||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
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