Benaroya Research Institute at Virginia Mason (BRI) received an $11.7 million federal research grant from the National Heart Lung and Blood Institute of the National Institutes of Health to bring together key researchers with different but complementary specialties to look broadly at the regulation of lung inflammatory diseases. Steven Ziegler, PhD, program director for the grant and director of the Immunology Program at BRI, will lead the team of researchers from BRI and the University of Washington. The scientific program has great potential for improving the health of critically ill patients in the U.S. and internationally.

These diseases, also called pulmonary inflammation, have a tremendous impact on people throughout the world and can lead to serious illness and death. They include influenza, pneumonia, chronic bronchitis, tuberculosis and HIV/AIDS related respiratory illnesses. Recent emerging lung infections include avian influenza and the severe acute respiratory syndrome (SARS). Of great concern is that some of these infections can lead to pandemics. Lung infections can also lead to asthma.

“Our goal is to understand what drives the inflammatory response to lung infections, and then learn how best to control that response to eliminate the associated pathology,” says Dr. Ziegler. “This new program is unique in that we are bringing great experts in various areas of lung biology to work together. Our program will include four individual projects that probe different, yet complementary and sequential processes of this inflammatory cascade.”

This novel approach to study pulmonary diseases will not only lead to important insights into disease development and progression, it may also identify new therapeutic targets. “Science is evolving to where groups of scientists with complementary skills will come together to tackle these big questions in a systematic way,” says Dr. Ziegler. “This is a powerful approach to finding solutions for complex problems. The National Institutes of Health recognizes this by granting us this significant award.” BRI is well-known throughout the world for leading broad collaborations of scientists to investigate diseases.

Pulmonary inflammatory diseases are immune-mediated. These conditions result from abnormal activity of the body's immune system, usually in response to infection. The body’s immune system is designed to protect the body from bacteria, viruses, cancerous cells and other threats by detecting and destroying them. In the case of lung infections, the immune system can overreact and escalate the inflammatory response. “The immune system is a delicate balance,” says Dr. Ziegler. “You want the immune system to react enough to remove the infection, but not to overact and cause damage leading to disease.”

The four projects of the program include: 1) Understanding the extracellular matrix in lung infection that regulates and shapes the immune response. The extracellular matrix is a complex mixture of molecules that provides structural support to tissues and regulates the growth and organization of cells. This project will be lead by Thomas Wight, PhD, principal investigator of the project, director of the Hope Heart Program at BRI and an expert in extracellular matrix. 2) Understanding the role of thymic stromal lymphopoeitin (TSLP) in coordinating immune system responses in the lung. In a significant discovery, Dr. Ziegler and his team identified that TSLP leads to the onset and progression of asthma and other allergic diseases. Dr. Ziegler will be the principal investigator of this project. 3) Understanding the role of a key enzyme, stromelysin-2 (MMP10), and how it works in moderate inflammation in acute infection of the lungs. A leader in this area, William Parks, PhD, professor, Pulmonary and Critical Care Medicine and director of the Center for Lung Biology at the University of Washington School of Medicine, is the principal investigator for this project. 4) Understanding the role of the immune system, particularly cells that regulate the immune system, in controlling chronic infection in the lung. The principal investigator for this project will be Daniel Campbell, PhD, associate member at BRI and an expert in this area.

Three core laboratories will support this program, including a system model core headed by Charles Frevert, associate professor of Comparative Medicine and Pulmonary and Critical Care Medicine, University of Washington, a histology and imaging core, led by Robert Vernon, PhD, research associate member, BRI, and an administrative core directed by Dr. Ziegler of BRI.