Characterization of a nose-only inhaled phosgene acute lung injury mouse model.

Autor: Plahovinsak JL; a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and., Perry MR; a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and., Knostman KA; a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and., Segal R; b Discovery Laboratories, Inc , Warrington , PA , USA., Babin MC; a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and.
Jazyk: angličtina
Zdroj: Inhalation toxicology [Inhal Toxicol] 2015; Vol. 27 (14), pp. 832-40.
DOI: 10.3109/08958378.2015.1117549
Abstrakt: 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 (8 ppm) or air (sham). An inhalation lethality study was conducted to determine the 8 ppm median lethal exposure (LCt50) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt50. 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 LCt50 was 226 ppm*min (8 ppm for 28.2 min) and the 48-hour LCt50 was 215 ppm*min (8 ppm for 26.9 min). 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 LCt50 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 8 ppm phosgene exposure for 34 min (1.2 × LCt50) 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.
Databáze: MEDLINE
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