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Sandamali Amarasingha Ekanayaka, Sharon A McClellan, Ronald P Barrett, Shikhil Kharotia, Linda D Hazlett; Glycyrrhizin is protective against keratitis induced by P. aeruginosa and reduces both neutrophil infiltrate and plate count.. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
High mobility group box 1 (HMGB1) contributes to poor disease outcome in P. aeruginosa keratitis by amplifying inflammation. Immunomodulatory drugs such as glycyrrhizin (GLY) and its derivative, carbenoxolone (CBX) which bind HMGB1 and reduce its levels have been found to be protective in other non-ocular disease models. However, their effects have not been tested in P. aeruginosa keratitis and is the purpose of this study.
C57BL/6 (B6) mice were treated subconjunctivally with GLY or CBX (pre infection), infected with a non-cytotoxic clinical isolate (KEI 1025) or a cytotoxic strain (ATCC 19660) of P. aeruginosa, and injected intraperitoneally (post infection) with either agent. Clinical score, photography with a slit lamp, real time RT-PCR, ELISA, MPO assay, bacterial plate count and histopathology were used to assess treatment efficacy.
Only GLY treatment reduced HMGB1 (mRNA and protein) in KEI 1025 infected cornea and resulted in reduced corneal disease with concomitant reduction in mRNA levels of: RAGE, IL-1β, TLR4, CXCL2, and IL-12 compared to CBX or PBS. IL-1β and CXCL2 protein expression, neutrophil infiltrate and bacterial plate count also were significantly reduced in the GLY treated infected cornea. GLY treatment also enhanced antimicrobial protein levels, including cathelicidin-related antimicrobial peptide (CRAMP) and murine beta defensin (mBD) 2 but not mBD3. Only GLY reduced clinical scores and improved disease outcome in corneas infected with strain 19660. However, neither HMGB1 mRNA or protein levels were reduced, but rather, CXCL2 expression (mRNA and protein) and neutrophil infiltrate (MPO assay) were reduced significantly.
GLY reduces HMGB1 and is protective against P. aeruginosa induced keratitis with a clinical isolate that is non-cytotoxic. It is less effective, as it fails to reduce HMGB1 when a cytotoxic strain is used.
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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