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Mechanism That Causes Infection in Rare Lung Disease Found
Published March 2007
Nearly 20 percent of reported deaths in people with the rare lung disorder pulmonary alveolar proteinosis (PAP) are attributed to microbial infections.
Researchers at UC and Cincinnati Children’s Hospital Medical Center have identified a molecular defect in PAP sufferers, explaining why they are more susceptible to these deadly infections.
The study, led by Bruce Trapnell, MD, and reported in the Feb. 8, 2007, issue of the New England Journal of Medicine, could support the development of new therapies for treating infection in people with PAP.
“PAP develops when surfactant—a protein- and lipid-based material on the lung’s surface that keeps the tiny air sacs (alveoli) from collapsing—builds up inside the air sacs,” says Trapnell. “When this happens, breathing becomes difficult and microbial infections are common.”
In healthy people, Trapnell says, proteins, called antibodies, attack microbes to help fight off infections. Sometimes, however, our bodies produce “autoantibodies”—antibodies that attack our own tissues instead of microbes.
It was recently discovered that people with PAP produce high levels of autoantibodies that attack granulocyte–macrophage colony-stimulating factor (GM-CSF), an important regulator of the innate immune system.
The researchers, in human and animal studies, determined that other important infection fighters—white blood cells called neutrophils—were impaired in PAP. In addition to this finding, the researchers found that their impairment was being caused by the autoantibodies against GM-CSF.
Trapnell says knowing the mechanism that causes infection in PAP patients could lead to therapies to stimulate immune defenses.
“This is an important development in our understanding of PAP and provides new hope for the future treatment of this serious and deadly condition,” says Louie Schimpf, president of the national PAP Foundation.
Trapnell, who leads UC’s Adult Cystic Fibrosis Center, the Cystic Fibrosis Therapeutics Develop-ment Network Center at Cincinnati Children’s and the international Rare Lung Diseases Clinical Research Consortium, says that PAP, the causes of which are unknown, can affect people of any age and range from mild to severe.
PAP sufferers often experience unexplained, progressive shortness of breath and sometimes cough and fever, especially when infection is present. There are few treatments for PAP, but symptoms are often relieved by periodic whole-lung lavage—a procedure in which lungs are individually filled with saline solution to “wash” out the surfactant.
Lung transplantation is not a useful treatment approach, since the new lungs would come under the same misguided autoimmune attack.
The study was funded by grants from the National Heart, Lung and Blood Institute, the National Center for Research Resources and the National Institute of Health Office of Rare Diseases.
Coauthors, all from UC and Cincinnati Children’s, include Shuichi Abe, MD, PhD, David Beck, MD, PhD, Pierre-Yves Berclaz, MD, PhD, Brenna Carey, PhD, Lee Denson, MD, Marie-Dominique Filippi, PhD, Diane Hauck, Jonathan Puchalski, MD, Margaret Staudt, Kanji Uchida, MD, PhD, Susan Wert, PhD, and Takashi Yamamoto, MD, PhD.