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

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Physiol Rep


. 2021 Nov;9(21):e15081.
doi: 10.14814/phy2.15081.
Delayed angiopoietin-2 blockade reduces influenza-induced lung injury and improves survival in mice


Jeffrey E Gotts ¹ , Mazharul Maishan ¹ , Lauren Chun ¹ , Xiaohui Fang ¹ , Chun-Ya Han ² , Venice Chiueh ² , Aarif Y Khakoo ² , TaeWeon Lee ² , Marina Stolina ² , Michael A Matthay ¹



Affiliations

• PMID: 34755490
• DOI: 10.14814/phy2.15081

Free article

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.

Keywords: angiopoietin-2; influenza; pneumonia; pulmonary edema; viral lung injury.