Document Detail


Sulfur mustard-induced arachidonic acid release is mediated by phospholipase D in human keratinocytes.
MedLine Citation:
PMID:  12135602     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sulfur mustard (2,2(')-dichloroethyl sulfide) is a chemical warfare agent that causes incapacitating skin blisters in humans 12-24h post-exposure following a variable asymptomatic phase. Recent reports demonstrate that inflammation plays a vital role in sulfur mustard toxicity. One of the key biochemical pathways involved in inflammation is the arachidonic acid cascade. In this report, we demonstrate that arachidonic acid is released in response to sulfur mustard and investigate the mechanisms of arachidonic acid release. Exposure to sulfur mustard caused a 5- to 8-fold increase in arachidonic acid release from human keratinocytes that had been radiolabeled with arachidonic acid. Maximal arachidonic acid release occurred between 12 and 24h. Several enzymatic pathways can lead to arachidonic acid release. Treatment with 2.0% (v/v) ethanol, an inhibitor of phospholipase D, decreased sulfur mustard-induced arachidonic acid release 40+/-7%. Additionally, 100 microM (+/-)-propranolol, an inhibitor of phosphatidic acid phosphohydrolase, blocked sulfur mustard-induced arachidonic acid release by 62+/-3%. These findings suggest that arachidonic acid release is mediated by phospholipase D and phosphatidic acid phosphohydrolase in human keratinocytes following sulfur mustard exposure. Due to the 12-24h delay in arachidonic acid release following sulfur mustard exposure, delayed therapeutic intervention may be possible. Indeed, we found that the addition of 100 microM (+/-)-propranolol up to 18 h after sulfur mustard exposure was still able to block arachidonic acid release by 30+/-3%.
Authors:
Lee J Lefkowitz; William J Smith
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  295     ISSN:  0006-291X     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-07-23     Completed Date:  2002-08-22     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1062-7     Citation Subset:  IM    
Affiliation:
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA. lee.lefkowitz@amedd.army.mil
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MeSH Terms
Descriptor/Qualifier:
Arachidonic Acid / metabolism*
Cells, Cultured
Dermatologic Agents / pharmacology*
Drug Interactions
Enzyme Inhibitors / pharmacology
Humans
Keratinocytes / drug effects*,  enzymology,  metabolism
Mustard Gas / pharmacology*
Phosphatidate Phosphatase / antagonists & inhibitors,  metabolism
Phospholipase D / antagonists & inhibitors,  metabolism*
Propranolol / pharmacology
Chemical
Reg. No./Substance:
0/Dermatologic Agents; 0/Enzyme Inhibitors; 505-60-2/Mustard Gas; 506-32-1/Arachidonic Acid; 525-66-6/Propranolol; EC 3.1.3.4/Phosphatidate Phosphatase; EC 3.1.4.4/Phospholipase D

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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