Excessive inflammation or disordered wound repair in the cornea significantly impairs vision or ends in blindness, affecting millions of people worldwide. Our understanding of endogenous mechanisms that govern the natural resolution is limited, especially in the eye; pathways that disrupt pro-inflammatory circuits or promote epithelial healing remain to be identified. We have uncovered a novel class of anti-inflammatory lipid autacoids (resolvins) that are generated from omega-3 fatty acids and inhibit cardinal signs of inflammation. Their molecular mechanisms of action and routes of formation are shared with the well-documented anti-inflammatory lipid mediators, lipoxins (LX). These lipid circuits are present in the cornea and, more significantly, therapeutic applications of LXA4 or 17S-resolvins inhibit inflammation and promote wound healing in mouse corneas. Hence, we hypothesize that corneal injury induces formation of anti-inflammatory lipid mediators, namely, lipoxins and DHA-derived 17S-resolvins, and that dietary or therapeutic amplification of these protective lipid circuits promotes wound healing and limits the sequelae of corneal injury. To establish a role for lipid autacoids in limiting corneal injury, we will employ an approach of lipid analysis, molecular biology and in vivo genetic manipulation to address three specific AIMS: I) establish that anti-inflammatory lipid mediators, namely lipoxins and DHA-derived 17S-resolvins, are formed as part of the inflammatory reparative response; II) determine if omega-3 dietary amplification of the 17S-resolvin pathway or direct topical application of LXA4 or 17S-resolvin accelerates inflammatory resolution and wound healing in the cornea; III) demonstrate that expression of the LXA4 receptor or biosynthetic pathways for the formation of 17S-resolvins and lipoxins is a determinant for limiting corneal damage. Results of this proposal will identify endogenous mechanisms that limit corneal inflammation and promote epithelial wound healing and, therefore, may be critical to preserving corneal transparency. Moreover, they may provide a novel alternative approach to treating corneal injury, namely, the amplification of endogenous protective lipid circuits.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY016136-01A1
Application #
6965915
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$390,000
Indirect Cost
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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
von Moltke, Jakob; Trinidad, Norver J; Moayeri, Mahtab et al. (2012) Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490:107-11
Wang, Samantha B; Hu, Kyle M; Seamon, Kyle J et al. (2012) Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea. FASEB J 26:1506-16
Tamang, David L; Pirzai, Waheed; Priebe, Gregory P et al. (2012) Hepoxilin A(3) facilitates neutrophilic breach of lipoxygenase-expressing airway epithelial barriers. J Immunol 189:4960-9
Hurley, Bryan P; Pirzai, Waheed; Mumy, Karen L et al. (2011) Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells. Am J Physiol Lung Cell Mol Physiol 300:L286-94
Sapieha, Przemyslaw; Stahl, Andreas; Chen, Jing et al. (2011) 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ?-3 polyunsaturated fatty acids. Sci Transl Med 3:69ra12
Liclican, Elvira L; Gronert, Karsten (2010) Molecular circuits of resolution in the eye. ScientificWorldJournal 10:1029-47
Leedom, Alexander J; Sullivan, Aaron B; Dong, Baiyan et al. (2010) Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury. Am J Pathol 176:74-84
Liclican, Elvira L; Nguyen, Van; Sullivan, Aaron B et al. (2010) Selective activation of the prostaglandin E2 circuit in chronic injury-induced pathologic angiogenesis. Invest Ophthalmol Vis Sci 51:6311-20
Gronert, Karsten (2010) Resolution, the grail for healthy ocular inflammation. Exp Eye Res 91:478-85

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