Study Title:

Antioxidants Protect Lungs from the Flu

Study Abstract

The mechanisms by which replicating influenza viruses decrease the expression and function of amiloride-sensitive epithelial sodium channels (ENaCs) have not been elucidated. We show that expression of M2, a transmembrane influenza protein, decreases ENaC membrane levels and amiloride-sensitive currents in both Xenopus oocytes, injected with human -, β-, and -ENaCs, and human airway cells (H441 and A549), which express native ENaCs. Deletion of a 10-aa region within the M2 C terminus prevented 70% of this effect. The M2 ENaC down-regulation occurred at normal pH and was prevented by MG-132, a proteasome and lysosome inhibitor. M2 had no effect on Liddle ENaCs, which have decreased affinity for Nedd4-2. H441 and A549 cells transfected with M2 showed higher levels of reactive oxygen species, as shown by the activation of redox-sensitive dyes. Pretreatment with glutathione ester, which increases intracellular reduced thiol concentrations, or protein kinase C (PKC) inhibitors prevented the deleterious effects of M2 on ENaCs. The data suggest that M2 protein increases steady-state concentrations of reactive oxygen intermediates that simulate PKC and decrease ENaCs by enhancing endocytosis and its subsequent destruction by the proteasome. These novel findings suggest a mechanism for the influenza-induced rhinorrhea and life-threatening alveolar edema in humans.

From press release:

Scientists Discover Influenza's Achilles Heel: Antioxidants

As the nation copes with a shortage of vaccines for H1N1 influenza, a team of Alabama researchers have raised hopes that they have found an Achilles' heel for all strains of the flu -- antioxidants.

In an article appearing in the November 2009 print issue of the FASEB Journal, they show that antioxidants -- the same substances found in plant-based foods -- might hold the key in preventing the flu virus from wreaking havoc on our lungs.

"The recent outbreak of H1N1 influenza and the rapid spread of this strain across the world highlights the need to better understand how this virus damages the lungs and to find new treatments," said Sadis Matalon, co-author of the study. "Additionally, our research shows that antioxidants may prove beneficial in the treatment of flu."

Matalon and colleagues showed that the flu virus damages our lungs through its "M2 protein," which attacks the cells that line the inner surfaces of our lungs (epithelial cells). Specifically, the M2 protein disrupts lung epithelial cells' ability to remove liquid from inside of our lungs, setting the stage for pneumonia and other lung problems. The researchers made this discovery by conducting three sets of experiments using the M2 protein and the lung protein they damage.

First, frog eggs were injected with the lung protein alone to measure its function. Second, researchers injected frog eggs with both the M2 protein and the lung protein and found that the function of the lung protein was significantly decreased. Using molecular biology techniques, scientists isolated the segment of the M2 protein responsible for the damage to the lung protein. Then they demonstrated that without this segment, the protein was unable to cause damage. Third, the full M2 protein (with the "offending" segment intact) and the lung protein were then re-injected into the frog eggs along with drugs known to remove oxidants. This too prevented the M2 protein from causing damage to the lung protein. These experiments were repeated using cells from human lungs with exactly the same results.

"Although vaccines will remain the first line of intervention against the flu for a long time to come, this study opens the door for entirely new treatments geared toward stopping the virus after you're sick," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "and as Thanksgiving approaches, this discovery is another reason to drink red wine to your health."

Study Information

1.Ahmed Lazrak, Karen E. Iles, Gang Liu, Diana L. Noah, James W. Noah, and Sadis Matalon
Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species
1.Ahmed Lazrak, Karen E. Iles, Gang Liu, Diana L. Noah, James W. Noah, and Sadis Matalon
2009 October
Department of Medicine, Schools of Medicine and Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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