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.
Highlights
Activities[24,25]
While we are undertaking mechanistic studies following exposure to these arsenicals with MRIGlobal (Kansas City, MO), we found a relatively less toxic arsenical ‘phenylarsine oxide (PAO)’ which could be procured from Sigma
Ptch1+/−/SKH-1 is highly sensitive murine model developed in our laboratory to demonstrate the toxic manifestations of environmental agents on the skin[35]
Summary
The exact molecular mechanism by which these arsenicals contribute to pathobiology of skin injury remains undefined. PAO is a membrane-permeable trivalent arsenical that complexes with vicinal sulfhydryl groups of proteins to form stable ring structures[29,30,31] It binds with thiol groups and inhibits the action of many thiol containing enzymes[29,32]. Our data show that cutaneous exposure to PAO in Ptch1+/−/SKH-1 mice causes intense inflammatory and tissue damaging responses These effects are similar but potentially less severe than those reported to be manifested by lewisite and other similar more reactive arsenicals[17,28,33,34]. Our studies demonstrate that the pathogenesis of arsenicals-induced cutaneous injury is mediated by the activation of UPR signaling pathway
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