Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard.

Published on Oct 15, 2014in Toxicology and Applied Pharmacology3.347
· DOI :10.1016/J.TAAP.2014.07.016
Yoke-Chen Chang7
Estimated H-index: 7
(RU: Rutgers University),
James D. Wang2
Estimated H-index: 2
(RU: Rutgers University)
+ 10 AuthorsDonald R. Gerecke18
Estimated H-index: 18
(RU: Rutgers University)
Sources
Abstract
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 mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 hr post-SM exposure. After 96 hr, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermalepidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure.
📖 Papers frequently viewed together
147 Citations
57 Citations
32 Citations
References53
Newest
#1Kazushi Morimoto (Kyoto University)H-Index: 11
#2Naritoshi Shirata (Kyoto University)H-Index: 5
Last. Yukihiko Sugimoto (Kyoto University)H-Index: 81
view all 11 authors...
PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist tre...
72 CitationsSource
#1Ivan Zanoni (University of Milano-Bicocca)H-Index: 34
#2Renato OstuniH-Index: 23
Last. Francesca GranucciH-Index: 51
view all 8 authors...
Inflammation is a multistep process triggered when innate immune cells — for example, DCs — sense a pathogen or injured cell or tissue. Edema formation is one of the first steps in the inflammatory response; it is fundamental for the local accumulation of inflammatory mediators. Injection of LPS into the skin provides a model for studying the mechanisms of inflammation and edema formation. While it is known that innate immune recognition of LPS leads to activation of numerous transcriptional act...
31 CitationsSource
#1Sherri C. Young (Lehigh University)H-Index: 7
#2Karine Fabio (Lehigh University)H-Index: 6
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
view all 11 authors...
As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants...
19 CitationsSource
#1Brenda J. Curtis (Loyola University Medical Center)H-Index: 10
#2Katherine A. Radek (Loyola University Medical Center)H-Index: 19
Several cutaneous inflammatory diseases and their clinical phenotypes are recapitulated in animal models of skin disease. However, the identification of shared pathways for disease progression is limited by the ability to delineate the complex biochemical processes fundamental for development of the disease. Identifying common signaling pathways that contribute to cutaneous inflammation and immune function will facilitate better scientific and therapeutic strategies to span a variety of inflamma...
34 CitationsSource
#1Laurie B. Joseph (RU: Rutgers University)H-Index: 12
#2Donald R. Gerecke (RU: Rutgers University)H-Index: 18
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
view all 10 authors...
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...
47 CitationsSource
#1Adrienne T. Black (RU: Rutgers University)H-Index: 12
#2Laurie B. Joseph (RU: Rutgers University)H-Index: 12
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
view all 8 authors...
Abstract Dermal exposure to sulfur mustard causes inflammation and tissue injury. This is associated with changes in expression of antioxidants and eicosanoids which contribute to oxidative stress and toxicity. In the present studies we analyzed mechanisms regulating expression of these mediators using an in vitro skin construct model in which mouse keratinocytes were grown at an air–liquid interface and exposed directly to 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. CEE...
47 CitationsSource
#1Sherri Young (Lehigh University)H-Index: 1
#2Karine Fabio (Lehigh University)H-Index: 6
Last. Ned D. Heindel (Lehigh University)H-Index: 20
view all 9 authors...
The design and study of two classes of noncompetitive acetylcholinesterase inhibitors (AChEIs) which also function as NSAID prodrugs are reported. The most potent AChEIs disclosed contain an aromatic alkyl-aryl linker between an NSAID and a lipophilic choline mimic and they inhibit acetylcholinesterase (AChE) in the submicromolar range. These agents have the therapeutic potential to dually target inflammation by releasing an NSAID in vivo and activating the cholinergic anti-inflammatory pathway ...
19 CitationsSource
#1Michael P. Shakarjian (NYMC: New York Medical College)H-Index: 12
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 38
Last. Jeffrey D. Laskin (UMDNJ: University of Medicine and Dentistry of New Jersey)H-Index: 69
view all 10 authors...
Sulfur mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mecha...
147 CitationsSource
#1Kai KeheH-Index: 30
#2Frank BalszuweitH-Index: 15
Last. Horst ThiermannH-Index: 50
view all 4 authors...
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 ...
189 CitationsSource
#1Mike RowellH-Index: 1
#2Kai KeheH-Index: 30
Last. Horst ThiermannH-Index: 50
view all 4 authors...
Abstract Whilst the acute effects of sulfur mustard have been relatively well characterised, the chronic effects of short term but significant exposures are still evolving. The approximately 30,000 Iranian victims of CW exposure from the 1980 to 1988 Iran–Iraq war who are currently being followed form a key population who are now 20 years post-exposure. The key chronic findings in this population reflect the common acute effects of sulfur mustard, and are related to the skin, eye and respiratory...
113 CitationsSource
Cited By18
Newest
#1Muhammad JamilH-Index: 14
#2Nargis SultanaH-Index: 5
Last. Muhammad Ilyas TariqH-Index: 9
view all 10 authors...
Alzheimer’s disease (AD) causes dementia and continuous damage to brain cells. Cholinesterase inhibitors can alleviate the condition by increasing communication between the nerve cells and reducing the risk of dementia. In an effort to treat Alzheimer’s disease, we synthesized flurbiprofen-based diamines (1,2 diaminoethane and 1,3 diaminopropane) Zn(II), Cu(II) metal complexes and characterized them by single-crystal X-ray analysis, NMR, (FT)-IR, UV-Vis, magnetic susceptibility, elemental analys...
Source
#1Hemanta C Rao Tumu (St. John's University)H-Index: 1
#2Benedette J. Cuffari (St. John's University)H-Index: 1
Last. Blase Billack (St. John's University)H-Index: 14
view all 6 authors...
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...
3 CitationsSource
#1Yoke Chen Chang (RU: Rutgers University)H-Index: 3
#2James D. Wang (RU: Rutgers University)H-Index: 2
Last. Donald R. Gerecke (RU: Rutgers University)H-Index: 18
view all 8 authors...
: 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...
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
#1Yoke Chen Chang (RU: Rutgers University)H-Index: 3
#2Melannie Soriano (RU: Rutgers University)H-Index: 1
Last. Donald R. Gerecke (RU: Rutgers University)H-Index: 18
view all 7 authors...
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...
5 CitationsSource
#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: 38
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
#1Lopa M. Das (Case Western Reserve University)H-Index: 6
#2Amy M. Binko (Case Western Reserve University)H-Index: 4
Last. Kurt Q. Lu (Case Western Reserve University)H-Index: 9
view all 5 authors...
AbstractObjective: Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25-hydroxyvitamin D3 (25(OH)D) g...
3 CitationsSource
#1Saeid Amini-Nik (U of T: University of Toronto)H-Index: 23
#2Yusef Yousuf (Sunnybrook Research Institute)H-Index: 6
Last. Marc G. JeschkeH-Index: 86
view all 3 authors...
Abstract In recent decades, there have been tremendous improvements in burn care that have allowed patients to survive severe burn injuries that were once fatal. However, a major limitation of burn care currently is the development of hypertrophic scars in approximately 70% of patients. This significantly decreases the quality of life for patients due to the physical and psychosocial symptoms associated with scarring. Current approaches to manage scarring include surgical techniques and non-surg...
48 CitationsSource
#1Yoke-Chen Chang (RU: Rutgers University)H-Index: 7
#2Marion K. Gordon (RU: Rutgers University)H-Index: 21
Last. Donald R. Gerecke (RU: Rutgers University)H-Index: 18
view all 3 authors...
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...
3 Citations
The aim of this study was the development and optimization of some topical collagen-dextran sponges with flufenamic acid, designed to be potential dressings for burn wounds healing. The sponges were obtained by lyophilization of hydrogels based on type I fibrillar collagen gel extracted from calf hide, dextran and flufenamic acid, crosslinked and un-crosslinked, and designed according to a 3-factor, 3-level Box-Behnken experimental design. The sponges showed good fluid uptake ability quantified ...
22 CitationsSource