Inflammatory Biomarkers of Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide–Induced Skin Injury in SKH-1 Hairless Mice

Abstract

Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05-2 mg) and time- (3-168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.

IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

“…Similarly, FFPE mice psoriatic plaques were stained with H&E and stained with anti-mouse VCAM pAb (Boster, Wuhan, China). Additionally, to detect mast cells, mice psoriatic plaque sections were stained with toluidine blue (AMRESCO, Solon, OH), as previously described (22). Images of the stained slides of animal biopsies and human psoriatic plaques were obtained with an Olympus BX60 or Olympus DP72 microscope (both from Olympus Optical, Tokyo, Japan).…”

Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In Vivo

“…In addition, the results from our study using the SKH-1 hairless mouse model indicate that CEES induces oxidative stress and the activation of interlinked complex mechanisms of CEES-mediated skin inflammation and injury Tewari-Singh et al, 2009). To analyze further the role of GSH and oxidative stress in CEES-induced biological and molecular responses in these skin toxicity models, we evaluated the efficacy of exogenous GSH in attenuating CEES-caused skin injury in both cell culture and mouse skin models.…”

“…Apart from HD, its monofunctional analog 2-chloroethyl ethyl sulfide (CEES) also causes several skin toxic effects comparable with HD, and therefore CEES is used extensively to uncover the mechanism of action of HD and to screen effective therapeutic agents (Han et al, 2004;Paromov et al, 2007;Gould et al, 2009;Tewari-Singh et al, 2009. HD/CEES-caused oxidative stress results in the 8-oxo-2-deoxyguanosine DNA adduct as well as lipid and protein oxidation, which can cause inflammation and other toxic responses in skin Black et al, 2010).…”

Sulphur Mustard Induced Toxicity, Mechanism of Action and Current Medical Management

“…as useful animal models for evaluating efficacy of various antidotes against SM-induced skin toxicity. But there are many variables that influence the differential severity of pathogenesis of SM induced lesions such as dose of SM, physical and chemical nature of diluents and duration of SM exposure 92 . Vijayaraghavan 93 , et.…”