Influenza A virus inhibits alveolar fluid clearance in BALB/c mice.
BACKGROUND
Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown.


OBJECTIVE
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.


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 A(1) 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 beta-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.
Wolk
Kendra E
KE
Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210, USA.
Lazarowski
Eduardo R
ER
Traylor
Zachary P
ZP
Yu
Erin N Z
EN
Jewell
Nancy A
NA
Durbin
Russell K
RK
Durbin
Joan E
JE
Davis
Ian C
IC
D000818:Animals; D001693:Biological Transport, Active; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000821:virology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D009980:Influenza A virus / Q000378:metabolism*; D008168:Lung / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D010539:Permeability; D013997:Time Factors
D016207:Cytokines; D010100:Oxygen