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Influenza A Virus Inhibits Alveolar Fluid Clearance in BALB/c Mice

¹ Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio; ² Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; ³ Columbus Children's Research Institute, Columbus, Ohio; and ⁴ Department of Pediatrics, Ohio State University, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Ian C. Davis, D.V.M., Ph.D., Department of Veterinary Biosciences, Ohio State University, 331 Goss Lab, 1925 Coffey Road, Columbus, OH 43210. E-mail: davis.2448{at}osu.edu

Rationale: Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown.

Objectives: To determine effects of IAV infection on AFC, and to identify intercellular signaling mechanisms underlying influenza-mediated inhibition of AFC.

Methods: BALB/c mice were infected intranasally with influenza A/WSN/33 (10,000 or 2,500 focus-forming units per mouse). AFC was measured in anesthetized, ventilated mice by instilling 5% bovine serum albumin into the dependent lung.

Measurements and Main Results: Infection with high-dose IAV resulted in a steady decline in arterial oxygen saturation and increased lung water content. AFC was significantly inhibited starting 1 hour after infection, and remained suppressed through Day 6. AFC inhibition at early time points (1–4 h after infection) did not require viral replication, whereas AFC inhibition later in infection was replication-dependent. Low-dose IAV infection impaired AFC for 10 days, but induced only mild hypoxemia. High-dose IAV infection increased bronchoalveolar lavage fluid ATP and UTP levels. Impaired AFC at Day 2 resulted primarily from reduced amiloride-sensitive AFC, mediated by increased activation of the pyrimidine-P2Y purinergic receptor axis. However, an additional component of AFC impairment was due to activation of A₁ adenosine receptors and stimulation of increased cystic fibrosis transmembrane regulator–mediated anion secretion. Finally, IAV-mediated inhibition of AFC at Day 2 could be reversed by addition of β-adrenergic agonists to the AFC instillate.

Conclusions: AFC inhibition may be an important feature of early IAV infection. Its blockade may reduce the severity of pulmonary edema and hypoxemia associated with influenza pneumonia.

Key Words: orthomyxovirus infections • pneumonia, viral • pulmonary edema • ion transport • adenosine

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Active transport of sodium ions by bronchoalveolar epithelial cells drives alveolar fluid clearance (AFC), which is crucial to efficient gas exchange in the lung. What This Study Adds to the Field Infection with influenza A virus has physiologically significant inhibitory effects on AFC in vivo in BALB/c mice, which result from uridine diphosphate–mediated inhibition of sodium transport and adenosine-mediated stimulation of chloride secretion.