UVa scientists hot on trail of therapies for deadly lung failure

February 21, 2006

Researchers at the University of Virginia Health System have identified a molecular target, or receptor, for potential drugs to treat acute respiratory distress syndrome (ARDS), a sudden and life-threatening failure of the lung. Interestingly, the receptor is in the same class that gives people their sense of sight, smell and taste (G-protein coupled receptors.)

In ARDS, patients cannot breathe on their own because fluid gets into the lungs. Essentially, the body's immune system causes lung inflammation and accumulation of fluid in the air sacs, or alveoli, leading to low blood-oxygen levels. Up to 30 percent of patients in intensive care units can die from ARDS. There is no current therapy other than general life support and putting patients on a breathing machine. If they survive, many people face long-term lung problems. Common causes of ARDS are pneumonia, septic shock, trauma, or inhaling chemicals.

The receptor identified by UVa doctors is called CXCR2. It's expressed on the endothelial cells that line the blood vessels of the lung and on inflammatory leukocytes. Using animal models, UVa doctors have found that CXCR2 attracts white blood cells called neutrophils into the lung, a key event in the early development of ARDS. CXCR2 has been characterized in the past, but the endothelial cell effects define a new role for this receptor in the body's physiology.

"We can't say yet that if you target this receptor you will stop ARDS," said Klaus Ley, M.D., Ph.D., director of the cardiovascular research center at UVa. "But it is reasonable to be hopeful and to pursue this type of research that might one day translate into clinical application." Ley is senior author on a paper describing the receptor CXCR2 in the Feb. 16, 2006 "Online First Articles" of The Journal of Clinical Investigation found on the web at www.jci.org.

Dr. Jörg Reutershan, M.D., an anesthesiologist from Germany doing research in Ley's lab, discovered that CXCR2 expressed on endothelial cells is involved in acute respiratory syndrome. "Our finding is that expression of this receptor is in the lung itself," Reutershan said. "Our hope is that drug companies might be able to target the lung with an aerosol, which would have the advantage of hitting receptor without compromising the entire immune system, which is always a problem. Aerosol treatment would be a great advantage."
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The paper is titled "Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung." 10.1172/JCI27009

University of Virginia Health System

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