title: Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard.
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 h post-SM exposure. After 96 h, 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 dermal-epidermal 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.
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Yoke-Chen
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Hahn
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Marion K
authors.initials: MK
authors.lastname: Gordon
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Joseph
authors.affiliation: Department of Environmental Science, New York Medical College, Valhalla, NY, United States.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, PA, United States.
authors.forename: Ned D
authors.initials: ND
authors.lastname: Heindel
authors.affiliation: Department of Chemistry, Muhlenberg College, Allentown, PA, United States.
authors.forename: Sherri C
authors.initials: SC
authors.lastname: Young
authors.affiliation: Department of Pharmaceutics, Rutgers University, Piscataway, NJ, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
authors.affiliation: MRIGlobal, Kansas City, MO, United States.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Casillas
authors.affiliation: Environmental & Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.affiliation: Department of Pharmacology & Toxicology, Rutgers University, Piscataway, NJ, United States. Electronic address: gerecke@eohsi.rutgers.edu.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gerecke
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018680:Cholinergic Antagonists / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000633:toxicity*; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018680:Cholinergic Antagonists; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D009151:Mustard Gas
keywords: Non-steroid bifunctional anti-inflammatory and anti-cholinergic agent; Skin; Sulfur mustard; Wound repair