title: Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation: Chemical Chaperones as Potential Novel Antidotes.
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(+/-)/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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ritesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Medical Countermeasures Division, MRIGlobal Research Institute, Kansas City, Missouri.
authors.forename: Claire R
authors.initials: CR
authors.lastname: Croutch
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: mathar@uab.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001152:Arsenicals / Q000009:adverse effects; D001768:Blister / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002619:Chemical Warfare Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000494:pharmacology*; D000072081:Patched-1 Receptor / Q000235:genetics* / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000931:Antidotes; D000975:Antioxidants; D001152:Arsenicals; D002619:Chemical Warfare Agents; D018832:Molecular Chaperones; D000072081:Patched-1 Receptor; D010654:Phenylbutyrates; C000606240:Ptch1 protein, mouse; D017382:Reactive Oxygen Species; C035965:lewisite; C075773:4-phenylbutyric acid; D000111:Acetylcysteine