Mucocutaneous cholinergic system is targeted in mustard-induced vesication.
The purpose of this research is to elucidate the pharmacological mechanism mediating vesicating effects of sulfur mustard (HD) and identify an antidote to its action. HD causes blisters because epithelial cells lose their attachments. Epithelial cell adhesion is under control of the local cytotransmitter acetylcholine (ACh) working through the muscarinic and nicotinic receptor, mAChR and nAChR, classes expressed by epithelial cells. In this study, nitrogen mustard (NM)-a structural analog of HD-was used to elucidate the mechanism of vesicating effects of mustards in mucocutaneous tissues. NM caused cell detachment and cholinergic agents antagonized its effect. Radioligand binding inhibition experiments showed that NM binds to the ligand-binding site of ACh receptors (AChRs) of both classes. Ligation of AChRs on the cell membrane of keratinocytes (KC) and bronchial epithelial cells (BEC) with NM increased total esterolytic activity of serine proteinases (TEASP). Antagonists of both classes of AChRs, atropine and mecamylamine, diminished NM-induced changes, suggesting that the pathobiological effects of NM on KC and BEC result from an agonist-like degradation of ligated AChRs, predominantly of the muscarinic class. Thus, biological effects of NM on cell adhesion were antagonist-like, whereas its pharmacological effect on TEASP was agonist-like. These findings support a hypothesis that pharmacologic protection from the vesicating action of HD can be achieved by using cholinergic drugs.
Grando
Sergei A
SA
Department of Dermatology, University of California, Davis, 4860 Y Street, #3400, Sacramento, CA 95817, USA. sagrando@ucdavis.edu
D000051:Acantholysis / Q000139:chemically induced / Q000473:pathology; D000109:Acetylcholine / Q000502:physiology*; D001667:Binding, Competitive / Q000187:drug effects; D001768:Blister / Q000139:chemically induced* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D009092:Mucous Membrane / Q000473:pathology / Q000502:physiology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D012697:Serine Endopeptidases / Q000378:metabolism; D012867:Skin / Q000473:pathology; D012879:Skin Physiological Phenomena
D009588:Nitrogen Mustard Compounds; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D012697:Serine Endopeptidases; D000109:Acetylcholine