June 3, 2004

$11M grant funds lung injury research

The University has received an $11 million Program Project Grant (PPG) from the National Institutes of Health to define the mechanisms that cause changes in the alveolar epithelium during lung injury.

Jacob I. Sznajder, M.D., Dr. Roy Patterson Professor of Medicine and chief of pulmonary and critical care medicine at the Feinberg School of Medicine, is the principal investigator and head of one of the five research projects and an administrative and a cell culture and physiology core that make up the PPG.

The alveolar epithelium is a layer of plate-like cells that line the air sacs in the lung where oxygen and carbon dioxide are exchanged between alveolar air and pulmonary capillary blood. The layer formed by alveolar epithelial cells is the most resistant component of the alveolo-capillary — or “gas-blood” — barrier, allowing us to breathe normally and protecting the body from literally drowning in its own fluids.

In lung injury, increased permeability of this barrier and leaks in protein-rich fluid from the capillaries into the alveoli reduce the lung’s ability to pump fluid out of airspaces, causing the patient to “drown from within.”

Normal epithelial function is required for reabsorption of edema fluid and healing of the lungs in patients with acute lung injury and acute respiratory distress syndrome, such as during severe pneumonia, congestive heart failure and SARS. As such, restoration of the alveolar epithelial cell barrier is crucial for recovery from lung injury and normal breathing, Sznajder said.

The Program Project consists of a multidisciplinary group of researchers who designed experiments to develop new strategies to expand understanding of the mechanisms mediating epithelial lung injury, particularly the mechanisms by which cells sense and respond to injurious stimuli, such as hypoxia (lack of oxygen), shear, stretch and hyperoxia (abnormally high oxygen level).

The first four projects will determine the mechanisms by which alveolar cells sense stimuli, elucidate signal transduction pathways elicited by these sensors and examine the consequences of the stimuli on epithelial cell sodium pump function, cell cytoskeleton and cell function and survival. The fifth project will examine the mechanisms by which stretch improves non-viral gene transfer to the lung. The projects will promote development of novel tools to investigate the downstream effects of these stimuli on the structure, function and survival of alveolar epithelial cells.

Sznajder, will lead the first project, which focuses on the effects of severe hypoxia on sodium-potassium ATPpase regulation in the alveolar epithelium.

The second program, led by Robert D. Goldman, Stephen Walter Ranson Professor and chair of cell and molecular biology, and third project, led by Jonathan Jones, professor of cell and molecular biology, will explore the role of the cell cytoskeleton and the extracellular matrix in the pathophysiology of epithelial cell injury.

Navdeep Chandel, assistant professor of medicine and expert in oxygen-sensing and cell apoptosis, will head the fourth project, which will examine the mechanisms regulating alveolar epithelial cell death following exposure to hyperoxia.

The fifth project, led by David Dean, associate professor of medicine and microbiology-immunology, will focus on the mechanisms by which non-viral genes delivered to the alveolar cells via electroporation are transported from the cytoplasm to the nucleus in stretch and non-stretch conditions.