Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

Abstract

Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45highF4/80low macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by ≥ 2.0-fold. VPA also specifically reduced tissue NF-кB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-α, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-кB2 p100. In corroboration, VPA suppressed TNF-α stimulation of NF-кB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva.Key messages VPA inhibited recruitment of a CD45highF4/80low macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues.VPA selectively suppressed tissue NF-кB2 p100 levels.VPA suppressed TNF-α induction of chemokines, cytokines and NF-кB2 p100 expression.VPA suppressed TNF-α stimulation of NF-кB reporter.

Effect of valproic acid on functional bleb morphology in a rabbit model of minimally invasive surgery

“…It is also possible that VPA may modulate the development of vascular abnormalities by reducing hypoxia through restraining the inflammatory response, which has a high metabolic demand for oxygen. 51 Overall, the distinct histological differences between PBS-treated and VPA-treated postoperative conjunctiva provide the evidence for the capacity of VPA to ameliorate the fibrotic phenotype, including vascular remodelling.…”

Pluripotent epigenetic regulator OBP-801 maintains filtering blebs in glaucoma filtration surgery model

“…OBP-801 (OBP), a novel pluripotent epigenetic repressor of diverse genes that are involved in multiple steps of tissue inflammation and wound healing, as introduced in the present study, showed potent HDACi activity at a very low concentration, such as 1 nM, at levels that are 1/1000 times lower than the classical levels so far reported for HDACi, SAHA, valproic acid (VPA), and trichostatin A (TSA) 10,33 .…”

Valproic acid inhibits interferon-γ production by NK cells and increases susceptibility to Listeria monocytogenes infection

“…Several reports have shown the effect of HDCAi on NF-κB activity, for instance: VPA has an inhibitory effect on NF-κB activation in human NK cells stimulated with IL-2 49 ; and TSA reduced NF-κB translocation to the nucleus in NK cells stimulated with IL-12, IL-15 and IL-18 27 . Furthermore, VPA is able to inhibit NF-κB activation in other cell populations, like monocytes 50 , macrophages 51 , dendritic cells 52 , fibroblast 53 and epithelial cells 54 .…”