ATP catabolism by tissue nonspecific alkaline phosphatase contributes to development of ARDS in influenza-infected mice.

Abstract

Influenza A viruses are highly contagious respiratory pathogens that are responsible for significant morbidity and mortality worldwide on an annual basis. We have shown previously that influenza infection of mice leads to increased ATP and adenosine accumulation in the airway lumen. Moreover, we demonstrated that A1-adenosine receptor activation contributes significantly to influenza-induced acute respiratory distress syndrome (ARDS). However, we found that development of ARDS in influenza-infected mice does not require catabolism of ATP to adenosine by ecto-5'-nucleotidase (CD73). Hence, we hypothesized that increased adenosine generation in response to infection is mediated by tissue nonspecific alkaline phosphatase (TNAP), which is a low-affinity, high-capacity enzyme that catabolizes nucleotides in a nonspecific manner. In the current study, we found that whole lung and BALF TNAP expression and alkaline phosphatase enzymatic activity increased as early as 2 days postinfection (dpi) of C57BL/6 mice with 10,000 pfu/mouse of influenza A/WSN/33 (H1N1). Treatment at 2 and 4 dpi with a highly specific quinolinyl-benzenesulfonamide TNAP inhibitor (TNAPi) significantly reduced whole lung alkaline phosphatase activity at 6 dpi but did not alter TNAP gene or protein expression. TNAPi treatment attenuated hypoxemia, lung dysfunction, histopathology, and pulmonary edema at 6 dpi without impacting viral replication or BALF adenosine. Treatment also improved epithelial barrier function and attenuated cellular and humoral immune responses to influenza infection. These data indicate that TNAP inhibition can attenuate influenza-induced ARDS by reducing inflammation and fluid accumulation within the lung. They also further emphasize the importance of adenosine generation for development of ARDS in influenza-infected mice.

• Authors: Parker S Woods, Lauren M Doolittle, Judy M Hickman-Davis, Ian C Davis
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 314 Issue 1 Pg. L83-L92 (01 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 28982733 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adenosine Triphosphate
• Alkaline Phosphatase
• 5'-Nucleotidase

Topics

• 5'-Nucleotidase (metabolism)
• Adenosine Triphosphate (metabolism)
• Alkaline Phosphatase (metabolism)
• Animals
• Influenza A Virus, H1N1 Subtype (pathogenicity)
• Mice
• Mice, Inbred C57BL
• Orthomyxoviridae Infections (complications, virology)
• Pulmonary Edema (etiology, metabolism, pathology)
• Respiratory Distress Syndrome (etiology, metabolism, pathology)
• Virus Replication