Liles studies good neutrophils gone bad in lung tissue

Conrad Liles

Like spawning salmon, certain cells that develop in our bone marrow enter our bloodstream programmed to reach the site of their mission and then die. Among those cells with the shortest life span are neutrophils, which are the first wave of cells to defend against invading pathogens and the first to arrive at the site of an inflammation.

Neutrophils are committed to this fate, termed apoptosis, or programmed cell death, as they migrate from the marrow of our bones. One goal researchers are working toward is to increase the life span of these cells, so that patients can receive neutrophil transfusions for the treatment of serious infections following bone marrow transplantation or high dose cancer chemotherapy. Another area of research concerns the habit of these cells under certain conditions to abort their natural mission and injure healthy tissue.

Dr. W. Conrad Liles, assistant professor of medicine in the Division of Allergy and Infectious Disease, is one of the UW’s leading experts in the role neutrophils play in acute inflammatory tissue injury. Liles and colleagues are currently investigating lung injury resulting in acute respiratory distress syndrome (ARDS).

When a patient who is experiencing severe infection is wheeled into the ER, even under the best conditions of care, the victim stands a chance of developing ARDS. Doctors have no cure, nor do they know how to prevent the syndrome. Approximately 30 to 50 percent of the patients who do develop the syndrome die, unless their immune system balances out and their neutrophils are brought under control.

“Often all you can do is provide the patient the best support you can, if they develop it,” said Liles.

Liles’ research concerns the molecular interactions between neutrophils and the “target” cells in healthy lung tissue that they destroy. Named by the Japanese researchers who discovered it about eight years ago, the Fas/Fas ligand system plays a central role in this process.

Under normal circumstances, as in the case of an invading pathogen, neutrophils enter the bloodstream and bear down on the pathogen through a complicated series of cell communications. When it reaches the pathogen, the neutrophil degranualizes — lets loose its granules, or small intercellular sacks, which contain pre-formed acid that destroys the pathogen.

In cases of severe infection, or sepsis, while our neutrophils are busy attacking pathogens in our lungs, the Fas/Fas ligand system is triggered between the neutrophils and healthy cells, which leads to “rogue inflammation” and detrimental tissue injury in the host, Liles said. The Fas/Fas ligand system is the combination of a Fas receptor, a molecule on the outside of one cell, and a complementary Fas-activated molecule on the neutrophil that triggers its destructive mission.

Liles and colleagues have provided evidence from animal studies that the Fas/Fas ligand system is in fact operative in ARDS. In mice that have the system disrupted, less injury occurs when their lung cells are exposed to neutrophils.

Liles will discuss his research identifying the molecular interactions of these processes in a Science in Medicine Lecture on Thursday, April 15, from noon to 1 p.m. in room T-625 of the Health Sciences Center. His lecture, titled “Apoptosis and the Regulation of Acute Inflammatory Tissue Injury: Insights into the Pathogenesis of Acute Lung Injury,” is the 10th in this year’s School of Medicine-sponsored series.

Last year’s Fialkow Scholar, Liles is currently chair of the infection control committee for UW Medical Center and co-director of the Infectious Disease and Tropical Medicine Clinic. He is a fellow of the American College of Physicians and a past Pfizer fellow. He received his Ph.D and M.D. degrees from the UW School of Medicine in 1987.

He completed an internship and residency in internal medicine at Massachusetts General Hospital in 1990 and returned to the UW for a chief residency. Liles completed a three-year fellowship in the Division of Allergy and Infectious Diseases Residency in 1994 and joined the faculty as an assistant professor of medicine in 1996. ¶

Will Morton