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J Mol Med (Berl). 2019 Jan;97(1):63-75. doi: 10.1007/s00109-018-1722-x. Epub 2018 Nov 19.

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

Seet LF1,2,3, Toh LZ4, Finger SN4, Chu SWL4, Wong TT5,6,7,8,9.

Author information

1
Ocular Therapeutics and Drug Delivery, Singapore Eye Research Institute, The Academia, 20 College Road, Singapore, 169856, Singapore. seet.li.fong@seri.com.sg.
2
Department of Ophthalmology, Yong Loo Lin Sc hool of Medicine, National University of Singapore, Singapore, Singapore. seet.li.fong@seri.com.sg.
3
Duke-NUS Medical School Singapore, Singapore, Singapore. seet.li.fong@seri.com.sg.
4
Ocular Therapeutics and Drug Delivery, Singapore Eye Research Institute, The Academia, 20 College Road, Singapore, 169856, Singapore.
5
Ocular Therapeutics and Drug Delivery, Singapore Eye Research Institute, The Academia, 20 College Road, Singapore, 169856, Singapore. tina.wong.t.l@singhealth.com.sg.
6
Department of Ophthalmology, Yong Loo Lin Sc hool of Medicine, National University of Singapore, Singapore, Singapore. tina.wong.t.l@singhealth.com.sg.
7
Duke-NUS Medical School Singapore, Singapore, Singapore. tina.wong.t.l@singhealth.com.sg.
8
Glaucoma Service, Singapore National Eye Center, 11 Third Hospital Avenue, Singapore, 168751, Singapore. tina.wong.t.l@singhealth.com.sg.
9
School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore. tina.wong.t.l@singhealth.com.sg.

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.

KEYWORDS:

Conjunctiva; Glaucoma filtration surgery; Histone deacetylase inhibitor; Inflammation; NF-kB; TNF-α; Valproic acid

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