||Researchers at the University
of Pennsylvania School of Medicine 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.
||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, and this finding
suggests a new therapeutic target for treating lung infections
in some CF patients.
||The study was published this month in
the Proceedings of the National Academy of Sciences.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine 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
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
plan; a primary-care provider network; two multispecialty satellite
facilities; and home care and hospice.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.