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Research, treatment help children breathe easier by Heather Woolwine Public Relations Everyone has experienced a moment of breathlessness. Maybe you stayed under water just a minute too long or had a hard timing catching your breath after a ball careened into your chest.   Imagine that sensation extended for long periods of time, maybe even throughout your life. It’s obvious that without proper lung function, good quality of life is much more difficult to achieve.   In fact, asthma is the most common reason for school absence. Cystic fibrosis is the most common genetic pulmonary illness and respiratory distress is the most frequent reason for emergency admission to pediatric intensive care units.   Fortunately, the Children’s Hospital and its staff of pediatric pulmonologists and researchers are there to take these medical conditions and do their best to remedy them through treatment, care and investigation.   Led by Michael Bowman, M.D., Ph.D., the Division of Pediatric Pulmonology, Allergy, and Asthma has grown in the last several years. “When I arrived at MUSC, children with lung diseases saw community allergists or adult pulmonologists or even went out of town for care,” Bowman said. “I came here with the goal of establishing a premier academic pediatric pulmonology program, hoping for the addition of allergy and immunology at some point.”   Part of being that premier academic pediatric pulmonary program lies in embracing pulmonary research, and the commitment of the Children’s Hospital and the Charles P. Darby Children’s Research Institute to care for children together.   Involved in various research projects himself, Bowman understands that it is the marriage of basic science and clinical practice that produces the best treatments and potential for new discovery for pediatric pulmonary patients.   With the pulmonology division now responsible for more than 2,000 patients suffering from a variety of lung diseases and allergies, translational research is more important than ever.   The Pediatric Pulmonary Biology Program, led by John Baatz, Ph.D., associate professor in the Department of Pediatrics, focuses on the molecular and cellular events required for normal perinatal pulmonary adaptation and methodologies for treatment or cure of pediatric lung diseases.   By combining a group of established senior and junior investigators, the program forms a strong alliance with major interests in mechanisms of lung injury, surfactant homeostasis, structure and function of surfactant proteins, antibacterial lung proteins in normal and diseased pediatric patients, methods for effective gene therapy of lung cells, and effects of toxins on the innate lung immune system.   “Our translational approach to research will allow us to not only develop a strong basic science focus, but also to develop a stronger clinical research program with our collaborators in the clinical sciences,” Baatz said. “Each area of our program also has exceptional corresponding clinical programs, facilities and a patient base at the Children’s Hospital and includes neonatology, pediatric pulmonology, pediatric hematology/oncology, the Cystic Fibrosis Center, the neonatology intensive care unit and the pediatric intensive care units. Therefore, development of Phase I, II and III clinical trials for treatments or pharmaceuticals developed from the basic research of this program will be readily feasible.” First Breath Among the many issues that can complicate the early delivery of a child, pulmonary impairment can be one of the most distressful. Without properly functioning lungs, neonates must struggle for life and families hope that time and excellent care really will heal all wounds.   With an extensive research history investigating surfactant protein functioning and now moving forward in determining better surfactant based therapies, Baatz described the lung-based protein as the material that makes the air and water in the lungs get along. “It is essential because without it, the lungs collapse,” he said. “And children born before the 32 week mark are not producing it yet.” Currently, preemies are given surfactant therapy until they are capable of breathing on their own, but more discoveries are needed in terms of the structural/function relationships of pulmonary surfactant proteins. Baatz and his colleagues want to learn more about normal surfactant protein function and development of surfactant-based therapies for treatment of respiratory distress syndrome, genetic surfactant protein deficiencies and viral and bacterial lung infections.   Another aspect of this research involves smoking during pregnancy and its impact on lung development.  “We are in the preliminary stages of designing experiments and protocols to obtain preliminary data for a grant proposal submission that would address these issues,” Baatz said.    “The specific aims of this project would be to determine the effects of second hand smoke byproducts on surfactant protein function; to assess the effects of cigarette smoke exposure of mothers on surfactant protein secretion in neonates using a mouse model; to define the effects of second hand smoke exposure on key components of the innate immune system of the adolescent mouse lung; to determine effects of second hand smoke on the oxidative state of surfactant proteins in adolescent mice; and to establish the pattern of surfactant protein secretion in (human) neonates of mothers exposed to direct or second hand cigarette smoke.” Cystic Fibrosis With 75 percent of her time spent in a lab and the other quarter with patients, Isabel Virella-Lowell, M.D., is the embodiment of the translational research she conducts for patients suffering from cystic fibrosis (CF).   Cystic fibrosis is the most common autosomal recessive disease in North America, a product of thousands of possible mutations to a specific gene. Treatments for CF are geared towards symptoms of the disease and are timely and often invasive. CF patients experience pulmonary inflammation and infection throughout the progression of the disease and have a general life expectancy into early adulthood. Understanding pulmonary inflammation and infection is the key to unlocking the mysteries surrounding CF.   Lowell’s work centers on the concept of gene therapy for correction of the CF defect and decreasing inflammation in the lung. In basic terms, gene therapy involves a copy of the normal gene piggybacking on a harmless “helper” virus (also known as a vector) into the cells of the CF patient’s lungs. It then replicates along with the virus in the target cells and encodes normal protein production, thus counteracting the progression of the disease.   “While some CFTR gene therapy may eventually serve to prevent the development of CF lung disease in infants, it will not have an effect in ameliorating the lung disease already present in older patients,” Baatz said. “Lowell and other investigators in our program are focusing on developing and evaluating potential gene therapies that would be more useful in patients with established lung disease, as well as examining other strategies aimed at enhancing gene transfer to the airway. In an effort to enhance gene expression in the lung, they will be working to determine the optimal vector dose for the highest levels of expression with the lowest number of adverse effects.”   “To me, the most exciting part of medicine is taking things from the bench to the bedside,” Lowell said. “I try to take what my patients teach me back to the lab and vice versa. I want the research we do at MUSC and the CRI to impact their quality of life and increase their life expectancies. The CF Center team does an excellent job of keeping on top of current research and new treatments. Because of my involvement, I get a lot of questions from my patients about potential CF treatment and gene therapy research. I do my best to help them understand research timelines, precautions and how that fits into what they’re going through.   “We invite our patients to take part in our clinical trials to help further research into new therapies. There are always challenges and many people with CF were discouraged by premature promises of a cure and the waiting involved for new treatments or medications. We try to educate our patients about the importance of continuing therapies that are proven, remaining positive and supporting efforts to discover new therapies.”   The collaborative spirit that the creators of the CRI hoped for was evident when Lowell discussed another aspect of her research.   “Dr. Bruce Hollis and Carol Wagner conducted very interesting research on vitamin D deficiency in pregnant women and newborns here at MUSC. For some time, we’ve known that CF patients were having a problem with osteoporosis even though they take a vitamin D supplement as part of their treatment,” Lowell said. “Recently the Cystic Fibrosis Foundation released a consensus statement calling for CF physicians to be more aggressive in our treatment of CF bone disease and vitamin D deficiency.   “Well, Bruce sits on the other side of the hall from me, which made it very easy for us to talk about his research and that of others who study vitamin D. Interestingly, I found a lot of vitamin D research might be relevant to CF. For example, there is some data to suggest vitamin D therapy may prevent type I diabetes, may help decrease inflammation in multiple sclerosis, and improve lung function in other chronic lung diseases.   “My discussions with Dr. Hollis made me wonder if vitamin D supplementation in children and adults with CF could not only help prevent osteoporosis, but might also help decrease the inflammation in their lungs and prevent CF-related diabetes. Both of us working here in the CRI enabled those ideas to be put together and we are collaborating on pilot studies that will investigate these concepts.” What Dolphins Can Teach Us Scientists and clinical practitioners grasp what havoc toxins can wreak on the human body, and from that knowledge comes the desire to guard against harmful toxins and contaminants. Enter that lovable symbol of oceanic kinship, the dolphin.   “Marine mammals of this area, such as bottlenose dolphins, may be more vulnerable to contaminants and biotoxins due to constant exposure and bioaccumulation of these compounds through aspiration of contaminated seawater or inhaled toxic particulates,” Baatz said. “While dolphins share similar respiratory structure with humans, dolphins have increased air exchange during respiration and increased flow rate in comparison.   “Therefore, increased exposures of dolphin lungs to pathogens implicate the dolphin as a sentinel for human lung health in threatened coastal environments. In an effort to assess dolphin health, immunity, and response to stress and environmental insult we aim to identify variations in expression of immunoglobin proteins and cytokines in the dolphin lung in site-specific environments so that humoral and cellular immune responses to marine bio-contaminants can be defined. Identification of antibacterial proteins in dolphin airway surface fluid may lead to unique treatments of bacterial infections in the human lung. Since children are often intrigued by the dolphin, it is a goal that this research is shared directly with the pediatric patients in the hospital setting.”  Friday, Aug. 26, 2005 Catalyst Online is published weekly, updated as needed and improved from time to time by the MUSC Office of Public Relations for the faculty, employees and students of the Medical University of South Carolina. Catalyst Online editor, Kim Draughn, can be reached at 792-4107 or by email, catalyst@musc.edu. Editorial copy can be submitted to Catalyst Online and to The Catalyst in print by fax, 792-6723, or by email to petersnd@musc.edu or catalyst@musc.edu. To place an ad in The Catalyst hardcopy, call Community Press at 849-1778.