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1 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA
2 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
3 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: sadis{at}uab.edu.
Respiratory syncytial virus (RSV) is the commonest cause of lower respiratory tract disease in infants and children worldwide. Intranasal infection of BALB/c mice with RSV strain A2, but not ultraviolet-inactivated RSV, for 2 or 4 days reduced basal alveolar fluid clearance (AFC), a seminal function of bronchoalveolar epithelium, and caused loss of AFC sensitivity to amiloride inhibition. Reduced AFC was temporally associated with increased lung water content, but was not a consequence of increased epithelial permeability or cell death. Reduced AFC was also not due to decreased transcription of epithelial sodium channel (ENaC) subunit genes in lung tissue. RSV-mediated inhibition of AFC at day 2 was rapidly prevented by addition to the instillate of either P2Y receptor antagonists (suramin, XAMR 0721) or enzymes that degrade UTP, but not those that degrade ATP. After UTP degradation, AFC returned to control levels, but was no longer amiloride-sensitive. UTP at nanomolar concentrations recapitulated the AFC inhibitory effect of RSV in normal mice, and in mice infected with RSV for 6 days, indicating that normalization of AFC at this timepoint is a consequence of cessation of UTP release, rather than P2Y receptor desensitization. We conclude that RSV infection of the bronchoalveolar epithelium results in reduced AFC, as a consequence of autocrine feedback inhibition mediated by UTP. These studies are the first to demonstrate AFC inhibition by an important pulmonary viral pathogen. Reduced AFC may result in formation of an increased volume of fluid mucus, airway congestion, and rhinorrhea, all features of severe RSV disease.
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