title: Prostaglandin E2 and nitric oxide mediate the acute inflammatory (erythemal) response to topical 5-aminolaevulinic acid photodynamic therapy in human skin.
abstract: BACKGROUND
  Topical 5-aminolaevulinic acid photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown.
  
  
  OBJECTIVE
  To look for involvement of the proinflammatory mediators prostaglandin (PG)E2 and nitric oxide (NO) in topical PDT-induced erythema in human skin.
  
  
  METHODS
  A series of studies was performed in healthy volunteers (n = 35). Following definition of the erythemal time course and dose response to 5-ALA-PDT, duplicate 5-ALA dose series were iontophoresed into the skin of each ventral forearm and exposed to 100 J cm(-2) broadband red light. Within subject, arms were randomized to control, or treatment with the cyclooxygenase and NO synthase inhibitors indometacin and Nω -nitro-l-arginine methyl ester (l-NAME), respectively, and the impact on 5-ALA-PDT-induced erythema was quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT administration.
  
  
  RESULTS
  A 5-ALA dose-related delayed erythema occurred by 3 h (r = 0·97, P < 0·01), with erythema persisting to 48 h post-PDT. Topical indometacin applied immediately post-PDT reduced the slope of erythemal response at 3 h and 24 h (P < 0·05). Intradermal injection of l-NAME into 5-ALA-PDT-treated sites reduced the slope of response at 24 h post-PDT (P < 0·001), while significantly inhibiting erythema from 3 h to 48 h post-PDT (P < 0·01). Analysis of dermal microdialysate showed release of NO and PGE2 following treatment.
  
  
  CONCLUSIONS
  Topical 5-ALA-PDT upregulates PGE2 and NO in human skin, where they play a significant role in the clinical inflammatory response. The potential relevance of these mediators to PDT in human cutaneous pathology warrants study.
authors.affiliation: Dermatology Centre, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester, U.K.
authors.forename: R C C
authors.initials: RC
authors.lastname: Brooke
authors.forename: M
authors.initials: M
authors.lastname: Sidhu
authors.forename: A
authors.initials: A
authors.lastname: Sinha
authors.forename: R E B
authors.initials: RE
authors.lastname: Watson
authors.forename: P S
authors.initials: PS
authors.lastname: Friedmann
authors.forename: G F
authors.initials: GF
authors.lastname: Clough
authors.forename: L E
authors.initials: LE
authors.lastname: Rhodes
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology*; D003875:Drug Eruptions / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004890:Erythema / Q000139:chemically induced* / Q000517:prevention & control; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D017319:Photosensitizing Agents; D009569:Nitric Oxide; D000622:Aminolevulinic Acid; D019001:Nitric Oxide Synthase; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin