Delayed angiopoietin-2 blockade reduces influenza-induced lung injury and improves survival in mice.

Abstract

Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin-2 (Ang-2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang-2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang-2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang-2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin-1 (Ang-1), Ang-2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post-infection (dpi). We tested a peptide-antibody inhibitor of Ang-2, L1-7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air-liquid interface culture with influenza and measured Ang-2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang-2 lung RNA and a dramatic increase in Ang-2 protein in bronchoalveolar lavage. Inhibition of Ang-2 improved oxygenation and survival and reduced pulmonary edema and alveolar-capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang-2 RNA in human AT2 cells. The increased Ang-2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang-2 antagonism suggest that the Ang-1/Ang-2 Tie-2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.

• Authors: Jeffrey E Gotts, Mazharul Maishan, Lauren Chun, Xiaohui Fang, Chun-Ya Han, Venice Chiueh, Aarif Y Khakoo, TaeWeon Lee, Marina Stolina, Michael A Matthay
• Journal: Physiological reports (Physiol Rep) Vol. 9 Issue 21 Pg. e15081 (11 2021) ISSN: 2051-817X [Electronic] United States
• PMID: 34755490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Angiopoietin-2
• Antibodies, Neutralizing
• Cytokines
• Receptor, TIE-2

Topics

• Angiopoietin-2 (antagonists & inhibitors, immunology)
• Animals
• Antibodies, Neutralizing (immunology, pharmacology, therapeutic use)
• Cells, Cultured
• Cytokines (metabolism)
• Humans
• Lung (metabolism, virology)
• Mice
• Mice, Inbred C57BL
• Orthomyxoviridae (pathogenicity)
• Pneumonia, Viral (drug therapy, metabolism, virology)
• Receptor, TIE-2 (metabolism)
• Viral Load