Acute Nitrogen Mustard Skin Exposure Induces Persistent Inflammation and Delayed Psoriasiform Pathology Associated with Oxidative Damage, Mast Cell Activation, and Cytokine Signaling in Mice

Sulfur mustard (SM) and nitrogen mustard (NM) are potent chemical threat agents that cause severe acute- and long-term injuries. Their long-lasting skin complications include dry skin, chronic urticaria, psoriasis, and fibrosis; however, studies on these effects are limited, and a useful in vivo injury model is lacking. Hence, we developed a long-term (84-day study) dermal injury mouse model from exposure to NM, a safer-to-use analog of SM, dissolved in acetone and applied as a liquid to the dorsal skin. NM exposure resulted in significant weight loss and gross lesions, including erythema, edema, and persistent wounds. Long-term histological lesions included scab formation, neutrophil infiltration, acanthosis, hyperkeratosis, necrosis, fibrosis, and rete ridges resembling psoriatic lesions. Increased gene expression of key psoriatic-related markers interleukin (IL)-17 and IL-23 was also observed. Increased trichrome staining and elevated expression of fibrotic markers, like transforming growth factor beta, confirmed fibrosis. Bi-phasic increases in mast cell degranulation and oxidative DNA damage were seen; these were elevated at days 1 or 7 and again by day 84 post-exposure. Increased macrophage numbers were seen at days 14 and 84 post-exposure. These responses were associated with elevated gene expression levels of inflammatory markers including C-C chemokine ligand 2, cyclooxygenase 2, tumor Necrosis Factor-α, Il-6 , Il-1b , matrix metalloproteinase 9, and antioxidant heme oxygenase-1. This novel study provides information on mustard vesicant-induced long-term skin inflammatory pathophysiology, including markers that can be further investigated to establish potential mechanisms of toxicity and treatment options.