title: Prolonged impairment of corneal innervation after exposure to sulfur mustard and its relation to the development of delayed limbal stem cell deficiency.
abstract: OBJECTIVE
  Ocular injuries after exposure to the vesicant sulfur mustard (SM) are characterized by acute corneal erosions and inflammation of the anterior segment that may be followed by delayed limbal stem cell deficiency (LSCD), expressed clinically by corneal neovascularization and epithelial defects. The present study aimed to investigate the involvement of corneal nerves in the development of the delayed LSCD.
  
  
  METHODS
  Rabbit eyes were exposed to SM vapor and observed clinically up to 1 month. Morphology and density of corneal nerves were studied in acetylcholinesterase-stained whole-mount corneas at different time points after exposure. Corneal calcitonin gene-related peptide (CGRP) was measured and the relation to clinical symptoms was tested.
  
  
  RESULTS
  Degeneration of nerve terminals was observed a few hours after exposure simultaneously with the typical signs of SM ocular toxicity. Although corneal erosions healed within days, the nerves continued to disintegrate under a Wallerian degeneration pattern and their density declined significantly at 1 week in both central and peripheral corneal regions. Sprouting and regenerative nerve fibers were observed later in most of the corneas; however, healing was partial and often abnormal and was correlated with corneal edema. CGRP levels decreased at 24 hours and then increased significantly at 1 to 4 weeks, concomitant with the reinnervation process and development of the late injuries.
  
  
  CONCLUSIONS
  The prolonged impairment of corneal nerves, together with chronic inflammation implied by edema, and abnormal increase in CGRP may contribute to a pathological environment for corneal epithelial stem cells, leading to their death and to the development of the SM-induced delayed LSCD.
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona, Israel. tamark@iibr.gov.il
authors.forename: Tamar
authors.initials: T
authors.lastname: Kadar
authors.forename: Shlomit
authors.initials: S
authors.lastname: Dachir
authors.forename: Maayan
authors.initials: M
authors.lastname: Cohen
authors.forename: Hila
authors.initials: H
authors.lastname: Gutman
authors.forename: Liat
authors.initials: L
authors.lastname: Cohen
authors.forename: Rachel
authors.initials: R
authors.lastname: Brandeis
authors.forename: Vered
authors.initials: V
authors.lastname: Horwitz
authors.forename: Adina
authors.initials: A
authors.lastname: Amir
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003315:Cornea / Q000294:innervation*; D003316:Corneal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D016850:Limbus Corneae / Q000166:cytology*; D009151:Mustard Gas / Q000633:toxicity*; D009882:Ophthalmic Nerve / Q000187:drug effects / Q000473:pathology; D011817:Rabbits; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D002619:Chemical Warfare Agents; D015740:Calcitonin Gene-Related Peptide; D009151:Mustard Gas