The Gene Expression Profile of Lung Tissue Following Sulfur Mustard Inhalation Exposure in Large Anesthetized Swine
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ABSTRACT:
ORGANISM(S): Sus scrofa
SUBMITTER: Heidi Hoard-Fruchey
PROVIDER: E-GEOD-73088 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Sulfur mustard (HD) is a potent alkylating agent that induces cutaneous injury. The molecular mechanisms of cutaneous injury are not completely understood, and the molecular pathways involved in post-exposure wound healing are not well characterized. To elucidate these molecular pathways for the purpose of identifying potential therapeutic targets, we used oligonucleotide microarrays to identify gene expression profile changes induced by HD in porcine skin, an established animal model of HD injury and wound healing. Female Yorkshire crossbred pigs were exposed to neat HD to generate a superficial dermal (second degree) injury. Skin punch biopsies were collected at 1 h, 2 h, 4 h, 24 h, 48 h, 72 h, 7 d, 14 d or 21 d post-exposure. Biopsies were scored for histopathology, and RNA extracted from biopsies was used for microarray analysis. Gene expression profiles were analyzed for significant temporal response to HD by analysis of variance (false discovery corrected p<0.05). Gene expression profiles were also correlated (Pearson linear correlation |r|>0.7, false discovery corrected p<0.05) to histopathology scores to identify molecular pathways significantly correlated with specific clinical endpoints of injury and repair. Several pathways linked to aspects of inflammatory response and cell cycle checkpoint regulation were altered by HD exposure through 72 h. Several of these inflammatory pathways were highly correlated with clinical endpoints assessed through 72 h, including epidermal necrosis and vesicle formation. Pathways linked to inflammation were also highly correlated with 7-21 d total histopathology scores, suggesting that inflammation is continual through the course of injury and healing. Specific therapeutic targets were identified within these inflammatory pathways, and potential therapeutics were also identified for future drug screening efforts.
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Project description:Sulfur mustard (SM) is a potent alkylating agent. We are developing medical countermeasures to reduce the injury caused by SM exposure. Screening in the mouse ear vesicant model has identified three effective compounds: dimercaprol (British anti-lewisite), indomethacin, and octyl homovanillamide (OHV). To identify gene expression changes that correlate with compound efficacy we used oligonucleotide microarrays to compare gene expression profiles in vehicle-exposed skin, SM-exposed skin, and skin pretreated with each compound before SM exposure. Mice were topically exposed on the inner surface of the right ear to SM alone or pretreated for 15 min with one of the compounds and then exposed to SM. Left ears were vehicle-exposed. Ear tissue was harvested 24 hr later for ear weight determination (an endpoint indicating compound efficacy). The exposure groups were: methylene chloride (sulfur mustard vehicle); ethanol (drug vehicle); 0.08 mg sulfur mustard; 6.25 mg dimercaprol 15 min before 0.08 mg sulfur mustard; 1.34 mg indomethacin 15 min before 0.08 mg sulfur mustard; 0.6 mg octylhomovanillamide 15 min before 0.08 mg sulfur mustard; 6.25 mg dimercaprol alone; 1.34 mg indomethacin alone; 0.6 mg octylhomovanillamide alone. RNA was extracted from the tissues and used to generate oligonucleotide microarray probes. Principal component analysis of the gene expression data revealed partitioning of the samples based on drug treatment and SM exposure. Vehicle-exposed mouse ears clustered away from the other treatment groups. SM-exposed mouse ears pretreated with dimercaprol or OHV clustered more closely with vehicle-exposed ears, while SM-exposed mouse ears pretreated with indomethacin clustered more closely with SM-exposed ears. This clustering of the samples is supported by the ear weight data, in which the indomethacin group has ear weights closer to the SM-exposed group, whereas the dimercaprol and OHV groups have ear weights closer to the vehicle-exposed group. Correlation coefficients were calculated for each gene based on the correlation between gene expression level and ear weight. These data provide the basis for understanding what gene expression changes are important in the development of effective SM medical countermeasures. Experiment Overall Design: Exposure of mouse ears to sulfur mustard alone, sulfur mustard preceded by drug treatment, or vehicle compounds. Naive controls were also included. Biological replicates of at least n=3 were examined for each exposure condition.
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Project description:Normal human epidermal keratinocytes (NHEKs) and HaCaTs have been widely used as cell culture models to study the effects of cutaneous sulfur mustard (HD) exposure. While these cell lines are similar, one key difference is that NHEKs are primary cells, whereas HaCaT cells are a transformed line with a mutation in the p53 gene. However, the impact of this mutation on the response of HaCaT cells to HD is unclear. Thus, gene expression profiling was performed to compare the transcriptional responses of NHEKs and HaCaTs after HD exposure. Cells were exposed to 0, 25, and 200 µM HD, harvested at 1 h and 8 h post-exposure, and processed for microarray analysis. Principal component analysis of the microarray data suggested profile differences based on cell type, but both cell types respond similarly to HD with regard to dose and time. To further analyze the expression profiles at various doses, the dataset was filtered by dose, and an analysis of variance was performed using cell type as the factor; the pathways most significantly different between these cell types were identified. At all three doses, the p53 and N-glycan degradation pathways were significantly different between NHEKs and HaCaTs. Interestingly, p53 responsive genes showed differences and similarities across cell types, which may provide insight into the role of p53 in HD toxicity. The inflammatory pathways expected to respond to HD exposure were not significantly different between cell types, suggesting that both NHEKs and HaCaTs are appropriate models to study the inflammatory effects of HD.
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