title: Therapeutic potential of trichostatin A to control inflammatory and fibrogenic disorders of the ocular surface.
abstract: OBJECTIVE
  To examine the effects of a histone deacetylase inhibitor, Trichostatin A (TSA), on the behavior of macrophages and subconjunctival fibroblasts in vitro and on ocular surface inflammation and scarring in vivo using an alkali burn wound healing model.
  
  
  METHODS
  Effects of TSA on expression of inflammation-related growth factors or collagen I were examined by real-time RT-PCR or immunoassay in mouse macrophages or human subconjunctival fibroblasts. Effects of TSA on trans forming growth factor β (TGFβ)/Smad signaling were evaluated with western blotting and/or immunocytochemistry. Alkali-burn injuries on the eyes of mice were performed with three µl of 0.5 N NaOH under general and topical anesthesia. TSA (600 µg/Kg daily) or vehicle was administered to animals via intraperitoneal (i.p.) injection. Histology and real-time RT-PCR investigations evaluated the effects of TSA on the healing process of the cornea.
  
  
  RESULTS
  TSA inhibited TGFβ 1 and vascular endothelial growth factor (VEGF) expression in macrophages, and TGFβ1 and collagen I in ocular fibroblasts. It elevated the expression of 5'-TG-3'-interacting factor (TGIF) and Smad7 in fibroblasts and blocked nuclear translocation of phospho-Smad2. Real-time PCR and immunocytochemistry studies showed that systemic administration of TSA suppressed the inflammation and fibrotic response in the stroma and accelerated epithelial healing in the alkali-burned mouse cornea.
  
  
  CONCLUSIONS
  Systemic administration of TSA reduces inflammatory and fibrotic responses in the alkali-burned mouse ocular surface in vivo. The mechanisms of action involve attenuation of Smad signal in mesenchymal cells and reduction in the activation and recruitment of macrophages. TSA has the potential to treat corneal scarring in vivo.
authors.affiliation: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan. aikitano@wakayama-med.ac.jp
authors.forename: Ai
authors.initials: A
authors.lastname: Kitano
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okada
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamanka
authors.forename: Kumi
authors.initials: K
authors.lastname: Shirai
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Mohan
authors.forename: Shizuya
authors.initials: S
authors.lastname: Saika
mesh_terms: D000818:Animals; D002057:Burns, Chemical / Q000150:complications / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003228:Conjunctiva / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005128:Eye Diseases / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D016207:Cytokines; D006877:Hydroxamic Acids; D016212:Transforming Growth Factor beta; C012589:trichostatin A