Cincinnati Researchers Publish Pioneering Work Characterizing The Basis For Predisposition To Infection In Deadly Lung Disease

Researchers at Cincinnati Children's
Hospital Medical Center and University of Cincinnati have published
pioneering work characterizing the molecular defect contributing to the
predisposition to microbial infection in people with Pulmonary Alveolar
Proteinosis (PAP), a rare lung disorder that can lead to respiratory
failure and death. Their findings suggest that patients with PAP are unable
to mount an effective defense against microbes due to severe functional
impairment of an important class of white blood cells called neutrophils.
The study published in the Feb. 8, 2007 edition of the New England Journal
of Medicine also highlighted the importance of the immune system regulator
Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF) in securing
resistance against microbes.


"Clinical investigations and effective translation of findings from the
bench to the bedside have considerably changed our concepts of the
pathogenesis and treatment of PAP," said Bruce Trapnell, M.D., M.S., senior
author of the study and Director of the Rare Lung Diseases Consortium, and
the Cystic Fibrosis Therapeutics Development Network Center at Cincinnati
Children's Hospital Medical Center, and Associate Director of the Adult
Cystic Fibrosis Center at the University of Cincinnati. "In addition to
illuminating the mechanism of this disorder, these results provide support
for the feasibility of therapies that modulate GM-CSF activity to stimulate
immune defenses in patients with serious infections and reduce neutrophil
priming in patients with chronic inflammatory disorders."



PAP is characterized by an increased incidence of mortality caused by
microbial infections. This susceptibility to infection is attributed to a
defect in the body's ability to mount an effective immune response that
consequently impairs its normal capacity to kill microbes and avert
infection. Previous evidence had suggested that a potentially important
underlying cause of PAP was misguided generation of antibodies to GM-CSF, a
molecule known to be important to the function of neutrophils, by the PAP
patient's immune system.



The Cincinnati researchers tested neutrophil functions in patients with
PAP, mice lacking the protein GM-CSF and control subjects. The results
showed that neutrophils from patients with PAP have wide ranging defects in
antimicrobial functions owing to the presence of GM-CSF antibodies. The
effects of these antibodies show that GM-CSF is an essential regulator of
neutrophil functions.



"This is an important development in our understanding PAP and provides
new hope for the future treatment of this serious and deadly condition,
said Louie Schimpf, president of the PAP foundation.



About Pulmonary Alveolar Proteinosis



Pulmonary alveolar proteinosis is an extremely rare disease in which a
fluid accumulates within spaces in the lungs where oxygen and carbon
dioxide are exchanged. Symptoms include a persistent, unproductive cough,
weight loss, fatigue and shortness of breath. Standard treatment consists
of periodic whole-lung lavage, which is performed routinely at the
Cincinnati Children's Hospital and University of Cincinnati Medical
Centers. Additional information can be found at
papfoundation.
















About the Rare Lung Diseases Consortium



The Rare Lung Diseases Consortium (RLDC) is a network of cooperating
clinical centers and patient support organizations who are working with the
National Institutes of Health (NIH) in a collaborative network whose novel
structure is designed to accelerate clinical research and improve the
delivery of medical care to individuals affected by rare lung diseases.
Additional information can be found at rarediseasesnetwork.



Cincinnati Children's Hospital Medical Center



Cincinnati Children's Hospital Medical Center, one of the leading
pediatric research institutions in the nation, is dedicated to changing the
outcome for children throughout the world. Cincinnati Children's ranks
second among all pediatric institutions in the United States in grants from
the National Institutes of Health. It has an established tradition of
research excellence, with discoveries including the Sabin oral polio
vaccine, the surfactant preparation that saves the lives of thousands of
premature infants each year, and a rotavirus vaccine that saves the lives
of hundreds of thousands of infants around the world each year. Current
strategic directions include the translation of basic laboratory research
into the development of novel therapeutics for the treatment of disease,
and furthering the development of personalized and predictive medicine.
Additional information can be found at cincinnatichildrens.


Cincinnati Children's Hospital Medical Center

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