A murine model of vesicant-induced Acute Lung Injury.

Burn injuries including those caused by chemicals can result in systemic effects and acute lung injury (ALI). Cutaneous exposure to Lewisite, a warfare and chemical burn agent, also causes ALI. To overcome the limitations in conducting direct research on Lewisite-induced ALI in a laboratory setting, an animal model was developed using phenylarsine oxide (PAO) as a surrogate for lewisite. Due to lack of a reliable animal model mimicking the effects of such exposures, development of effective therapies to treat such injuries is challenging. We demonstrated that a single cutaneous exposure to PAO resulted in disruption of alveolar-capillary barrier as evidenced by elevated protein levels in the bronchoalveolar lavage fluid (BALF). BALF supernatant of PAO-exposed animals had increased levels of HMGB1, a damage associated molecular pattern (DAMP) molecule. Arterial blood-gas measurements showed decreased pH, increased PaCO 2 , and decreased PaO 2 , indicative of respiratory acidosis, hypercapnia, and hypoxemia. Increased protein levels of IL-6, CXCL-1, CXCL-2, CXCL-5, GM-CSF, CXCL-10, LIF, Leptin, IL-18, CCL-2, CCL-3, and CCL-7, were observed in the lung of PAO-exposed mice. Further, VEGFA levels were reduced in the lung. Pulmonary function evaluated using a flexiVent showed a downward shift in the PV loop, decreases in static compliance and inspiratory capacity, increases in respiratory elastance and tissue elastance. These changes are consistent with an ALI phenotype. These results demonstrate that cutaneous PAO exposure leads to ALI and that the model can be used as an effective surrogate to investigate vesicant-induced ALI. Significance Statement This study presents a robust model for studying acute lung injury (ALI) resulting from cutaneous exposure to PAO, a surrogate for the toxic vesicating agent Lewisite. The findings in this study mimic the effects of cutaneous lewisite exposure, providing a reliable model for investigating mechanisms underlying toxicity. The model can also be used to develop medical countermeasures to mitigate ALI associated with cutaneous Lewisite exposure.