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.
Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1–14 days later. After 1 da...
Abstract Sulfur mustard (SM) is a strong alkylating agent, which produces subepidermal blisters, erythema and inflammation after skin contact. Despite the well-described SM-induced gross and histopathological changes, the exact underlying molecular mechanisms of these events are still a matter of research. As part of an international effort to elucidate the components of cellular signal transduction pathways, a large body of data has been accumulated in the last decade of SM research, revealing ...
Epithelial cell migration during wound healing is regulated in part by enzymatic processing of laminin-332 (formerly LN-5), a heterodimer formed from α, β, and γ polypeptide chains. Under static conditions, laminin-332 is secreted into the extracellular matrix as a proform and has two chains processed to smaller forms, allowing it to anchor epithelial cells to the basement membrane of the dermis. During incisional wounding, laminin γ2 chains in particular are processed to smaller sizes and funct...
Epithelial stem cells in the skin are specified during development and are governed by epithelial–mesenchymal interactions to differentially adopt the cell fates that enable them to form the epidermis, hair follicle, and sebaceous gland. In the adult, each of three epithelial lineages maintains their own stem cell population for self-renewal and normal tissue homeostasis. However, in response to injury, at least some of these stem cell niches can be mobilized to repair an epithelial tissue whose...
Last. Prabhati Ray(WRAIR: Walter Reed Army Institute of Research)H-Index: 15
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Summary Background Increased nitric oxide (NO) synthesized by inducible NO synthase (iNOS) is involved in inflammatory and pathological conditions. iNOS also regulates several biomarkers that accelerate normal wound healing. Effects of exposure to sulfur mustard (SM) on the skin include formation of blisters and slow-healing injuries. Promoting re-epithelialization is a challenging issue in the treatment of the delayed healing of SM-induced skin injuries. Objectives To clarify the role(s) of iNO...
Objective: Sulfur mustard (SM) is a potent alkylating agent that can induce severe cutaneous injury. Though much is known regarding the gross pathology of SM injury, the molecular and cellular basis for this pathology is not well understood. General cellular processes such as inflammation, DNA damage response, and apoptosis have been hypothesized to be involved in SM injury. However, the specific molecules, signaling pathways, and gene products involved in the pathogenesis of SM injury have not ...
#1Teruo Hayashi(NIDA: National Institute on Drug Abuse)H-Index: 28
#2Tsung-Ping Su(NIDA: National Institute on Drug Abuse)H-Index: 67
Summary Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca 2+ directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca 2+ -sensitive and l...
The basement membrane molecule laminin 332 (previously known as laminin 5) activates various signalling pathways and interacts with other basement membrane components to promote squamous-cell carcinoma (SCC) development. How does laminin 332 coordinate SCC tumorigenesis and can it be targeted therapeutically?
As lithium has been shown to have a protective effect against suicidal behavior, genes on which mood stabilizers act may be involved in biological susceptibility to suicide. A recent study showed that endoplasmic reticulum (ER) stress response was impaired in the bipolar disorders and the impairment was ameliorated by a mood stabilizer, valproate. We hypothesized that an alteration of ER stress response is involved in the biological susceptibility to suicide through genetic polymorphisms, and ex...
Objective: The objective was to examine the efficacy of several treatment regimens in improving wound healing of cutaneous sulfur mustard (HD) injuries. Methods: Wound healing studies were conducted in weanling pigs. Superficial dermal HD injuries were debrided at 48 hours postexposure using an erbium-doped yttrium aluminum garnet (Er:YAG) laser, followed by application of a treatment adjunct. A variety of noninvasive bioengineering methods were conducted during the postsurgical observation peri...
Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metab...
Abstract Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for it...
Last. Blase Billack(St. John's University)H-Index: 14
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AbstractMechlorethamine (HN2) is an alkylating agent and sulfur mustard mimetic. Topical exposure to HN2 is associated with tissue blistering. Previous work in our laboratory has shown that ebselen (EB-1) possesses anti-vesicant, anti-inflammatory, anti-bacterial, anti-fungal, and cytoprotective properties, both in vivo and in vitro. We recently reported that ebselen oxide (EB-2), an analog of EB-1 with a tetravalent selenium atom, also possesses anti-bacterial and anti-fungal activity and confe...
: Laminin-332 is a basement membrane protein composed of three genetically distinct polypeptide chains that actively promote both skin epidermal cell adhesion and migration. Proteolytic fragments of the laminin γ2 chain stimulate migration and scattering of keratinocytes and cancer cells. Sulfur mustard (SM) is a bifunctional alkylating agent that induces separation of basal keratinocytes from the dermal-epidermal junction and invokes a strong inflammatory response leading to delayed wound repai...
Abstract Sulfur mustard (2,2′-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemok...
#1Yunes Panahi(BMSU: Baqiyatallah University of Medical Sciences)H-Index: 38
#2Mostafa Ghanei(BMSU: Baqiyatallah University of Medical Sciences)H-Index: 39
Last. Amirhossein Sahebkar(MUMS: Mashhad University of Medical Sciences)H-Index: 104
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Sulfur mustard (SM) is a vesicating agent that has been employed as a chemical warfare agent. High-dose exposure to sulfur mustard may lead to the damage of rapidly proliferating cells of bone marrow and, therefore, suppression of the immune system. This may be continued as dysfunction of the immune system, and ultimately result in secondary immune disorders. Studies have suggested a role for T cells in SM-induced lung injury. Moreover, observations from animal studies indicate a delayed-type hy...
Sulfur Mustard (SM) is a potent vesicant or blistering agent. It is a highly reactive bi-functional alkylating agent that cross links proteins, DNA, and other cellular components. Laminin 332 is a heterotrimer glycoprotein and a crucial skin component that attaches the epidermal basal keratinocytes to the dermis. SM wounds histologically appear similar to Epidermolysis Bullosa (EB), human genetic blistering diseases that involve genetic changes in laminin 332. The specific mechanism of action of...
Abstract Sulfur mustard (SM) is a chemical warfare, which has been used for one hundred years. However, its exact pathomechanisms are still incompletely understood and there is no specific therapy available so far. In this systematic review, studies published between January 2000 and July 2017 involving pathomechanisms and experimental treatments of SM-induced skin lesions were analyzed to summarize current knowledge on SM pathology, to provide an overview on novel treatment options, and to iden...
AbstractContext: Mustard gas (e.g. sulfur mustard (SM)) has been used as a chemical agent in several battles and is still a potential worldwide menace. Besides local absorption, particularly in the skin, eyes and lungs, systemic spread of the agent also has detrimental effects on gonads, bone marrow and nervous system. Moreover, chronic exposure of SM to respiratory system causes death. Inducing oxidative stress, and disturbing DNA and tissue repair systems, inflammation and cell death signaling...
2,4-Dichlorophenol (2,4-DCP) is an environmental pollutant exhibiting a wide spectrum of toxic effects. We investigated the toxic effects and potential mechanisms underlying 2,4-DCP-induced hepatotoxicity. In vitro, 2,4-DCP caused hepatotoxicity manifested by a decrease in cell viability and inhibition of colony formation. Bip and CHOP expression was up-regulated at the mRNA and protein levels. Moreover, 2,4-DCP induced eIF2a phosphorylation and Xbpl mRNA splicing, indicating that endoplasmic re...