Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model.
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 24h to 168h 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 72h 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 24h 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.
Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
Yoke-Chen
YC
Chang
James D
JD
Wang
Kathy K
KK
Svoboda
Robert P
RP
Casillas
Jeffrey D
JD
Laskin
Marion K
MK
Gordon
Donald R
DR
Gerecke
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004423:Ear; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000032:analysis; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000096:biosynthesis; D008297:Male; D051379:Mice; D023421:Models, Animal; D009151:Mustard Gas / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000032:analysis; D014945:Wound Healing
D002619:Chemical Warfare Agents; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C498522:Lamc2 protein, mouse; D007797:Laminin; D051742:Transcription Factor CHOP; D009151:Mustard Gas