Project Summary/Abstract Corneal wounds and abrasions occurring as a result of injury, chemical burns, surgery, contact lens wear and dry eye syndrome are painful and can predispose individuals to infection. Although these wounds tend to heal rapidly, in some cases, such as in diabetes, the healing may be delayed or may even fail; in other cases individuals may continue to show persistent or chronic inflammation despite resolution of the injury or infection. This persistent sterile inflammation can interfere with corneal clarity thereby compromising vision; therefore, treatments to inhibit inflammation while improving corneal wound healing are needed. In exciting novel results we have found that a naturally occurring phospholipid, dioleoylphosphatidylglycerol (DOPG), enhances corneal epithelial wound healing in wild-type mice and in an experimental mouse model of impaired corneal wound healing in vivo. These data suggest the possibility of using DOPG to enhance corneal wound healing therapeutically. Information in the literature also supports a potential role for DOPG in suppressing inflammation. Thus, we have recently demonstrated that DOPG suppresses skin inflammation by inhibiting the activation of pattern recognition receptors, such as toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4), in response to damage-associated molecular patterns (DAMPs), endogenous molecules released from injured cells to alert the innate immune system to the presence of danger so that a protective immune response can be mounted. Indeed, a recent article examining an in vivo rodent model of sterile inflammation demonstrated that heat shock protein B4 (HSPB4, also known as crystallin Alpha A) released from corneal keratocytes in response to damaged corneal epithelial cells serves as a DAMP to activate TLR2 on corneal macrophages and induce corneal inflammation. In innovative preliminary studies we have found that DOPG can inhibit macrophage inflammatory mediator production in response to HSPB4, suggesting the likelihood that this lipid will suppress this corneal inflammation. Based on our preliminary results, we hypothesize that DOPG will act not only to accelerate corneal wound healing but also to suppress inflammation by inhibiting TLR2 and/or TLR4 activation. In the research proposed, we will test the idea that DOPG will: (1) dose-dependently, safely and physiologically accelerate corneal epithelial wound healing without adverse effects, at an optimal dose to be determined, in normal and diabetes-impaired corneal wound healing mouse models, and (2) inhibit neutrophil infiltration and inflammation in in vivo mouse models of corneal injury through its ability to inhibit TLR2/4 activation. In a third aim we will also determine the mechanism by which DOPG exerts these effects to stimulate corneal epithelial wound healing and inhibit TLR2/4 activation and inflammation. If our hypothesis proves correct, it would suggest the possibility of developing DOPG as a safe and effective treatment to hasten healing of corneal wounds and to prevent inflammation following injury, infection, ophthalmic surgery or other disorders necessitating corneal epithelial wound healing, thereby improving the quality of life for these patients.
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