Sulfur mustard-increased proteolysis following in vitro and in vivo exposures.
The pathologic mechanisms underlying sulfur mustard (HD)-induced skin vesication are as yet undefined. Papirmeister et al. (1985) postulate enhanced proteolytic activity as a proximate cause of HD-induced cutaneous injury. Using a chromogenic peptide substrate assay, we previously reported that in vitro exposure of cell cultures to HD enhances proteolytic activity. We have continued our investigation of HD-increased proteolytic activity in vitro and have expanded our studies to include an in vivo animal model for HD exposure. In vitro exposure of human peripheral blood lymphocytes (PBL) to HD demonstrated that the increase in proteolytic activity is both time- and temperature-dependent. Using a panel of 10 protease substrates, we established that the HD-increased proteolysis was markedly different from that generated by plasminogen activator. The hairless guinea pig is an animal model used for the study of HD-induced dermal pathology. When control and HD-exposed PBL and hairless guinea pig skin where examined, similarities in their protease substrate reactivities were observed. HD-exposed hairless guinea pig skin biopsies demonstrated increased proteolytic activity that was time-dependent. The HD-increased proteolytic response was similar in both in vitro and in vivo studies and may be useful for elucidating both the mechanism of HD-induced vesication and potential treatment compounds.
Cowan
F M
FM
Biochemical Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5424.
Yourick
J J
JJ
Hurst
C G
CG
Broomfield
C A
CA
Smith
W J
WJ
D000818:Animals; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009151:Mustard Gas / Q000633:toxicity*; D010455:Peptides / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013379:Substrate Specificity; D013696:Temperature
D010455:Peptides; D010450:Endopeptidases; D009151:Mustard Gas