Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Abstract

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 þ/À /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 speciesedependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisitetreated cultured human skin keratinocytes. We discovered that chemical chaperone 4ephenyl 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.

Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype

“…Ptch1 +/− /SKH-1 is highly sensitive murine model developed in our laboratory to demonstrate the toxic manifestations of environmental agents on the skin 35 . Selection of Ptch1 +/− /SKH-1 hairless mouse strain employed in this study was based on the effects of PAO on cutaneous injury (erythema and edema) in various mouse strains such as FVB, C57BL/6, SKH-1 and Ptch1 +/− /SKH-1 36 . Single application of PAO to Ptch1 +/− /SKH-1 mouse skin caused marked redness within 45 min which became more pronounced with the progression of time.…”

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals

“…While investigating the molecular pathogenesis of Lewisite, we recently found that its exposure to murine skin induces activation of the unfolded protein response (UPR) signaling pathway, and blocking UPR signaling with the chemical chaperone 4‐phenylbutyric acid (4‐PBA) protected against Lewisite‐induced skin damage (Fig. ) . Despite an earlier belief that some of the key toxic effects of arsenical vesicants are due to arsenic, the rapidity with which arsenical vesicants act distinguishes the two biological responses and suggests arsenic‐independent mechanisms associated with the exposure to organic arsenicals.…”

“…We recently found that Lewisite induces ROS‐dependent activation of UPR signaling in exposed skin. Thus, treatment with the antioxidant NAC and the chemical chaperone 4‐PBA showed remarkable effects . These agents can decrease UPR signaling and may provide a mechanism‐based intervention against the progression of skin injuries.…”

“…2). 85 Despite an earlier belief that some of the key toxic effects of arsenical vesicants are due to arsenic, the rapidity with which arsenical vesicants act distinguishes the two biological responses and suggests arsenic-independent mechanisms associated with the exposure to organic arsenicals. Cutaneous exposure to ATO or sodium arsenite does not cause painful inflammation or blistering, which further indicates that the early molecular pathobiology of the two agents (arsenic and arsenicals) could be distinct.…”

“…Thus, treatment with the antioxidant NAC and the chemical chaperone 4-PBA showed remarkable effects. 85 These agents can decrease UPR signaling and may provide a mechanism-based intervention against the progression of skin injuries. However, it is difficult to predict at this stage whether chemical chaperone treatment will also be effective against arsine toxicity.…”