title: Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma.
abstract: OBJECTIVE
  In glaucoma, the optic nerve head (ONH) is the principal site of initial axonal injury, and elevated intraocular pressure (IOP) is the predominant risk factor. However, the initial responses of the ONH to elevated IOP are unknown. Here the authors use a rat glaucoma model to characterize ONH gene expression changes associated with early optic nerve injury.
  
  
  METHODS
  Unilateral IOP elevation was produced in rats by episcleral vein injection of hypertonic saline. ONH mRNA was extracted, and retrobulbar optic nerve cross-sections were graded for axonal degeneration. Gene expression was determined by microarray and quantitative PCR (QPCR) analysis. Significantly altered gene expression was determined by multiclass analysis and ANOVA. DAVID gene ontology determined the functional categories of significantly affected genes.
  
  
  RESULTS
  The Early Injury group consisted of ONH from eyes with <15% axon degeneration. By array analysis, 877 genes were significantly regulated in this group. The most significant upregulated gene categories were cell cycle, cytoskeleton, and immune system process, whereas the downregulated categories included glucose and lipid metabolism. QPCR confirmed the upregulation of cell cycle-associated genes and leukemia inhibitory factor (Lif) and revealed alterations in expression of other IL-6-type cytokines and Jak-Stat signaling pathway components, including increased expression of IL-6 (1553%). In contrast, astrocytic glial fibrillary acidic protein (Gfap) message levels were unaltered, and other astrocytic markers were significantly downregulated. Microglial activation and vascular-associated gene responses were identified.
  
  
  CONCLUSIONS
  Cell proliferation and IL-6-type cytokine gene expression, rather than astrocyte hypertrophy, characterize early pressure-induced ONH injury.
authors.affiliation: Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97201, USA. johnsoel@ohsu.edu
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Johnson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Doser
authors.forename: William O
authors.initials: WO
authors.lastname: Cepurna
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dyck
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Wendi S
authors.initials: WS
authors.lastname: Lambert
authors.forename: John C
authors.initials: JC
authors.lastname: Morrison
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D005901:Glaucoma / Q000235:genetics* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics*; D007429:Intraocular Pressure; D008297:Male; D046228:Microarray Analysis; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009898:Optic Disk / Q000378:metabolism* / Q000473:pathology; D020221:Optic Nerve Injuries / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger