There is a great interest and unresolved paradox regarding the complex role of estrogen in immune and inflammatory responses. Sex-specific differences and estrogen's role in ocular inflammatory diseases are not well understood, even though Dry Eye Syndromes primarily affect women. Receptors for estrogens, ER? and ER?, are expressed in leukocytes and in every ocular tissue. Acute healthy inflammation depends on the early recruitment of neutrophils, their tightly controlled activation and subsequent removal by recruited macrophages. Dysregulation of this essential response likely represent the early event that triggers inflammatory and chronic diseases. The lipid mediator lipoxin A4 (LXA4) has been identified as key mediator of inflammatory resolution and regulators of leukocyte function. The cornea highly expresses a key enzyme for LXA4 formation, 15-lipoxygenase (15-LOX), and its G-protein coupled receptor ALX. Genetic disruption of the 15-LOX/LXA4 circuit leads to dysregulated inflammation, wound healing and pathological angiogenesis in the cornea. Preliminary studies demonstrate that female mice consistently exhibit delayed epithelial wound closure. A prospective clinical trial in 120 patients with corneal ulcers, documents for the first time, that epithelial wounds healed twice as slow in female patients. The female phenotype of delayed wound healing can be recapitulated by treating male mice with topical estrogen and in in vitro experiments with corneal epithelial cells. More importantly, ER? and ER? specific agonists differentially regulated inflammation, epithelial wound healing and the expression and activity of the intrinsic 15-LOX/LXA4 circuit. These findings correlate with lipidomic analysis from a dry eye model that demonstrates striking impairment in corneal 15-LOX activity in female mice. Estrogen's selective regulation of this intrinsic lipid circuit may provide novel insights into the etiology or pathogenesis of sex-specific ocular surface inflammatory diseases, which will be tested in three specific aims: I. Characterize sex-specific differences in the intrinsic 15-LOX and LXA4 circuit during acute and reoccurring epithelial injury and inflammation in the cornea. II. Elucidate the role of the estrogen receptors (ER? and ER?) in the regulation of corneal epithelial and leukocyte wound healing function and define receptor specific regulation of the 15-LOX and LXA4 circuit in these cells. III. Delineate the role ER? and ER? in the corneal pathogenesis of dry eye in mice and define the protective role of the intrinsic 15-LOX and LXA4 circuit. Result from this study will address critical gaps of knowledge regarding the role of estrogen and its receptors in acute inflammatory/reparative responses in the eye and will define for the first time sex-specific (estrogen) regulation of intrinsic lipid circuits that are critical for inflammatory resolution. Our knowledge of structure function relationships, receptors and signal transduction pathways for LXA4 and related mimetics is relatively advanced and efficacy/safety in animal models have been established. Hence, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic. !

Public Health Relevance

This study will address critical gaps of knowledge regarding the role of estrogen and its receptors in acute inflammatory/reparative responses in the eye and will define for the first time sex-specific (estrogen) regulation of intrinsic lipid circuits that are critical for inflammatory resolution. Due to the advanced pharmacology and clearly defined targets of endogenous protective lipid mediators, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022208-02
Application #
8463546
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2012-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$357,323
Indirect Cost
$119,823
Name
University of California Berkeley
Department
None
Type
Schools of Optometry/Ophthalmol
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Pruss, Harald; Rosche, Berit; Sullivan, Aaron B et al. (2013) Proresolution lipid mediators in multiple sclerosis - differential, disease severity-dependent synthesis - a clinical pilot trial. PLoS One 8:e55859
Bhowmick, Rudra; Tin Maung, Nang H; Hurley, Bryan P et al. (2013) Systemic disease during Streptococcus pneumoniae acute lung infection requires 12-lipoxygenase-dependent inflammation. J Immunol 191:5115-23