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

Ian C. Davis^1,*, Eduardo R. Lazarowski², Fu-Ping Chen³, Judy M. Hickman-Davis^1,, Wayne M. Sullender^3,4 and Sadis Matalon^1,4,5

Departments of ¹ Anesthesiology, ³ Pediatrics, ⁴ Microbiology, and ⁵ Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and ² Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Sadis Matalon, Ph.D., Department of Anesthesiology, University of Alabama at Birmingham, BMR II, Rm. 224, 901 19th Street South, Birmingham, AL 35205-3703. 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. The aim of our study was to determine whether post-infection administration of de novo pyrimidine synthesis inhibitors could prevent the reduction in alveolar fluid clearance (AFC) and hypoxemia that occurs at Day 2 after 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 after instillation of 5% bovine serum albumin 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 dimethyl sulfoxide, maintains its beneficial effect on AFC and lung water content until Day 2. Intranasal instillation of A77-1726 at Day 1 also reduces bronchoalveolar lavage 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.

Key Words: paramyxovirus • leflunomide • dihydroorotate dehydrogenase • pulmonary edema

CLINICAL RELEVANCE Herein we show that prophylactic intranasal administration of A77-1726, an agent that decreases UTP levels, prevents the respiratory syncytial virus–induced decrease of alveolar fluid clearance and onset of arterial hypoxemia in mice.

 

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