Writing The Story Of The ‘Alcoholic
Lung’
Researchers show how
alcohol harms the lung’s cellular machinery
FORT LAUDERDALE, FL (Nov. 3, 2006) _ Chronic
alcohol abuse disrupts the proteins that keep fluids out of the lung,
lowers a protective antioxidant, disrupts immune defenses and can lead
to a condition known as ‘alcoholic lung,’ according to research to be
presented at the conference, “Physiological Genomics and Proteomics
of Lung Disease.” The findings give insight into how excessive
drinking can harm the molecular life of the lung and lead to serious
illness, including pneumonia and acute respiratory distress syndrome (ARDS).
The study “Chronic alcohol ingestion renders the
lung epithelium susceptible to acute injury by alteration in
granulocyte-macrophage colony-stimulating factor
signaling and alveolar epithelial permeability,” was carried out by
David Guidot, Pratibha Joshi, Jesse Roman, Lou Ann Brown and Michael
Koval of Emory University in Atlanta. Guidot and Joshi are also
associated with the Veterans Affairs Medical Center in Atlanta.
“We’re trying to understand what’s happening with
the alcoholic lung at the molecular level,” said Koval, who will present
the findings at The American Physiological Society lung disease
conference taking place Nov. 2-5 in Fort Lauderdale.
Beyond the liver
Although chronic alcohol abuse is closely
associated with liver disease, the condition affects many of the body’s
organs. In recent years, researchers have turned their attention to the
‘alcoholic lung.’
Alcoholics are more susceptible to pneumonia and
more than twice as likely to develop ARDS compared to non-alcoholics,
Koval said. The alcoholic lung has been found to have lower levels of
glutathione, an antioxidant that helps protect the lung from oxidative
stress.
The Emory research team has found that alcohol
disrupts claudins, a family of proteins that helps maintain a tight
air-fluid barrier. This barrier allows air into the lung, while keeping
blood and other potentially smothering fluids out.
When the claudin proteins are disrupted, the lung
leaks more, the researchers have found. The lung can usually pump out
this excess fluid, but when the lung suffers an injury or infection it
is unable to handle the greater volume, Koval explained. And that’s when
pneumonia or ARDS may develop.
The researchers also previously found that the
alcoholic lung has fewer granulocyte-macrophage colony-stimulating
factor (GM-CSF) receptors and a dampened response to signaling by GM-CSF
in the epithelial cells, which form the lining inside the lung. GM-CSF
is a hormone that plays a role in immunity within the lung.
The researchers keyed into GM-CSF after a clinical
study found that GM-CSF treatment appeared to decrease acute lung injury
in patients with septic shock. They have found that lung epithelial
cells depend on GM-CSF signaling to maintain the tight barrier that is
critical for gas exchange. They have also found that the air-fluid
barrier is enhanced when the alcoholic lung is treated with GM-CSF.
GM-CSF connection
strengthened
With these findings in mind, the researchers fed
rats an alcohol-containing liquid diet for six weeks to mimic chronic
alcohol abuse. They then applied GM-CSF to epithelial cells impaired by
the rats’ alcohol ingestion. They found that GM-CSF restores claudin
protein function and the cells’ air-fluid barrier function improved.
These findings complement their recently published study showing that
this same GM-CSF treatment restores immune function in alcohol-fed rats.
“These findings suggest that alcohol abuse dampens
GM-CSF signaling, which, in turn, contributes to the alcoholic lung
phenotype and renders the lung susceptible to edematous injury,” the
authors wrote. Treating lung epithelial cells with GM-CSF can reverse
the deleterious effects of alcohol, the authors concluded. “GM-CSF
treatment, in part by restoring tight junction protein assembly, may
decrease the risk of acute lung injury in susceptible patients.”
These results are sufficiently intriguing that a
clinical study in which ARDS patients are being treated with GM-CSF is
now taking place, Koval said. An important next step is to understand
how different elements of the lung respond to GM-CSF at the molecular
level, to better optimize treatment of alcoholic lung disease.
Funding
The research was funded by the National Institute
on Alcohol Abuse and Alcoholism of the National Institutes of Health.
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The
American Physiological Society was founded in 1887 to foster basic and
applied bioscience. The Bethesda, Maryland-based society has 10,500
members and publishes 14 peer-reviewed journals containing almost 4,000
articles annually.
* * *
APS
provides a wide range of research, educational and career support and
programming to further the contributions of physiology to understanding
the mechanisms of diseased and healthy states. In 2004, APS received
the Presidential Award for Excellence in
Science, Mathematics and Engineering Mentoring.
