Persistent Neutrophilic Inflammation is Associated with Delayed Toxicity of Phenylarsine Oxide in Lungs

Phenyl arsine oxide (PAO) is a vesicant, similar to Lewisite, a potential chemical warfare agent and an environmental contaminant. PAO-induced skin burns can trigger acute organ injury, including lungs. We have recently demonstrated that PAO burns can also has a delayed toxicity, although the specific mechanism/s remain to be determined. A single cutaneous exposure to PAO resulted in inflammatory acute lung injury at 6 and 24 hours. While acute injury subsiding by 1 week, we observed a significant airway remodeling at 10 weeks post-PAO exposure. The mechanism of prolonged PAO toxicity was associated with the influx of neutrophils that produced harmful neutrophil extracellular traps (NETs). We demonstrated that the crosstalk between NET deployments and expression of IL-33, a pro-remodeling mediator was associated with the development of peribronchial fibrosis. In summary, these results suggest that a single cutaneous exposure to PAO causes the acute inflammatory phase followed by NETs/IL-33 feed forward signaling implicated for the persistent neutrophil influx and NETs formation resulting in airway remodeling.