Characterization of lewisite toxicity in isolated perfused skin.
Lewisite (L) is a potent organic arsenical that causes rapid onset of pain and severe vesication on contact with epithelial tissues. The isolated perfused porcine skin flap (IPPSF) is an in vitro model that has shown potential as a model for cutaneous vesicant research. The objective of this study was to characterize IPPSF responses after topical exposure to six concentrations of L ranging from 0.07 to 5.0 mg/ml (n = 4/treatment plus controls). Biochemical markers of viability (glucose utilization (CGU) and lactate dehydrogenase (LDH) release), vascular resistance (VR), venous arsenic flux, and morphological parameters (light and electron microscopy) were evaluated. In addition, lewisite lesions were characterized at 1, 3, 5, and 8 hr after exposure (n = 4/time plus controls) using these morphological parameters, as well as enzyme histochemistry. Macroscopic and microscopic lesions caused by L exposure were dose related. Mild decreases in CGU were noted with the higher concentrations of L, while generally increased responses in LDH release and VR were seen. Marked increases in LDH activity were noted in the blister fluid of IPPSFs treated with 5.0 mg/ml of L. Also, significant cutaneous arsenic flux was noted at the 5.0 mg/ml dose of L. The formation of gross blisters, the location and characterization of epidermal-dermal junction separation, and the time course of lesion production paralleled the description of L-induced lesions in humans. The sensitivity of the IPPSF to L exposure and the similarity of lesions to those described for humans suggests that this model provides a relevant in vitro model with which to study mechanisms of chemical vesication and arsenic toxicity, as well as protective and therapeutic intervention for vesicant exposure.
King
J R
JR
Cutaneous Pharmacology and Toxicology Center, North Carolina State University, College of Veterinary Medicine, Raleigh 27606.
Riviere
J E
JE
Monteiro-Riviere
N A
NA
D000287:Administration, Topical; D000818:Animals; D001151:Arsenic / Q000097:blood; D020261:Arsenic Poisoning; D001152:Arsenicals / Q000493:pharmacokinetics; D005260:Female; D005947:Glucose / Q000378:metabolism; D006651:Histocytochemistry; D066298:In Vitro Techniques; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008853:Microscopy; D010477:Perfusion; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D001152:Arsenicals; C035965:lewisite; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D001151:Arsenic