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Histopathologic and immunohistochemical features in human skin after exposure to nitrogen and sulfur mustard
K J Smith1, W J Smith, T Hamilton
1United States Army Institute of Chemical Defense, Aberdeen, Maryland, USA.
Abstract:
N-methyl-2,2'-dichlorodiethylamine (HN2)is a topical chemotherapeutic agent used as therapy for cutaneous T-cell lymphomas (CTCL). Di(2-chloroethyl)sulfide (SM), and less often HN2, have been used as chemical weapons, with the skin being a principle target. The mechanisms by which these chemicals produce their therapeutic and toxic effects in skin, however, are not clearly defined. We exposed human skin explants to two doses of HN2 and SM. At 18 hours after exposure, histopathologic features were compared. In addition, immunohistochemical markers to basement membrane proteins were used to evaluate the effects of both chemicals on the basement membrane zone. Gross vesication was not seen. Pyknotic nuclei with or without dyskeratotic changes within epidermal keratinocytes were present at both doses. These changes varied more between skin specimens than they did between doses. Ballooning degeneration was more marked after SM exposures. Diffuse dermal-epidermal separation was present only at high-dose exposures and did not appear to correlate with the degree of changes locally in the overlying epidermis. Antibodies to laminin-5 showed decreased immunoreactivity after exposure to HN2 and SM. Immunoreactivity for laminin- was decreased to a lesser extent, and immunoreactivity for collagen IV and VII was unchanged. HN2 and SM produce similar histopathologic and immunohistochemical features after cutaneous exposure. These features suggest that part of mechanism of action of HN2 and SM is a direct effect on the basement membrane zone. Understanding the effects of HN2 and SM separate from their effect on DNA may be important in designing therapies and in advancing our understanding of the pathophysiologic changes induced by these chemicals when delivered topically.
Insights
N-methyl-2,2'-dichlorodiethylamine (HN2) and sulfur mustard (SM) cause similar skin damage by affecting the basement membrane zone. This finding is crucial for understanding their therapeutic and toxic effects beyond DNA damage.
Area of Science:
- Dermatology
- Toxicology
- Oncology
Background:
- N-methyl-2,2'-dichlorodiethylamine (HN2) is a topical chemotherapy for cutaneous T-cell lymphomas (CTCL).
- Di(2-chloroethyl)sulfide (SM) and HN2 have been used as chemical weapons, targeting the skin.
- The precise mechanisms of HN2 and SM in skin are not fully understood.
Purpose of the Study:
- To compare the histopathologic and immunohistochemical effects of HN2 and SM on human skin explants.
- To investigate the impact of these chemicals on the basement membrane zone.
- To elucidate the mechanisms of action of HN2 and SM in cutaneous exposure.
Main Methods:
- Human skin explants were exposed to two doses of HN2 and SM.
- Histopathologic features were assessed 18 hours post-exposure.
- Immunohistochemical markers for basement membrane proteins (laminin-5, laminin-, collagen IV, VII) were utilized.
Main Results:
- Both HN2 and SM induced pyknotic nuclei and dyskeratotic changes in epidermal keratinocytes.
- SM exposure resulted in more marked ballooning degeneration.
- Diffuse dermal-epidermal separation occurred at high doses, and decreased laminin-5 immunoreactivity was observed for both agents.
- Laminin- immunoreactivity decreased less, while collagen IV and VII remained unchanged.
Conclusions:
- HN2 and SM induce similar histopathologic and immunohistochemical changes in the skin.
- A direct effect on the basement membrane zone appears to be a significant mechanism of action for both chemicals.
- Understanding these effects, independent of DNA damage, is vital for developing therapies and comprehending topical chemical-induced skin pathology.