lewisite and Disease-Models--Animal

Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis. We investigated the molecular mechanism underlying lewisite-induced cutaneous blistering and inflammation and describe its novel antidotes. On the basis of our initial screening, we used a highly sensitive murine model that recapitulates the known human pathogenesis of arsenicals-induced cutaneous inflammation and blistering. Topically administered lewisite induced potent acute inflammation and microvesication in the skin of Ptch1(+/-)/SKH-1 mice. Even at a very low dose, lewisite up-regulates unfolded protein response signaling, inflammatory response, and apoptosis. These cutaneous lesions were associated with production of reactive oxygen species and extensive apoptosis of the epidermal keratinocytes. We confirmed that activation of reactive oxygen species-dependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisite-treated cultured human skin keratinocytes. We discovered that chemical chaperone 4-phenyl butyric acid and antioxidant N-acetylcysteine, which significantly attenuate lewisite-mediated skin injury, can serve as potent antidotes. These data reveal a novel molecular mechanism underlying the cutaneous pathogenesis of lewisite-induced lesions. We also identified novel potential therapeutic targets for lewisite-mediated cutaneous injury.

Topics: Acetylcysteine; Animals; Antidotes; Antioxidants; Arsenicals; Blister; Chemical Warfare Agents; Disease Models, Animal; Female; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Hairless; Mice, Inbred C57BL; Molecular Chaperones; Patched-1 Receptor; Phenylbutyrates; Reactive Oxygen Species; Signal Transduction

Lewisite (dichloro (2-chlorovinyl) arsine) was first synthesised in 1918 and its potential for use in military confrontations as a vesicant agent has been widely recognised. These agents cause blistering skin reactions with resultant full thickness burns. Effective treatments to date have been delayed by the lack of suitable animal models. Porcine skin has recently been used successfully to model the development and natural history of these burn injuries. A large white pig model (n=6) was employed to investigate the effectiveness of CO(2) and Erbium-YAG lasers (EYL) in laser dermabrasion of established Lewisite burns. Burns underwent treatment at 4 days post-exposure and were assessed at 1, 2 and 3 weeks, thereafter, for the rate of epithelial healing. The re-epithelialisation rates in the laser dermabraded groups were accelerated by a factor of four compared to untreated controls by the first week (analysis of vartiance, ANOVA, P=0.006 for pulsed CO(2) and P=0.011 for Erbium-YAG). Ablation of the burn eschar was thought to accelerate the rate of healing by causing partial debridement. This method has been termed 'lasablation' and represents a significant advance in the clinical management of this type of injury.

Topics: Animals; Arsenicals; Burns, Chemical; Debridement; Dermabrasion; Disease Models, Animal; Epithelium; Laser Therapy; Swine; Wound Healing

The severity and progression of skin lesions resulting from exposure to the chemical warfare agents Lewisite (L) and sulphur mustard (SM) have been investigated using the non-invasive biophysical methods of evaporimetry and reflectance spectroscopy in large white pigs in vivo. Erythema (redness) expressed immediately after exposure to L or SM vapours appeared to be related to the lesion severity as demonstrated by histopathological analysis. Skin brightness correlated well with scab formation whereas blueness (cyanosis) did not appreciably alter throughout the study. Rates of transepidermal water loss (TEWL) changed both with occlusion (during vapour exposure) and also mirrored the progression of macroscopic skin injury after 12 h. Whilst no single parameter could be used in isolation to ascertain the severity and subsequent progression of the skin lesions, measurement of erythema, skin brightness and TEWL could provide quantitative, non-invasive methods for determining the efficacy of antidotes or therapies to prevent the toxic effects of chemical warfare agents. However, neither colourimetry or TEWL provided a clinical evaluation of such lesions that were comparable with the prognostic capabilities of laser Doppler imaging.

Topics: Animals; Arsenicals; Burns, Chemical; Chemical Warfare; Dermatologic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Environmental Exposure; Environmental Monitoring; Female; Injury Severity Score; Mustard Gas; Skin; Swine; Water Loss, Insensible