Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

Abstract

The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury.

Time course of skin features and inflammatory biomarkers after liquid sulfur mustard exposure in SKH-1 hairless mice

“…This is concordant with our results demonstrating an association between the highest mRNA levels of Lamc2 at day 3 with a fine regenerating epidermis at day 7 for the SM dose of 0.6 mg/kg. Although the two highest doses of SM also induce an increase of Lamc2 mRNA levels in our study, the observed delay in wound repair would be explained by a lack of laminin-g2 secretion as a consequence of an endoplasmic reticulum stress related to a more severe SM-induced injury (Chang et al, 2013).…”

Endoplasmic reticulum stress is involved in 2,4-dichlorophenol-induced hepatotoxicity

“…ER stress serves as a warning mechanism against many organic environmental pollutants, and is usually indicated by up-regulation of Bip and CHOP (Chang et al, 2013;Faria et al, 2009). Previous studies have reported that 2,4-DCP affected aromatic amino acid biosynthesis (Yadav et al, 2011) and directly bound to proteins, to interfere with their conformation (Zhang et al, 2011), suggesting that 2,4-DCP may have a proteotoxicity that causes ER stress (Gardner et al, 2013).…”

Resveratrol attenuates HMGB1 signaling and inflammation in house dust mite-induced atopic dermatitis in mice

“…Activation of UPR is dependent on GRP78/BiP and increases in this protein are indicative of ER stress. If these ER stress survival pathways are insufficient to relieve ER stress, then the ER stress-induced apoptosis pathway involving molecules such as CHOP and caspase should be activated [37]. Moreover, Luo et al [38] reported that HMGB1 might trigger ER stress via the RAGE pathway in HMGB1 induced inflammatory endothelial cells.…”