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Basic Science
Uncovering Mysteries of Lung Development
 Chronic lung disease and emphysema in adults – the fourth most frequent cause of death in the United States – has long been thought of primarily as a disease of aging smokers. However, fewer than 25 percent of adult smokers actually get emphysema, leading scientists and public health experts to realize there must be other susceptibility factors causing the high rates of this disease. Wei Shi, MD, PhD*, has found a significant clue in innovative investigations at The Saban Research Institute of Childrens Hospital Los Angeles. His work at the laboratory bench is an example of the breakthroughs in our fundamental understanding of human biology that may eventually lead to new treatments at the patient’s bedside.
Dr. Shi is discovering developmental gene networks and cellular processes that determine how well the lung develops and how well it will stand up to life after birth and to such clinically relevant injuries as second-hand smoke. For the first time, he has shown that incomplete development of the lung predisposes it to more rapid “aging” or degeneration and that specific genetic mutations drive the lung’s susceptibility to cigarette smoke and possibly to traffic pollution and industrial exposures as well.
Specifically, Dr. Shi is focusing on a cellular network relay system called the Transforming Growth Factor (TGF-beta) signaling cascade. (Signaling cascades or pathways are essentially a sequence of enzymatic reactions by which external signals are transmitted into the nucleus of a cell.) Dr. Shi has found that mutations in the TGF-beta signaling pathway may be particularly dangerous for healthy lung development.
His interest lies in a critical signaling protein in this pathway known as Smad3. One function of the Smad protein family is to prevent tumors. “In the developing lung, Smad3 not only has a positive effect on neonatal lung development, but its absence may predispose the lung to emphysema later in life,” he says.
Another question he’s attempting to unravel is the role of a proteinase (an enzyme that breaks down proteins into amino acids). Matrix metalloproteinase-9 (MMP-9) is a member of a big family of enzymes thought to play a major role in cell behaviors and tissue structure remodeling. In the lab, MMP-9 appears in higher-than-normal activity levels during the destruction of lung tissue at a particular stage in development. “We’re trying to find out why,” says Dr. Shi.
David Warburton, DSc, MD, FRCP, FRCS*, director of the Developmental Biology Program, says that Dr. Shi’s work carries “a major take-home message” for public health. “This is very important information for the many ex-preemies who survived respiratory distress syndrome (RDS) and chronic lung disease as newborns in the 1970s and later, and who are now entering their twenties and thirties,” he notes. “Further, it shows that if you fall into this category and have a mutation in the TGF-beta pathway, you would be very unwise to smoke. And if you are a preemie, and your parents smoke around the house, that may be even worse for you.”
Babies affected by abnormal lung development often suffer from RDS, an acute lung disease, and have trouble breathing due to diminished lung volume and surface area for gas diffusion.
Dr. Shi is looking at other crucial processes in the body – including the role of bone morphogenetic proteins (BMP) in lung development and diseases. BMPs are members of a growth factor family of proteins involved in organ formation and development. Inadequate BMP signaling causes a variety of birth defects and can disrupt the healthy development of the embryonic lung. The result can be severe respiratory distress, collapse of the developing lung’s airways and death. “We’re trying to pinpoint the chain of events taking place at the molecular level so we can potentially devise interventions,” he says.
His BMP investigations are supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health, which was renewed in 2006 for a second five-year period. In addition, Dr. Shi and Dr. Warburton are collaborating with scientists at Harvard University’s genome sequence database in an attempt to pinpoint the frequency of changes in key genes in the population of children with asthma. Ultimately, Dr. Shi and Dr. Warburton would like to know whether newborns with abnormal neonatal lung development develop lung diseases such as asthma and chronic obstructive pulmonary disease as adults.
Dr. Shi understands that he’s doing the work of a long-distance runner. “This isn’t like developing a new drug that may be used in three to five years,” he says. “Instead, our investigations may have some impact in five years in changing the thinking about how lung disease happens and even in how we address the disease.”
Almost every major advance in health care has taken decades of research. As with any exploratory process, it can be difficult to predict the ultimate benefits. “We are working to identify each piece of the puzzle of development,” says Dr. Warburton. “The implications are tremendous, but it takes patience.”
*Faculty member, the Keck School of Medicine of the University of Southern California.
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