Delayed angiopoietin-2 blockade reduces influenza-induced lung injury and improves survival in mice.
Jeffrey E GottsMazharul MaishanLauren ChunXiaohui FangChun-Ya HanVenice ChiuehAarif Y KhakooTaeWeon LeeMarina StolinaMichael A MatthayPublished in: Physiological reports (2022)
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.
Keyphrases
- angiotensin ii
- acute respiratory distress syndrome
- poor prognosis
- induced apoptosis
- multiple sclerosis
- sars cov
- oxidative stress
- early onset
- extracorporeal membrane oxygenation
- young adults
- adipose tissue
- cell death
- signaling pathway
- climate change
- cell proliferation
- ionic liquid
- metabolic syndrome
- binding protein
- protein protein
- blood flow
- human health