title: Inhibition by all-trans retinoic acid of collagen degradation mediated by corneal fibroblasts.
abstract: BACKGROUND
  We examined the effect of all-trans retinoic acid on collagen degradation mediated by corneal fibroblasts.
  
  
  METHODS
  Rabbit corneal fibroblasts were cultured with or without all-trans retinoic acid in a three-dimensional collagen gel, and the extent of collagen degradation was determined by measurement of hydroxyproline in acid hydrolysates of culture supernatants. Matrix metalloproteinase expression was examined by immunoblot analysis and gelatin zymography. The abundance and phosphorylation state of the endogenous nuclear factor-kappaB inhibitor IκB-α were examined by immunoblot analysis. Corneal ulceration was induced by injection of lipopolysaccharide into the central corneal stroma of rabbits and was assessed by observation with a slitlamp microscope.
  
  
  RESULTS
  All-trans retinoic acid inhibited interleukin-1β-induced collagen degradation by corneal fibroblasts in a concentration- and time-dependent manner. It also attenuated the release and activation of matrix metalloproteinases as well as the phosphorylation and degradation of IκB-α induced by interleukin-1β in these cells. Topical application of all-trans retinoic acid suppressed corneal ulceration induced by injection of lipopolysaccharide into the corneal stroma.
  
  
  CONCLUSIONS
  All-trans retinoic acid inhibited collagen degradation mediated by corneal fibroblasts exposed to interleukin-1β, with this effect being accompanied by suppression of nuclear factor-kappaB signalling as well as of matrix metalloproteinase release and activation in these cells. All-trans retinoic acid also attenuated lipopolysaccharide-induced corneal ulceration in vivo. Our results therefore suggest that all-trans retinoic acid might prove effective for the treatment of patients with corneal ulceration.
authors.affiliation: Department of Ophthalmology, Yamaguchi University, Graduate School of Medicine, Yamaguchi, Japan.|Senju Pharmaceutical Co., Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Ophthalmology, Yamaguchi University, Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology, Yamaguchi University, Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Orita
authors.affiliation: Senju Pharmaceutical Co., Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Senju Pharmaceutical Co., Osaka, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Wada
authors.affiliation: Senju Pharmaceutical Co., Osaka, Japan.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Ophthalmology, Yamaguchi University, Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Ophthalmology, Yamaguchi University, Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Sonoda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D060527:Corneal Keratocytes / Q000187:drug effects* / Q000378:metabolism; D003320:Corneal Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D007641:Keratolytic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D007641:Keratolytic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014212:Tretinoin; D003094:Collagen; D020782:Matrix Metalloproteinases; D006909:Hydroxyproline
keywords: all-trans retinoic acid (ATRA); collagen; cornea; matrix metalloproteinase (MMP); ulceration