1 research outputs found
Acute Gene Expression Profile of Lung Tissue Following Sulfur Mustard Inhalation Exposure in Large Anesthetized Swine
Sulfur
mustard (HD) is a vesicating and alkylating agent widely used on the
battlefield during World War I and more recently in the Iran-Iraq
War. It targets the eyes, skin, and lungs, producing skin burns, conjunctivitis,
and compromised respiratory function; early acute effects lead to
long-term consequences. However, it is the effects on the lungs that
drive morbidity and eventual mortality. The temporal postexposure
response to HD within lung tissue raises the question of whether toxicity
is driven by the alkylating properties of HD on critical homeostatic
pathways. We have established an anesthetized swine model of inhaled
HD vapor exposure to investigate the toxic effects of HD 12 h postexposure.
Large white female swine were anesthetized and instrumented prior
to exposure to air, 60 (sublethal) or 100 μg·kg<sup>–1</sup> (∼LD<sub>40</sub>) doses of HD (10 min). Physiological parameters
were continuously assessed. Data indicate that exposure to 100 μg·kg<sup>–1</sup> HD lowered arterial blood oxygenation and increased
shunt fraction and lavage protein compared with those of air-exposed
controls and the 60 μg·kg<sup>–1</sup> dose of HD.
Histopathology showed an increased total pathology score between the
100 μg·kg<sup>–1</sup> HD group and air-exposed
controls. Principal component analysis of differentially expressed
genes demonstrated a distinct and separable response of inhaled HD
between air-exposed controls and the 60 and 100 μg·kg<sup>–1</sup> doses of HD. Canonical pathway analysis demonstrated
changes in acute phase response signaling, aryl hydrocarbon receptor
signaling, NRF-2 mediated oxidative stress, and zymosterol biosynthesis
in the 60 and 100 μg·kg<sup>–1</sup> HD dose group.
Transcriptional changes also indicated alterations in immune response,
cancer, and cell signaling and metabolism canonical pathways. The
100 μg·kg<sup>–1</sup> dose group also showed significant
changes in cholesterol biosynthesis. Taken together, exposure to inhaled
HD had a significant effect on physiological responses coinciding
with acute changes in gene expression and lung histopathology. In
addition, transcriptomics support the observed beneficial effects
of <i>N</i>-acetyl-l-cysteine for treatment of
acute inhalation HD exposure