional regulatory mechanism. Current research endeavors include: 1) identification of the RNA-binding regulatory proteins for MUC expression, 2) analysis of the oxidants/pro-oxidant enzymes regulating MUC expression and 3) evaluation of the mechanisms of airway remodeling following NE exposure.

Jo Rae Wright, Ph.D., Professor of Cell Biology

Dr. Wright studies the functions of pulmonary epithelial and immune cells at the cellular and molecular level. These two types of cells carry out functions that are important for normal breathing and for preventing infection. The alveolar epithelial type II cell synthesizes a substance known as surfactant, which is a soap-­like mixture of lipids and proteins that reduces surface tension in the lung and makes normal breathing possible. One aspect of her research is directed toward understanding the metabolism and clearance of surfactant and the role that receptors and surfactant proteins play in regulating surfactant pool size. The type II cell, in addition to synthesizing surfactant, participates in surfactant clearance by endocytosis. Her group is currently attempting to isolate the type H cell receptor, define the molecules and pathways involved in intracellular targeting of surfactant, and determine the factors that regulate endocytosis. Two of the surfactant proteins have been shown to be homologous to serum proteins that bind carbohydrates and are involved in non-antibody mediated host defense against infection. This observation has generated a new area of research on the immunomodulatory.