Published ahead of print on December 30, 2005, doi:10.1164/rccm.200508-1200OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 6, March 2006, 673-682
A more recent version of this article appeared on March 15, 2006
Submitted on August 3, 2005
Accepted on December 22, 2005
Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus
Ian C Davis1, Eduardo R Lazarowski2, Judy M Hickman-Davis1, James A Fortenberry3, Fu- Ping Chen4, Xiaodong Zhao4, Eric Sorscher5, Lee M Graves6, Wayne M Sullender7, and Sadis Matalon8*
1 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA,
2 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA,
3 Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA,
4 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA,
5 Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA,
6 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA,
7 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA,
8 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: sadis{at}uab.edu.
Rationale: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors.
Objectives: To confirm that RSV-induced inhibition of AFC is mediated by UTP, and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release following RSV infection, and thereby also prevents inhibition of AFC by RSV.
Methods: BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% BSA into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine.
Measurements and Main Results: RSV-mediated inhibition of AFC is associated temporally with a 20 nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volume-regulated anion channel inhibitors.
Conclusion: Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired AFC in RSV disease.
Key words: paramyxovirus infections; pneumonia, viral; pulmonary edema; ion transport
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Copyright © 2005 American Thoracic Society
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