Physicians say that smoking is by far the biggest cause of emphysema, but why doesn’t every smoker get the disease? If you ask that of Michael J. Holtzman, M.D., he might answer that for most cases of emphysema you need a mix of genes, viruses and cigarettes.
To study that mix, Holtzman and his colleagues have obtained funds from the National Heart, Lung, and Blood Institute of the National Institutes of Health totaling $14.9 million to establish a Specialized Center for Clinically Oriented Research (SCCOR), an ambitious grant program meant to foster research that quickly can apply basic science findings to clinical problems.
Emphysema and the associated condition of chronic bronchitis contribute to chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States. Research by Holtzman and his School of Medicine colleagues suggests that someone destined to suffer from COPD may start with a susceptible genetic makeup and then experience a severe viral lung infection in early childhood. The infection could “reprogram” the cells of the lung’s air passages and sacs, and the reprogrammed cells could react badly if the same person began smoking cigarettes, leading to COPD.
“Cigarette smoking has created a very large population of COPD patients worldwide,” said Holtzman, the Selma and Herman Seldin Professor of Medicine, professor of cell biology and physiology and director of the Division of Pulmonary and Critical Care Medicine. “At present, we can treat them with steroids to reduce inflammation, antibiotics to suppress infections and oxygen to help their breathlessness, but the disease will still progress until it’s fatal. We need to find treatments that stop the disease progression, and to do that we need a much better understanding of how COPD develops.”
Holtzman’s SCCOR program will take a comprehensive look at the molecular changes that occur as lungs become crippled by COPD — a disease that affects at least 16 million people in the United States.
Lungs have a tree-like structure of intricately branching airways ending in tiny sacs or alveoli, which exchange gases between the blood and the air. In chronic bronchitis, airways overproduce mucus and become inflamed, obstructing airflow. In emphysema, alveoli are destroyed so they can no longer take up oxygen from the air. COPD patients can have both problems at once, and Holtzman and his colleagues are studying both issues.
“A key project, led by Richard Pierce [Ph.D., research associate professor of medicine and of cell biology and physiology] examines the structural defects found in COPD and correlates them to changes at the molecular level,” Holtzman said.
Researchers will use newly developed imaging techniques, such as helium MRI, to look at the tissue of lungs removed from COPD patients undergoing lung transplants and home in on the tiny lung structures that are injured. “Then, if we find that a particular gene is overactive at a site where the disease is particularly severe, we’ll analyze the normal and abnormal function of that specific gene,” Holtzman said.
A defining characteristic of COPD is the breakdown of elastin, a stretchy fibrous protein that gives the lung its elastic properties. Damage to elastin prevents air sacs from deflating properly.
Holtzman’s colleague Zsolt Urban, Ph.D., assistant professor of pediatrics and of genetics, has identified a mutant gene responsible for abnormal elastin in humans and has teamed with Robert P. Mecham, Ph.D., who has engineered mice that carry the mutant elastin gene. These mice and others with different variants of the elastin gene will enable the researchers to probe the malfunctions associated with abnormal elastin genetics in the lungs. Mecham is the Alumni Endowed Professor of Cell Biology and Physiology and professor of internal medicine, of pediatrics and of biomedical engineering.
The fibrous protein collagen supports the lung’s structure, and both elastin and collagen can be affected if protein-digesting enzymes in the lungs aren’t tightly controlled by their normal inhibitors. Robert M. Senior, M.D., the Dorothy R. and Hubert C. Moog Professor of Pulmonary Diseases in Medicine and professor of cell biology and physiology, and colleagues are studying the imbalance that occurs in emphysema between the protein-digesting enzymes (proteases) and their inhibitors (antiproteases).
A fourth project area, led by Holtzman, addresses why COPD patients overproduce mucus in their airways. Earlier work suggested that a viral infection triggers a population boom in the mucus-producing cells of the airway.
All projects under the grant include both experimental models and patient studies, Holtzman said.