Preservation of tear film integrity and inhibition of corneal injury by dexamethasone in a rabbit model of lacrimal gland inflammation-induced dry eye.
OBJECTIVE
The aim of this study was to establish a clinically relevant short-term animal model of dry eye with utility in identifying compounds with potential therapeutic efficacy.


METHODS
Rabbit lacrimal glands were injected with the T-cell mitogen Concanavalin A (Con A) and inflammation, tear function, and corneal epithelial cell integrity were subsequently assessed. The inflammatory response was characterized by quantifying biochemical markers of inflammation ex vivo and by confirming inflammatory cell influx by histology. Matrix metalloproteinase-9 (MMP-9) and proinflammatory cytokines IL-1beta, IL-8, and TGF-beta1 were quantified in tissue extracts. Tear function was monitored by measuring tear fluorescein clearance and tear breakup time (TBUT). Corneal epithelial cell integrity was determined by quantifying the uptake of methylene blue dye following the exposure of rabbits to a low-humidity environment. The anti-inflammatory corticosteroid, dexamethasone, was administered topically as indicated for each study.


RESULTS
Histopathologic evaluation of lacrimal glands injected with Con A revealed a pronounced inflammatory process characterized by lymphocytic infiltration, multifocal necrosis, and fibroplasia. Elevated levels of MMP-9 and cytokines IL-1beta, IL-8, and TGF-beta1 were detected in the lacrimal gland and cornea. Inflammation of the rabbit lacrimal gland following an injection of Con A significantly reduced tear clearance and TBUT and increased susceptibility to desiccation-induced corneal damage. Dexamethasone was prophylactically and therapeutically effective in this inflammation model of dry eye, restoring tear function and inhibiting corneal injury following topical ocular application.


CONCLUSIONS
Characteristics of this rabbit lacrimal gland inflammation model of dry eye are consistent with the current understanding of dry eye as a local ocular surface inflammatory response to abnormal tear volume and composition. These results suggest that this rabbit model of dry eye may be employed to assess the therapeutic efficacy of mechanistically diverse agents on clinically relevant signs of ocular surface disease. These methods were strategically developed to be applicable for advancing drug discovery for a broad spectrum of dry eye patients.
Nagelhout
Teann J
TJ
Alcon Research, Ltd., Fort Worth, TX 76134, USA.
Gamache
Daniel A
DA
Roberts
Leighann
L
Brady
Milton T
MT
Yanni
John M
JM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003208:Concanavalin A; D003315:Cornea / Q000187:drug effects; D065306:Corneal Injuries; D016207:Cytokines / Q000378:metabolism; D003607:Dacryocystitis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003890:Desiccation; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005131:Eye Injuries / Q000209:etiology / Q000517:prevention & control; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D013666:Tears / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003208:Concanavalin A; D003907:Dexamethasone