Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model.
OBJECTIVE
Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model.


METHODS
Thirteen- to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination.


RESULTS
Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that α-smooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of α-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD⁴+ T cells and CD11b+ cells decreased after RvE1 treatment when compared with DE.


CONCLUSIONS
RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.
Li
Na
N
Neuroscience Center of Excellence and the Department of Ophthalmology, Louisiana State University Health Sciences Center , New Orleans, LA 70112, USA.
He
Jiucheng
J
Schwartz
Carl Eric
CE
Gjorstrup
Per
P
Bazan
Haydee E P
HE
D000199:Actins / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D058628:Myofibroblasts / Q000378:metabolism; D013666:Tears / Q000187:drug effects
D000199:Actins; D039481:CD11b Antigen; D015704:CD4 Antigens; C544013:alpha-smooth muscle actin, mouse; D015118:Eicosapentaenoic Acid; D051546:Cyclooxygenase 2; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid