Penn Study On Lung-Infecting Bacterial Enzyme Suggests New Approach To Cystic Fibrosis Treatment

Main Category: Cystic Fibrosis
Article Date: 20 Apr 2007 - 12:00 PDT

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Researchers at the University of Pennsylvania School of Medicine have discovered that an enzyme produced by lung-infecting bacteria further shuts down a protein that is defective in cystic fibrosis patients. The disruption to this protein that conveys ions from lung cells to airways causes thick mucus to buildup inside the lung. The finding suggests a new therapeutic target for treating lung infections in some cystic fibrosis (CF) patients.

Lung infection, facilitated by CF mutations, is the main cause of death in CF patients. This bacterial component to CF now helps explain why the severity of CF symptoms did not match the pathological effect of the CF mutation alone. The study was published this month in the Proceedings of the National Academy of Sciences.

The research, conducted by Zhe Lu, MD, PhD; Yajamana Ramu, PhD; and Yanping Xu, MD, PhD, of the Department of Physiology, shows that the bacterial enzyme, called sphingomyelinase (SMase), disables a protein in lungs called CFTR, for cystic fibrosis transmembrane conductance regulator. SMase is made by the bacteria that cause pneumonia, some anthrax-causing bacteria, and bacteria that cause opportunistic infections in CF and AIDS patients.

In healthy lungs, CFTR allows the passage of chloride ions (and accompanying water) into airways, creating a thin layer of fluid to keep airways clear. However, SMase, secreted by certain respiratory tract bacteria, breaks down lipids surrounding CFTR and thereby suppresses CFTR's chloride-passing function. To make matters worse, the products of the lipid breakdown are also known to trigger inflammation and cell death. Together, these facts compellingly suggest that SMase plays a critical role in the heretofore mysterious pathogenesis of lung injury in CF patients. They also present a new paradigm for treating CF. Specific inhibitors against the enzyme, in conjunction with current antibiotic treatments and supportive measures, might be a viable near-term approach to improving length and quality of life for many CF patients, before CF gene therapy becomes a reality.

The Penn research team demonstrated the disruptive action of SMase in frog oocytes (egg cells) engineered to place CFTR in their membrane. These oocytes are an experimental tool that allows the researchers to assess the flow of ions across the membrane by measuring electrical current. The researchers found that direct exposure of the CFTR-containing oocytes to SMase of Staphylococcus aureus and Bacillus anthracis bacteria shuts off the electrical current passing through not only the normal, but also the CF-causing mutant CFTR.

The next step for the research team is to develop specific inhibitors against the bacterial SMase and test the idea in an animal model.

The National Institute of General Medical Sciences provided funding for this research. This release can be viewed at http://www.pennhealth.com/news.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System. Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

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