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Neurturin-Deficient Mice Develop Dry Eye and Keratoconjunctivitis Sicca

¹From the Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; the ³Departments of Pediatrics and Molecular Biology and Pharmacology and ⁴Pathology and Internal Medicine, Washington University, St. Louis, Missouri; and the ²Third Hospital of the Hebei Medical University, Shijiazhuang, China.

PURPOSE. Neurturin has been identified as a neurotrophic factor for parasympathetic neurons. Neurturin-deficient (NRTN^-/-) mice have defective parasympathetic innervation of their lacrimal glands. This study was conducted to evaluate tear function and ocular surface phenotype in NRTN^-/- mice.

METHODS. Determined by tail genomic DNA PCR, 25 NRTN^-/- mice and 17 neurturin-normal (NRTN^+/+) mice aged 6 weeks to 4 months were evaluated. Aqueous tear production, tear fluorescein clearance and corneal sensation were serially measured. Corneal permeability to AlexaFluor dextran (AFD; Molecular Probes, Eugene, OR) was measured by a fluorometric assay at 485 nm excitation and 530 nm emission. Histology was evaluated in PAS-stained sections. Mucin and HLA class II (IA) antigen were assessed by immunofluorescent staining. Tear IL-1ß was measured by ELISA, and tear matrix metalloproteinase (MMP)-9 by zymography. Gene expression in the corneal epithelia was analyzed by semiquantitative RT-PCR.

RESULTS. In comparison to that in age-matched NRTN^+/+ mice, aqueous tear production, tear fluorescein clearance, and corneal sensation were significantly reduced in NRTN^-/- mice, whereas corneal permeability to AFD was significantly increased. Immunoreactive MUC-4 and -5AC mucin and goblet cell density (P < 0.001) in the conjunctiva of NRTN^-/- mice were lower than in NRTN^+/+ mice. The expression of MUC-1 and -4 mRNA by the corneal epithelium was reduced in NRTN^-/- mice. There were a significantly greater number of IA antigen-positive conjunctival epithelial cells in NRTN^-/- mice than NRTN^+/+ mice. Tear fluid IL-1ß and MMP-9 concentrations and the expression of IL-1ß, TNF-, macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (KC), and MMP-9 mRNA by the corneal epithelia were significantly increased in NRTN^-/- mice, compared with NRTN^+/+ mice.

CONCLUSIONS. Neurturin-deficient mice show phenotypic changes and ocular surface inflammation that mimic human keratoconjunctivitis sicca. This model supports the importance of a functional ocular surface-central nervous system-lacrimal gland sensory-autonomic neural network in maintaining ocular surface health and homeostasis.

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