An evaluation of Tie2 mRNA as a potential therapeutic for ventilator-induced lung injury

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Despite the necessary, lifesaving use of mechanical ventilation in critical care settings, it can often contribute to further lung injury in ARDS patients. Pulmonary inflammation and vascular leakage are hallmarks of ARDS. Recent studies suggest that endothelial dysfunction in pulmonary infection and ARDS may be mediated through dysregulation of the Angpt-1–Tie2 signalling pathway. Tyrosine kinase Tie2 as a vascular-associated receptor and its agonist ligand Angpt-1 play a key role in angiogenesis and anti-permeability of vessels. Thus, Tie2-targeted therapy is promising for the treatment of VILI. We ventured to evaluate the therapeutic potential of Tie2 mRNA in an in vitro model of VILI. Human A549 and endothelial cells were seeded in 6-well BioFlex® plate for 24 hours and followed by nebulised Tie2 mRNA transfection. Cyclical strain was applied through FX-4000™ Tension System to the 6-well plate. After 72 hours, the cell viability, NF-κB pathway activation and inflammation were assessed. Alamarblue and ELISA assay showed 72-hour stretch significantly (p<0.05) reduced cell viability and increased the expression of IL-8 compared to the controls. Significant overexpression of Tie2 was observed in A549 cells after 24h transfection. After 72-hour stretch, cells transfected with Tie2 significantly improved cell viability and decreased inflammation. Further analysis including cell membrane integrity quantification, NF-κB pathway activation, and testing endothelial cells is ongoing. In summary, a VILI in vitro model is established with reduced cell viability and increased inflammation. Current data suggest the Tie2 mRNA may alleviate in vitro stretch-induced epithelial cell injury.

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