title: Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype.
abstract: Arsenicals are painful, inflammatory and blistering causing agents developed as chemical weapons in World War I/II. However, their large stockpiles still exist posing threat to public health. Phenylarsine oxide (PAO), a strong oxidant and a prototype arsenical is tested for its suitability to defining molecular mechanisms underlying arsenicals-mediated tissue injury. Topically applied PAO induces cutaneous erythema, edema and micro-blisters. These gross inflammatory responses were accompanied by the enhanced production of pro-inflammatory cytokines, ROS and unfolded protein response (UPR) signaling activation. To demonstrate the involvement of UPR in the pathobiology of these lesions, we employed chemical chaperone, 4-phenylbutyric acid (4-PBA) which attenuates UPR. 4-PBA significantly reduced PAO-induced inflammation and blistering. Similar to its effects in murine epidermis, a dose- and time-dependent upregulation of ROS, cytokines, UPR proteins (GRP78, p-PERK, p-eIF2α, ATF4 and CHOP) and apoptosis were observed in PAO-treated human skin keratinocytes NHEK and HaCaT. In addition, 4-PBA significantly restored these molecular alterations in these cells. Employing RNA interference (RNAi)-based approaches, CHOP was found to be a key regulator of these responses. These effects are similar to those manifested by lewisite suggesting that PAO could be used as a prototype of arsenicals to define the molecular pathogenesis of chemical injury.
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Ritesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000818:Animals; D001152:Arsenicals / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D004487:Edema / Q000139:chemically induced / Q000276:immunology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004890:Erythema / Q000139:chemically induced / Q000276:immunology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D000072081:Patched-1 Receptor / Q000235:genetics; D010654:Phenylbutyrates / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D001152:Arsenicals; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000072081:Patched-1 Receptor; D010654:Phenylbutyrates; D034741:RNA, Small Interfering; C029341:oxophenylarsine; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid