Tissue injury and repair following cutaneous exposure of mice to sulfur mustard

Published on Jul 2, 2016in Annals of the New York Academy of Sciences4.728
· DOI :10.1111/NYAS.13125
Laurie B. Joseph12
Estimated H-index: 12
(RU: Rutgers University),
Gabriella M. Composto5
Estimated H-index: 5
(RU: Rutgers University),
Diane E. Heck38
Estimated H-index: 38
(NYMC: New York Medical College)
Sources
Abstract
In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the duration of exposure. Initial responses include erythema, pruritus, edema, and xerosis; this is followed by an accumulation of inflammatory leukocytes in the tissue, activation of mast cells, and the release of mediators, including proinflammatory cytokines and bioactive lipids. These proinflammatory mediators contribute to damaging the epidermis, hair follicles, and sebaceous glands and to disruption of the epidermal basement membrane. This can lead to separation of the epidermis from the dermis, resulting in a blister, which ruptures, leading to the formation of an eschar. The eschar stimulates the formation of a neoepidermis and wound repair and may result in persistent epidermal hyperplasia. Epidermal damage and repair is associated with upregulation of enzymes generating proinflammatory and pro-growth/pro-wound healing mediators, including cyclooxygenase-2, which generates prostanoids, inducible nitric oxide synthase, which generates nitric oxide, fibroblast growth factor receptor 2, and galectin-3. Characterization of the mediators regulating structural changes in the skin during SM-induced tissue damage and wound healing will aid in the development of therapeutic modalities to mitigate toxicity and stimulate tissue repair processes.
Download
📖 Papers frequently viewed together
7 Citations
5 Citations
2006
3 Authors (Hiroshi Ishida, ..., Radharaman Ray)
References45
Newest
#1Gabriella M. Composto (RU: Rutgers University)H-Index: 5
#2Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
Last. Diane E. Heck (NYMC: New York Medical College)H-Index: 38
view all 8 authors...
Abstract Nitrogen mustard (NM) is a bifunctional alkylating agent that is highly reactive in the skin causing extensive tissue damage and blistering. In the present studies, a modified cutaneous murine patch model was developed to characterize NM-induced injury and to evaluate the efficacy of an indomethacin pro-drug in mitigating toxicity. NM (20 μmol) or vehicle control was applied onto 6 mm glass microfiber filters affixed to the shaved dorsal skin of CD-1 mice for 6 min. This resulted in abs...
10 CitationsSource
#1Seong Hoong Chow (Monash University, Clayton campus)H-Index: 6
#2P. Deo (Monash University, Clayton campus)H-Index: 4
Last. Thomas Naderer (Monash University, Clayton campus)H-Index: 24
view all 3 authors...
Summary Macrophages can respond to microbial infections with programmed cell death. The major cell death pathways of apoptosis, pyroptosis and necroptosis are tightly regulated to ensure adequate immune reactions to virulent and persistent invaders. Macrophage death eliminates the replicative niche of intracellular pathogens and induces immune attack. Not surprisingly, successful pathogens have evolved strategies to modulate macrophage cell death pathways to enable microbial survival and replica...
23 CitationsSource
#1Sylvie SauvaigoH-Index: 25
#2Fanny SarrazyH-Index: 3
Last. Thierry DoukiH-Index: 78
view all 9 authors...
Abstract Sulfur mustard (SM) is a chemical warfare agent that, upon topical application, damages skin and reaches internal organs through diffusion in blood. Two major toxic consequences of SM exposure are inflammation, associated with oxidative stress, and the formation of alkylated DNA bases. In the present study, we investigated the impact of exposure to SM on DNA repair, using two different functional DNA repair assays which provide information on several Base Excision Repair (BER) and Excis...
7 CitationsSource
#1Kasey Rodgers (Tufts University)H-Index: 2
#2Mitch McVey (Tufts University)H-Index: 24
Preserving the integrity of the DNA double helix is crucial for the maintenance of genomic stability. Therefore, DNA double-strand breaks represent a serious threat to cells. In this review, we describe the two major strategies used to repair double strand breaks: non-homologous end joining and homologous recombination, emphasizing the mutagenic aspects of each. We focus on emerging evidence that homologous recombination, long thought to be an error-free repair process, can in fact be highly mut...
180 CitationsSource
#1Raphael Ceccaldi (Harvard University)H-Index: 14
#2Beatrice Rondinelli (Harvard University)H-Index: 5
Last. Alan D. D'Andrea (Harvard University)H-Index: 117
view all 3 authors...
DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alte...
710 CitationsSource
#1Chao He (UAB: University of Alabama at Birmingham)H-Index: 11
#2A. Brent Carter (UAB: University of Alabama at Birmingham)H-Index: 27
Macrophage plasticity is an important feature of these innate immune cells. Macrophage phenotypes are divided into two categories, the classically activated macrophages (CAM, M1 phenotype) and the alternatively activated macrophages (AAM, M2 phenotype). M1 macrophages are commonly associated with the generation of proinflammatory cytokines, whereas M2 macrophages are anti-inflammatory and often associated with tumor progression and fibrosis development. Macrophages produce high levels of reactiv...
39 CitationsSource
#1Anna Michopoulou (University of Lyon)H-Index: 4
#2Patricia Rousselle (University of Lyon)H-Index: 43
Epithelialization of normal wounds occurs by an orderly series of events whereby keratinocytes migrate, proliferate, and differentiate to restore the epidermal barrier function. Keratinocyte migration is one of the earliest and crucial events determining the efficiency of the overall wound repair process. In response to various stimuli including that of growth factors, cytokines and the extracellular matrix, activated keratinocytes at the edges of the wound undergo dramatic morphological changes...
17 CitationsSource
#1Mohamed BatalH-Index: 5
Last. Thierry DoukiH-Index: 78
view all 8 authors...
Abstract Sulfur mustard (SM) is an old chemical warfare but it remains a threat to both militaries and civilians. SM mainly targets skin, eyes and lungs and diffuses to internal organs. At the molecular level, SM is able to damage DNA through the formation of monoadducts and biadduct. Glutathione (GSH) is another critical target of SM in cells since it is part of the detoxification mechanism against alkylating agents. In the present work, we investigated whether SM could form covalent bonds simu...
19 CitationsSource
#1Stéphane MouretH-Index: 15
#2Julien WartelleH-Index: 5
Last. Isabelle BoudryH-Index: 9
view all 11 authors...
Sulfur mustard (SM) is a strong bifunctional alkylating agent that produces severe tissue injuries characterized by erythema, edema, subepidermal blisters and a delayed inflammatory response after cutaneous exposure. However, despite its long history, SM remains a threat because of the lack of effective medical countermeasures as the molecular mechanisms of these events remain unclear. This limited number of therapeutic options results in part of an absence of appropriate animal models. We propo...
19 CitationsSource
#1Yoke-Chen Chang (RU: Rutgers University)H-Index: 7
#2James D. Wang (RU: Rutgers University)H-Index: 2
Last. Donald R. Gerecke (RU: Rutgers University)H-Index: 18
view all 13 authors...
Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme med...
18 CitationsSource
Cited By5
Newest
#1Jeffrey D. Laskin (RU: Rutgers University)H-Index: 1
#1Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
Last. Laurie B. Joseph (RU: Rutgers University)H-Index: 12
view all 7 authors...
Abstract Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soa...
1 CitationsSource
#1Gabriella Wahler (RU: Rutgers University)H-Index: 1
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 4
Last. Laurie B. Joseph (RU: Rutgers University)H-Index: 12
view all 6 authors...
Abstract Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mi...
1 CitationsSource
#1Ensieh Sadat Mirsharif (Shahed University)H-Index: 2
#2Fatemeh Heidary (Shahed University)H-Index: 8
Last. Tooba Ghazanfari (Shahed University)H-Index: 21
view all 6 authors...
Background: The aim of this study was assessment of the chronic effects of sulfur mustard (SM) among victims. Methods: In this cohort study, 355 SM-exposed subjects from Sardasht, and 123 controls from Rabat, both from West Azerbaijan Province, Iran were included. The spirometric evaluation and the global initiative for chronic obstructive lung disease (GOLD) classification were applied for all. Serum levels of urea, creatinine (Cr), and uric acid (UA) and glomerular filtration rate (GFR) were a...
2 Citations
#1Laurie B. Joseph (RU: Rutgers University)H-Index: 12
#2Gabriella M. Composto (RU: Rutgers University)H-Index: 5
Last. Diane E. Heck (NYMC: New York Medical College)H-Index: 4
view all 13 authors...
Abstract Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal app...
8 CitationsSource
Synthetic toxic chemicals (toxicants) and biological poisons (toxins) have been developed as chemical warfare agents in the last century. At the time of their initial consideration as chemical weapon, only restricted knowledge existed about their mechanisms of action. There exist two different types of acute toxic action: nonspecific cytotoxic mechanisms with multiple chemo-biological interactions versus specific mechanisms that tend to have just a single or a few target biomolecules. TRPV1- and...
15 CitationsSource