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XJ Song, DQ Li, W Farley, RO Heuckeroth, J Milbrandt, SC Pflugfelder; Neurturin Deficient Mice, a Model for Dry Eye and Keratoconjunctivitis Sicca . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3126.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Neurturin (NRTN) has recently been identified as a neurotrophic factor for parasympathetic neurons. Neurturin-deficient (NRTN-/-) mice have defects in parasympathetic innervation of the lacrimal and salivary gland. This study explored the dry eye phenotype that develops in NRTN-/- mice. Methods: Determined by tail genomic DNA PCR, 10 NRTN-/- mice, generated by homologous recombination, and 8 neurturin-normal (NRTN+/+) mice aged 6 weeks to 4 months were evaluated. Aqueous tear production and tear fluorescein clearance were serially measured throughout this period. Zymography and ELISA were used to measure gelatinases and IL-1ß, respectively, in tear fluid. Gene expression in the corneal epithelium was evaluated by semi-quantitative RT-PCR. Corneal permeability to carboxyfluorescein (CF) was measured with a fluorometric assay. Immunofluorescent staining assessed infiltration of the cornea and conjunctiva by CD11b+ leukocytes, and conjunctival goblet cell density was evaluated in PAS-stained histological sections. Results: In comparison to age-matched NRTN+/+ mice, aqueous tear production and tear fluorescein clearance were significantly reduced (P<0.05-0.001), while corneal permeability to CF was significantly increased (P<0.05) in NRTN-/- mice. Tear MMP-9 concentration was markedly increased in NRTN-/- mice compared to NRTN+/+ mice where MMP-9 was barely detectable. Tear fluid IL-1ß concentration was increased by 4.4-fold (P<0.05) in NRTN-/- mice compared to controls. The expression of MMP-9, IL-1ß and TNF-α mRNA by the corneal epithelia was very low in NRTN+/+ mice, but was dramatically upregulated in the NRTN-/- mice. The CD11b+ leukocytes were assessed in the cornea and bulbar and tarsal conjunctiva. A significantly greater number of CD11b+ cells were observed infiltrating the cornea and tarsal conjunctiva in NRTN-/- mice than NRTN+/+ mice. Goblet cell density in the bulbar conjunctiva of NRTN-/- mice was significantly lower than NRTN+/+ mice. Conclusion: Neurturin deficient mice develop a phenotype of ocular surface pathology and inflammation that mimics human dry eye disease. This model supports the importance of a functional ocular surface-CNS-lacrimal gland sensory-autonomic neural network for maintenance of ocular surface health and homeostasis.
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