title: Heme oxygenase 1 attenuates the development of atopic dermatitis-like lesions in mice: implications for human disease.
abstract: BACKGROUND
  Oxidative stress has been implicated in the exacerbation of atopic dermatitis (AD).
  
  
  OBJECTIVE
  We sought to investigate the pathophysiologic roles of inducible antioxidant heme oxygenase (HO) 1 in the development of AD.
  
  
  METHODS
  Serum HO-1 levels of patients with AD (n = 100) and age-matched healthy control subjects (n = 72) were determined by means of ELISA. The relationships between serum HO-1 levels and clinical severities, laboratory parameters, and cytokines/chemokines were assessed. Skin lesions of patients with AD and psoriasis were analyzed by means of immunohistochemistry. A murine AD model, DS-Nh, was used to further investigate localization and function of HO-1. Evaluation of symptoms, serum IgE and IL-18 levels, immunoblotting results, and histologic analyses of skin were performed. The effect of intraperitoneally administered hemin, a potent HO-1 inducer, or zinc protoporphyrin IX, an inhibitor of HO, was monitored.
  
  
  RESULTS
  Serum HO-1 levels were significantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1-expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Immunofluorescence of mouse skin lesions revealed that HO-1-positive cells were macrophages and dendritic cells. Treatment with hemin, but not with zinc protoporphyrin IX, attenuated the development of the skin lesions in DS-Nh mice and reduced serum IL-18 levels.
  
  
  CONCLUSIONS
  HO-1 levels were increased in sera and skin lesions of patients with AD. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction offers a promising therapeutic strategy for AD.
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Kirino
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kirino
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takeno
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shuji
authors.initials: S
authors.lastname: Murakami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirasawa
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Ueda
authors.forename: Michiko
authors.initials: M
authors.lastname: Aihara
authors.forename: Zenro
authors.initials: Z
authors.lastname: Ikezawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
mesh_terms: D000328:Adult; D000818:Animals; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D020382:Interleukin-18 / Q000097:blood; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology
chemical_list: D020382:Interleukin-18; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006427:Hemin; D051547:Heme Oxygenase-1