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Published ahead of print on May 31, 2007, doi:10.1165/rcmb.2007-0142OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 4, October 2007, 379-386

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Submitted on April 20, 2007
Revised on May 31, 2007

Post Infection A77-1726 Blocks Pathophysiologic Sequelae of Respiratory Syncytial Virus Infection

Ian C Davis1, Eduardo R Lazarowski2, Fu-Ping Chen3, Judy M Hickman-Davis1, Wayne M Sullender4, and Sadis Matalon5*

1 Department of Anesthesiology, University of Alabama at Brimingham, Birmingham, AL, United States, 2 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA, 3 Department of Pediatrics, University of Alabama at Brimingham, Birmingham, AL, USA, 4 Department of Pediatrics, University of Alabama at Brimingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Brimingham, Birmingham, AL, USA, 5 Department of Anesthesiology, University of Alabama at Brimingham, Birmingham, AL, United States; Department of Microbiology, University of Alabama at Brimingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Brimingham, Birmingham, AL, USA

* To whom correspondence should be addressed. E-mail: sadis{at}uab.edu.

Despite respiratory syncytial virus (RSV) bronchiolitis remaining the most common cause of lower respiratory tract disease in infants worldwide, treatment has progressed little in the past 30 years. To determine whether postinfection administration of de novo pyrimidine synthesis inhibitors could prevent the reduction in alveolar fluid clearance (AFC) and hypoxemia that occurs at day 2 following intranasal infection of BALB/c mice with RSV. BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice following instillation of 5% BSA into the dependent lung. Post-infection systemic treatment with leflunomide has no effect on AFC. However, when added to the AFC instillate, leflunomide's active metabolite, A77-1726, blocks RSV-mediated inhibition of AFC at day 2. This block is reversed by uridine (which allows pyrimidine synthesis via the scavenger pathway) and not recapitulated by genistein (which mimics the tyrosine kinase inhibitor effects of A77-1726), indicating that the effect is specific for the de novo pyrimidine synthesis pathway. More importantly, when administered intranasally at day 1, A77-1726, but not its vehicle DMSO, maintains its beneficial effect on AFC and lung water content until day 2. Intranasal instillation of A77-1726 at day 1 also reduces BAL nucleotide levels, lung inflammation, and hypoxemia at day 2 without impairing viral replication at day 2 or viral clearance at day 8. Post-infection intranasal or aerosolized treatment with pyrimidine synthesis inhibitors may provide symptomatic relief from the pathophysiologic sequelae of impaired AFC in children with RSV bronchiolitis.




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