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Elvira L. Liclican, Van Nguyen, Aaron B. Sullivan, Karsten Gronert; Selective Activation of the Prostaglandin E2 Circuit in Chronic Injury-Induced Pathologic Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2010;51(12):6311-6320. doi: https://doi.org/10.1167/iovs.10-5455.
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Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) is a prevalent and established mediator of inflammation and pain in numerous tissues and diseases. Distribution and expression of the four PGE2 receptors (EP1-EP4) can dictate whether PGE2 exerts an anti-inflammatory or a proinflammatory and/or a proangiogenic effect. The role and mechanism of endogenous PGE2 in the cornea, and the regulation of EP expression during a dynamic and complex inflammatory/reparative response remain to be clearly defined.
Chronic or acute self-resolving inflammation was induced in mice by corneal suture or epithelial abrasion, respectively. Reepithelialization was monitored by fluorescein staining and neovascularization quantified by CD31/PECAM-1 immunofluorescence. PGE2 formation was analyzed by lipidomics and polymorphonuclear leukocyte (PMN) infiltration quantified by myeloperoxidase activity. Expression of EPs and inflammatory/angiogenic mediators was assessed by real-time PCR and immunohistochemistry. Mice eyes were treated with PGE2 (100 ng topically, three times a day) for up to 7 days.
COX-2, EP-2, and EP-4 expression was upregulated with chronic inflammation that correlated with increased corneal PGE2 formation and marked neovascularization. In contrast, acute abrasion injury did not alter PGE2 or EP levels. PGE2 treatment amplified PMN infiltration and the angiogenic response to chronic inflammation but did not affect wound healing or PMN infiltration after epithelial abrasion. Exacerbated inflammatory neovascularization with PGE2 treatment was independent of the VEGF circuit but was associated with a significant induction of the eotaxin-CCR3 axis.
These findings place the corneal PGE2 circuit as an endogenous mediator of inflammatory neovascularization rather than general inflammation and demonstrate that chronic inflammation selectively regulates this circuit at the level of biosynthetic enzyme and receptor expression.
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