A mouse model of keratoconjunctivitis sicca.
OBJECTIVE
To evaluate the effects of pharmacologic inhibition of aqueous tear production and desiccating environmental stress on aqueous tear production, tear clearance, corneal epithelial permeability, and conjunctival epithelial morphology, proliferation, and conjunctival goblet cell differentiation.


METHODS
Aqueous tear production was inhibited by applying transdermal scopolamine (scop) patches to the depilated midtail of female MC, CBA mice. Desiccating environmental stress was created by placing mice in a hood with a continuous airflow blower. Aqueous tear production and volume, tear clearance, and corneal barrier function were compared in four experimental groups: untreated control mice, mice placed in the blower hood, mice treated with a scop patch, and mice treated with a scop patch and blower hood (scop patch + blower). Cotton threads were used to evaluate aqueous tear production and volume. Tear clearance was assessed by fluorometric measurement of collected tear fluid 15 minutes after instillation of 1% sodium fluorescein. Corneal epithelial barrier function was assessed by fluorometric measurement of carboxyfluorescein uptake. Conjunctival morphology and goblet cell density were evaluated in stained histologic sections. Conjunctival epithelial proliferation was assessed by bromodeoxyuridine (BrdU) labeling.


RESULTS
Significant decreases in cotton thread wetting and tear clearance were observed in mice treated with a scop patch (P < 0.001) or with a scop patch and blower desiccation (P < 0.001), with a greater reduction in tear clearance in the latter group. Significantly increased corneal carboxyfluorescein uptake was noted in the scop patch group compared with untreated mice (P = 0.05) and in the scop patch + blower group compared with all the other groups (P < 0.0001). Changes in conjunctival epithelial morphology and a significant decrease in conjunctival goblet cell density (P < 0.001) were observed in the scop patch + blower group compared with the untreated control group. The number of proliferating conjunctival epithelial cells was significantly greater in the scop patch + blower group.


CONCLUSIONS
Pharmacologic inhibition of tear production in mice is accompanied by ocular surface epithelial changes resembling human keratoconjunctivitis sicca (KCS) that are exacerbated by desiccating environmental stress. Cholinergic stimulated tear production appears to be essential for maintaining a healthy ocular surface.
Dursun
Dilek
D
Ocular Surface and Tear Center, Bascom Palmer Eye Institute, Miami, Florida, USA.
Wang
Min
M
Monroy
Dagoberto
D
Li
De-Quan
DQ
Lokeshwar
Balakrishna L
BL
Stern
Michael E
ME
Pflugfelder
Stephen C
SC
D000818:Animals; D002452:Cell Count; D003228:Conjunctiva / Q000473:pathology; D003890:Desiccation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D019573:Epithelium, Corneal / Q000378:metabolism / Q000473:pathology; D005452:Fluoresceins; D015590:Fluorophotometry; D020397:Goblet Cells / Q000473:pathology; D007638:Keratoconjunctivitis Sicca / Q000209:etiology / Q000473:pathology*; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D018727:Muscarinic Antagonists / Q000494:pharmacology; D012601:Scopolamine / Q000494:pharmacology; D013312:Stress, Physiological / Q000150:complications; D013666:Tears / Q000378:metabolism
D005452:Fluoresceins; D018727:Muscarinic Antagonists; C024098:6-carboxyfluorescein; D012601:Scopolamine