Oct. 18, 2006 When a child under the age of 2 contracts a respiratory tract infection requiring hospitalization, odds are that the cause is respiratory syncytial virus (RSV).
One of the world's most common and dangerous early-childhood infections, RSV puts more than 100,000 children a year in the hospital in the U.S. alone; the infection may also increase the chances that a child will develop asthma.
Currently, neither a safe vaccine nor an effective therapy for RSV exists. Now, however, University of Texas Medical Branch at Galveston (UTMB) researchers have taken an important step toward developing a therapy for RSV.
Working with laboratory mice, the scientists have shown for the first time that RSV does its dirty work by causing cells to produce highly damaging molecules known as reactive oxygen species (ROS). These molecules prompt cells to produce signals that send the immune system into overdrive, creating an inflammatory response that actually does more damage than the virus itself and closely resembles the one seen in an asthma attack.
The researchers found that this effect, known as oxidative stress, can be substantially reduced by treating the mice with an antioxidant chemical. The treatment also lowers the asthma-like symptoms of "airway hyperreactivity" seen in RSV-infected mice even after the mice have recovered from the virus.
"We really need a good therapy for RSV," said UTMB associate professor of pediatric infectious diseases Antonella Casola, senior author of a paper on the research published online by the American Journal of Respiratory and Critical Care Medicine, which will publish the paper in an upcoming printed edition. "What we'd like to have is a safe therapy that could be given to a child as soon as he or she develops the initial upper respiratory symptoms of RSV infection. If we can treat children with RSV before a lower respiratory tract infection occurs--that is, before the virus gets into the lungs--we believe we can keep those children from developing the serious infections that require hospital care."
In their experiments, the Texas scientists initially checked for and found biochemical signs of oxidative stress in the lungs of mice infected by RSV. Recent studies have linked such stress to the development of such lung disorders as acute respiratory distress, asthma and chronic obstructive pulmonary disease.
The UTMB researchers divided mice infected with RSV into two groups, one of which was also fed an antioxidant compound called butylated hydroxyanisole (BHA), a food preservative. The scientists found that the BHA-treated mice showed far fewer outward clinical indicators of acute RSV infection. Detailed study of the animals' lung cells revealed that BHA substantially diminished the harmful inflammation associated with RSV without hampering the immune response necessary to eradicate the virus. Biochemical analysis of lung contents showed that BHA blocked the production of molecules associated with RSV-induced ROS production, known as lipid peroxidation products, as well as significantly reducing the explosion of pro-inflammatory molecules produced by lung cells that is normally associated with severe RSV infection.
"We see this as the proof of concept for a novel antioxidant approach to RSV therapy," Casola said. "Hopefully, in the future an antioxidant treatment can be developed that could be given orally and used before inflammatory symptoms appear in the lungs."
UTMB graduate student Shawn Castro was the lead author of the paper, titled "Antioxidant Treatment Ameliorates Respiratory Syncytial Virus-Induced Disease and Lung Inflammation." Co-authors include postdoctoral fellow Antonieta Guerrera-Plata, graduate student Giovanni Suarez-Real, associate professor Patrick A. Adegboyega and professor Roberto Garofalo of UTMB, as well as University of Texas Health Science Center-Houston professor Giuseppe Colasurdo and associate professor Amir Khan.
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