title: Inhibition of benzalkonium chloride-induced skin inflammation in mice by an indol-1-ylpropan-2-one inhibitor of cytosolic phospholipase A2 α.
abstract: BACKGROUND
  Irritant contact dermatitis (ICD) is a frequent and often underrated problem for which the major efficacious therapy is still local glucocorticoids, although they have known adverse effects due to their wide spectrum of action. A more focused therapeutic strategy would be the inhibition of a key enzyme for biosynthesis of the lipid mediators, cytosolic phospholipase A(2) α (cPLA(2) α), in ICD. We are analysing the pharmacological and biological effects of a selective cPLA(2) α inhibitor.
  
  
  OBJECTIVE
  To examine the usefulness of the potent and selective cPLA(2) α inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (compound 1) for therapy of inflammatory skin disorders.
  
  
  METHODS
  We examined clinical and cellular effects of a selective cPLA(2) α inhibitor (compound 1) on ICD in mice.
  
  
  RESULTS
  Topical application of the compound significantly reduced ear swelling after induction by the irritant benzalkonium chloride. Concomitantly, compound 1 inhibited the accumulation of granulocytes as well as the expression of inflammatory proteins such as tumour necrosis factor-α, interleukin-1β and macrophage inflammatory proteins 1α and 1β in the ear tissue. In primary murine keratinocytes, the benzalkonium chloride-induced expression of these proteins was also downregulated after treatment with compound 1 in vitro.
  
  
  CONCLUSIONS
  Compound 1 is a well-aimed agent for the treatment of nonspecific skin inflammation as it selectively inhibits cPLA(2) α and as it acts on an early stage of skin inflammation after its elicitation.
authors.affiliation: Institute of Immunology, University of Münster, Röntgenstrasse 21, 48149 Münster, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Roebrock
authors.forename: M
authors.initials: M
authors.lastname: Wolf
authors.forename: S
authors.initials: S
authors.lastname: Bovens
authors.forename: M
authors.initials: M
authors.lastname: Lehr
authors.forename: C
authors.initials: C
authors.lastname: Sunderkötter
mesh_terms: D000279:Administration, Cutaneous; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001548:Benzalkonium Compounds / Q000633:toxicity*; D018925:Chemokines / Q000378:metabolism; D002990:Clobetasol / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D017453:Dermatitis, Irritant / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007509:Irritants / Q000633:toxicity*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D010032:Otitis Externa / Q000517:prevention & control*; D009418:S100 Proteins / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D001548:Benzalkonium Compounds; D018925:Chemokines; D002990:Clobetasol; D016207:Cytokines; D004791:Enzyme Inhibitors; D054513:Group IV Phospholipases A2; D007211:Indoles; D007509:Irritants; D008994:Monoacylglycerol Lipases; D009418:S100 Proteins; D000099252:Fatty Acid Amide Hydrolases; C570945:3-(5-carboxypentanoyl)-1-(3-(4-octylphenoxy)-2-oxopropyl)indole-5-carboxylic acid