Gender differences in re-epithelialisation time in fungal corneal ulcers

Krishnan, Tiruvengada; Prajna, N Venkatesh; Gronert, Karsten; Oldenburg, Catherine E.; Ray, Kathryn J.; Keenan, Jeremy D.; Lietman, Thomas M.; Acharya, Nisha R.

doi:10.1136/bjophthalmol-2011-300441

Cited by 17 publications

(12 citation statements)

References 5 publications

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“…To the best of our knowledge, this study provides the first findings demonstrating a sex‐specific difference in ocular reparative‐inflammatory responses. The clinical relevance of our findings in mice is underscored by results from a post hoc analysis of a trial of 120 patients that received treatment for fungal corneal ulcers (53). The analysis demonstrated sex‐specific differences in the clinical outcome of corneal ulcers.…”

Section: Discussionmentioning

confidence: 85%

Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea

Wang

Seamon

et al. 2011

FASEB j.

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Estrogen receptors (ERs) are expressed in leukocytes and in every ocular tissue. However, sex-specific differences and the role of estradiol in ocular inflammatory-reparative responses are not well understood. We found that female mice exhibited delayed corneal epithelial wound closure and attenuated polymorphonuclear (PMN) leukocyte responses, a phenotype recapitulated by estradiol treatment both in vivo (topically in male mice) and in vitro (corneal epithelial cell wound healing). The cornea expresses 15-lipoxygenase (15-LOX) and receptors for lipoxin A(4) (LXA(4)), which have been implicated in an intrinsic lipid circuit that regulates corneal inflammation and wound healing. Delayed epithelial wound healing correlated with lower expression of 15-LOX in the regenerated epithelium of female mice. Estradiol in vitro and in vivo down-regulated epithelial 15-LOX expression and LXA(4) formation, while estradiol abrogation of epithelial wound healing was completely reversed by treatment with LXA(4). More important, ERβ and ERα selectively regulated epithelial wound healing, PMN cell recruitment, and activity of the intrinsic 15-LOX/LXA(4) circuit. Our results demonstrate for the first time a sex-specific difference in the corneal reparative response, which is mediated by ERβ and ERα selective regulation of the epithelial and PMN 15-LOX/LXA(4) circuit. These findings may provide novel insights into the etiology of sex-specific ocular inflammatory diseases.

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Section: Discussionmentioning

confidence: 85%

Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea

Wang

Seamon

et al. 2011

FASEB j.

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“…Resolution of minor epithelial defects depends on the time course for restoring the epithelial barrier, we have previously demonstrated that acute epithelial wound healing is delayed in female mice in response to repeated mild corneal abrasion injuries (24) or in human female patients treated for corneal fungal ulcers (25). The female-specific wound healing response can be induced in males by activation of the epithelial estrogen receptor ERβ and is mediated in large part by functional down-regulation an epithelial LXA 4 circuit (24).…”

Section: Discussionmentioning

confidence: 99%

“…The etiology of this common ocular immune disease is unknown or the cause for its striking prevalence in women (22, 23). We recently reported on marked sex-specific differences in corneal inflammatory/reparative responses in both humans and mice (24, 25). More importantly, we identified estrogen downregulation of the resident corneal LXA 4 circuit as a mechanism for the female phenotype of delayed epithelial wound healing and altered PMN functional responses (24).…”

Section: Introductionmentioning

confidence: 99%

Female-Specific Downregulation of Tissue Polymorphonuclear Neutrophils Drives Impaired Regulatory T Cell and Amplified Effector T Cell Responses in Autoimmune Dry Eye Disease

Gao

Min

Zhang

et al. 2015

The Journal of Immunology

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Immune-driven dry eye disease primarily affects women; the cause for this sex-specific prevalence is unknown. PMN have distinct phenotypes that drive inflammation but also regulate lymphocytes and are the rate-limiting cell for generating anti-inflammatory lipoxin A4 (LXA4). Estrogen regulates the LXA4 circuit to induce delayed female-specific wound healing in the cornea. However, the role of PMN in dry eye disease remains unexplored. We discovered a LXA4-producing tissue-PMN population in the corneal limbus, lacrimal glands and cervical lymph nodes of healthy male and female mice. These tissue-PMN, unlike inflammatory-PMN, expressed a highly amplified LXA4 circuit and were sex-specifically regulated during immune-driven dry eye disease. Desiccating stress in females, unlike in males, triggered a remarkable decrease in lymph node PMN and LXA4 formation that remained depressed during dry eye disease. Depressed lymph node PMN and LXA4 in females correlated with an increase in T effector cells (TH1 and TH17), a decrease in regulatory T cells (Treg) and increased dry eye pathogenesis. Antibody depletion of tissue-PMN abrogated LXA4 formation in lymph nodes, caused a marked increase in TH1 and TH17 and decrease in Treg cells. To establish an immune regulatory role for PMN-derived LXA4 in dry eye females were treated with LXA4. LXA4 treatment markedly inhibited TH1 and TH17 and amplified Treg cells in draining lymph nodes, while reducing dry eye pathogenesis. These results identify female-specific regulation of LXA4-producing tissue-PMN as a potential key factor in aberrant T effector cell activation and initiation of immune-driven dry eye disease.

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“…A 2011 post-hoc analysis of a prospective clinical trial identified for the first time a marked sex-specific difference in the outcome of wound healing in the cornea. Namely, after correcting for confounding factors, corneal wounds in men healed two times faster than in women [38]. Employing the mouse model of self-resolving corneal injury, it was discovered that estrogen regulates the 15-LOX-LXA 4 -ALX circuit via the epithelial ERβ receptor [39].…”

Section: Specialized Pro-resolving Mediators In Ocular Diseasesmentioning

confidence: 99%