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.
The research was funded by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.
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