Characterization Of A Nose-Only Inhaled Phosgene Acute Lung Injury Mouse Model

Context: Phosgene's primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6-24 h post-exposure.Objective: To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures.Methods: A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8ppm) or air (sham). An inhalation lethality study was conducted to determine the 8ppm median lethal exposure (LCt(50)) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt(50). At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life.Results and discussion: The 24-hour LCt(50) was 226ppm*min (8ppm for 28.2min) and the 48-hour LCt(50) was 215ppm*min (8ppm for 26.9min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt(50) phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies.Conclusion: An 8ppm phosgene exposure for 34min (1.2xLCt(50)) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant.