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

Abstract

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.

• Authors: Jennifer L Plahovinsak, Mark R Perry, Katherine A Knostman, Robert Segal, Michael C Babin
• Journal: Inhalation toxicology (Inhal Toxicol) Vol. 27 Issue 14 Pg. 832-40 ( 2015) ISSN: 1091-7691 [Electronic] England
• PMID: 26671199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Phosgene

Topics

• Acute Lung Injury (chemically induced, pathology)
• Administration, Intranasal
• Animals
• Male
• Mice
• Mice, Inbred C57BL
• Phosgene (administration & dosage, toxicity)