October 29, 2004

Prostacyclin’s role in guarding against RSV studied

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R. Stokes Peebles Jr., M.D., and colleagues have found that mice treated with prostacyclin were protected against illness caused by RSV.
photo by Dana Johnson

Prostacyclin’s role in guarding against RSV studied

A new treatment strategy for battling the most common cause of respiratory illness in infants and young children — respiratory syncytial virus, or RSV — may be on the horizon, according to a recent study by VUMC researchers.

The research team, led by R. Stokes Peebles Jr., M.D., associate professor of Medicine, found that a type of prostaglandin, called prostacyclin (PGI2), protects mice from developing RSV-induced illness. These results are reported in the October issue of the Journal of Virology.

According to the American Lung Association, RSV is the leading cause of respiratory failure in young children and is responsible for roughly 90,000 hospitalizations and 4,500 deaths each year among infants and young children. The RSV season typically runs from November to February each year with a peak in January and February.

Most children are infected by age 2. In most healthy children and adults, the symptoms are mild, similar to a common cold. But for premature infants, children with cardiopulmonary disease, and children born at the peak of RSV season, RSV infection can be life threatening.

“If you go into almost any pediatric ICU (during RSV season), many if not most of the beds would be filled with children with respiratory failure from RSV bronchiolitis. Quite a few of those will require mechanical ventilation,” Peebles said.

Currently, there is no effective treatment or vaccine for RSV. Passive antibody therapy can be used preventively in some high-risk infants, but it is expensive, has to be taken every month and carries the risk of blood-borne illness. Therefore, new treatments for RSV are needed.

“Recently prostacyclin has been shown to have immunomodulatory effects in allergic diseases. It seems to down-regulate allergic inflammation,” Peebles said. Since it alleviated allergic inflammation in the lungs, Peebles proposed that it also might suppress lung inflammation and allay illness associated with RSV infection. However, almost no prior research had even looked at this problem.

With the support of a recent $1.1 million grant from the National Institutes of Health, Peebles was able to pursue this novel idea.

“This is the first paper to ever look at prostacyclin in RSV or any respiratory virus, ” Peebles said.

In the new study, Peebles and colleagues found that levels of a urinary metabolite of prostacyclin were increased during the peak of RSV infection and recovery in normal mice. This suggested to the researchers that prostacyclin may be protective against RSV-induced illness.

Peebles and colleagues then examined the role of prostacyclin in RSV illness using two types of genetically engineered mice; one group produced increased amounts of prostacyclin, whereas the other lacked the prostacyclin receptor, blocking prostacyclin signaling.

When infected with RSV, the mice with increased amounts of prostacyclin lost less weight compared to control animals, suggesting that prostacyclin protected them against RSV illness. These mice also showed decreased levels of viral replication, less fluid in their lungs, and a blunted immune response to RSV infection. In contrast, when prostacyclin activity was blocked, RSV illness was more severe. These mice lost more weight than controls, had higher levels of virus in their blood, and showed a heightened immune response toward the virus.

“We found that if you can't signal through the prostacyclin receptor, RSV illness is exacerbated,” Peebles said. This exciting new role for prostacyclin has major implications for RSV therapy in humans, he said.

Putting it to the test

This RSV season, Peebles and colleagues in Pediatric Clinical Care — Frederick E. Barr, M.D., associate professor of Pediatrics and Anesthesiology, and Bradly Strohler, M.D., clinical fellow — will begin examining the role of prostacyclins in infants. First, they will measure prostacyclin metabolism in RSV-infected infants. If the human results corroborate those found in mice, Peebles anticipates that a clinical investigation of the efficacy of prostacyclin in treating RSV infections may be forthcoming.

The bench-to-bedside progression may happen quickly in this case because prostacyclin is already available and approved by the Food and Drug Administration for the treatment of primary pulmonary hypertension.

“The exciting thing about this particular drug in RSV is that it's not an experimental drug. It is already on the market, but it hasn't been used for this indication,” Peebles said.

Although there can be some complications from long-term prostacyclin use (i.e., infection from IV administration, headaches, low blood pressure), Peebles says that short-term use for treating acute RSV bronchiolitis might be less of a problem.

“We look at this as a potential treatment for acute RSV bronchiolitis, or perhaps could be used prophylactically in children at high risk,” Peebles said.

This study was supported by the American Academy of Allergy, Asthma and Immunology, the National Institutes of Health, and Fukushima Medical University.