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Li-Fong Seet, Li Zhen Toh, Tina T Wong; Valproic acid promotes inflammation in conjunctival wound healing. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3502.
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© ARVO (1962-2015); The Authors (2016-present)
Valproic acid (VPA) is a well-known anti-epileptic drug but its role in inflammation and wound healing is not well defined. We have previously shown that VPA was effective in reducing type I collagen levels in a murine model of conjunctival scarring. In this study, we further examined the effect of VPA on the inflammatory phase of wound healing in this model.
Experimental conjunctival scarring was carried out using the mouse model of glaucoma filtration surgery (GFS). VPA (300 μg/ml), or phosphate-buffered saline (PBS, control), was injected subconjunctivally following experimental surgery performed on only one eye of each animal. Operated tissues were harvested on day 2 post-surgery and pooled for quantitative analyses. Proinflammatory cell infiltration was measured by flow cytometry for CD45+, F4/80+ and CD3+ cells (n=3 groups per treatment, each group consisting of pooled tissues from 20 operated eyes) and visualized by immunofluorescence analyses. Cytokine levels were measured by multiplexed antibody-based assays (n=3 groups per treatment, each group consisting of pooled tissues from 5 independent operated eyes). mRNA levels of cytokine genes were measured by real-time polymerase chain reaction (n=6 groups per treatment, each group consisting of pooled tissues from 3 independent operated eyes).
VPA treatment resulted in a mean increase of 4.25% CD45+ cells in the operated conjunctival tissues compared with PBS-injected tissues. This increase in proinflammatory cells was accompanied by significant elevation in cytokine levels, including CCL2, CCL3, CCL4, CCL5, CCL11, CXCL2, IL1A, IL13, IL15, GM-CSF, IFNG, LIF and M-CSF. In general, the CC chemokine levels were about 2-fold higher in the VPA-treated tissues compared to PBS controls. The increase in these cytokines was however, not detected at the transcript level, suggesting that elevation in cytokines occurred predominantly via increase in proinflammatory cell numbers.
VPA can promote inflammation in the early phase of conjunctival wound healing by increasing the accumulation of proinflammatory cells. This proinflammatory activity of VPA may dampen its effectiveness as an anti-fibrotic therapeutic.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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