Involvement of tumor necrosis factor-alpha in sulfur mustard-induced skin lesion; effect of topical iodine.
Sulfur mustard (SM), also termed mustard gas, is a potent vesicant that elicits an inflammatory response upon exposure of the skin. Evaluation of mouse ear 3 h after SM exposure revealed acute inflammatory-cell aggregates in the vascular beds accompanied by strongly TNF-alpha-positive neutrophils. Eight hours after SM exposure, this phenomenon became intensified and associated with infiltration into the adjacent dermis. In ear skin topically treated with iodine, however, no inflammatory cells were observed 3 h after SM exposure; 8 h postexposure, blood vessels contained very few TNF-alpha-positive inflammatory cells. Since TNF-alpha induction was shown to be associated with reactive oxygen species production, we studied the effect of iodine on activated peritoneal mouse neutrophils. Iodine elicited a concentration-dependent reduction in the oxidative burst of activated neutrophils. Iodine also scavenged hydroxyl radicals generated by glucose oxidase in a concentration-dependent manner. The involvement of TNF-alpha in SM-induced skin toxicity was confirmed by reduction of 49 and 30% in ear edema following administration of 1 and 2 mug anti-TNF-alpha antibodies, respectively. These findings were corroborated by quantitative analysis of the histological findings showing 46% reduction in acute inflammation and no signs of subacute inflammation in the treated group, in contrast to the control group treated with SM only. Other epidermal (microblister formation, ulceration, and necrosis) and dermal (neutrophilia, hemorrhage, and necrosis) parameters also showed marked reductions in the antibodies-treated group in comparison to controls. The combination of iodine and antiTNF-alpha antibodies might constitute a new approach for treatment of SM-exposed individuals.
Department of Pharmacology, School of Pharmacy; Faculty of Medicine, Berman Building, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, 91904 Jerusalem, Israel. wormser@cc.huji.ac.il
Uri
U
Wormser
Berta
B
Brodsky
Elena
E
Proscura
Julie F
JF
Foley
Tinette
T
Jones
Abraham
A
Nyska
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D003877:Dermatitis, Contact; D020405:Dermis / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004423:Ear; D004487:Edema / Q000139:chemically induced; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017665:Hydroxyl Radical / Q000378:metabolism; D007455:Iodine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009151:Mustard Gas / Q000633:toxicity*; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D016897:Respiratory Burst / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha; D017665:Hydroxyl Radical; D007455:Iodine; D009151:Mustard Gas