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

• Published in: Toxicology and applied pharmacology Vol. 280; no. 2; pp. 236 - 244
• Main Authors: Chang, Yoke-Chen, Wang, James D., Hahn, Rita A., Gordon, Marion K., Joseph, Laurie B., Heck, Diane E., Heindel, Ned D., Young, Sherri C., Sinko, Patrick J., Casillas, Robert P., Laskin, Jeffrey D., Laskin, Debra L., Gerecke, Donald R.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.10.2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ALKYLATING AGENTS; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; BLISTERS; BRASSICA; Chemical and industrial products toxicology. Toxic occupational diseases; Cholinergic Antagonists - therapeutic use; Cyclooxygenase 2; EDEMA; ENZYMES; EPIDERMIS; Gas, fumes; INFLAMMATION; KERATIN; Ki-67 Antigen - analysis; Male; Matrix Metalloproteinase 9; Medical sciences; MEMBRANES; MICE; Mice, Hairless; Mustard Gas - toxicity; Non-steroid bifunctional anti-inflammatory and anti-cholinergic agent; REPAIR; Skin; Skin - pathology; Skin Diseases - chemically induced; Skin Diseases - drug therapy; Skin Diseases - pathology; STEROIDS; SULFIDES; SULFUR; Sulfur mustard; Toxicology; Wound Healing - drug effects; Wound repair; WOUNDS; LM332; NSAID; Sulfur mustard; DEJ; K6; K10; Non-steroid bifunctional anti-inflammatory and anti-cholinergic agent; MMP9; CEES; Wound repair; AChEI; COX2; SM; Skin; Toxic gas; Injury; Wound; Non steroidal antiinflammatory agent; Chemical warfare agent; Treatment; Lesion; Repair; Non steroid compound
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.07.016

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 72h post-SM exposure. After 96h, 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. •Bifunctional anti-inflammatory prodrug (NDH4338) tested on SM exposed mouse skin•The prodrug NDH4338 was designed to target COX2 and acetylcholinesterase.•The application of NDH4338 improved cutaneous wound repair after SM induced injury.•NDH4338 treatment demonstrated a reduction in COX2 expression on SM injured skin.•Changes of skin repair markers are associated with NDH4438 treatment on SM injury.