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Sex-dependent acrolein sensitivity in mice is associated with differential lung cell, protein, and transcript changes
Kiflai Bein1, Rahel L Birru1, Heather Wells1
1Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Physiological Reports
|October 4, 2021
Summary
Acrolein exposure causes acute lung injury, with males exhibiting higher sensitivity and more severe responses than females. This sex-dependent injury involves distinct inflammatory and molecular pathways, including increased IL6:IL10 ratios in males.
Area of Science:
- Toxicology
- Pulmonary Medicine
- Immunology
Background:
- Acrolein is a reactive inhalation hazard causing acute lung injury.
- The injury involves complex, time-dependent cellular and pulmonary responses.
- Sex-dependent differences in injury severity and progression are not fully understood.
Purpose of the Study:
- To investigate the sex-dependent pathophysiological progression of acrolein-induced acute lung injury.
- To identify molecular pathways and biomarkers associated with injury severity.
Main Methods:
- C57BL/6J mice (male and female) were exposed to sublethal or lethal concentrations of acrolein.
- Bronchoalveolar lavage (BAL) fluid and plasma were collected at 3 and 12 hours post-exposure.
- Cell counts, protein levels, and RNA sequencing (RNASeq) were performed to analyze lung responses.
Main Results:
- Male mice were more sensitive to acrolein than female mice, with distinct lethal doses.
- Acrolein exposure led to decreased BAL cell counts followed by increased neutrophils and protein.
- RNASeq revealed greater increases in lung neutrophil, glutathione metabolism, oxidative stress, and specific cytokine transcripts (IL6, CCL7, CXCL10) in males, while IL10 increased more in females, resulting in a higher IL6:IL10 ratio in males. Histone H3.3B (H3F3B) and pro-platelet basic protein (PPBP) transcripts and protein increased, suggesting a role in neutrophil extracellular trap formation.
Conclusions:
- Acrolein-induced acute lung injury exhibits significant sex-dependent differences in severity and inflammatory response.
- Elevated IL6:IL10 ratio in males indicates a more severe inflammatory state.
- H3F3B and PPBP may serve as potential biomarkers for acrolein-induced lung injury and neutrophil extracellular trap formation.
