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Our results are the first to demonstrate that hemin, a Food and Drug Administration-approved drug, promotes corneal allograft survival. These findings indicate that hemin might be a potential alternative treatment for CGR.

Citation: Huang J, Su W, Chen X, et al. Doxycycline attenuates endotoxin-induced uveitis by prostaglandin E2-EP4 signaling. Invest Ophthalmol Vis Sci. 2015;56:6686-6693. DOI:10.1167/ iovs.15-17045 PURPOSE. We explored the anti-inflammatory effects of doxycycline in experimental uveitis and the underlying mechanisms.METHODS. Rats with endotoxin-induced uveitis (EIU) received doxycycline (1.5 mg/kg) or the control vehicle via intraperitoneal injection. Clinical scores were graded under a slit lamp. Rat peritoneal macrophages were used in vitro to further explore the anti-inflammatory mechanisms of doxycycline. The levels of nitric oxide (NO), TNF-a, IL-1b, prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, I kappa B-a (IjB-a), inducible nitric oxide synthase (iNOS), Akt, caspase-3, and nuclear factor-kappa B (NF-jB) were analyzed.RESULTS. Treatment with doxycycline dramatically reduced the clinical scores of EIU (P < 0.001), with significant decreases in inflammatory cell infiltration, protein concentrations, and the production of NO, TNF-a, and IL-1b in the aqueous humor (AqH). In vitro, doxycycline significantly inhibited the production of NO, IL-1b, and TNF-a in peritoneal macrophages by modulating the PI3K/Akt/IjB-a/NF-jB pathway. Importantly, we found that doxycycline significantly enhanced COX2 expression and PGE2 production both in vivo and in vitro. More importantly, blockade of the EP4 receptor of PGE2 significantly reversed the doxycycline-mediated inhibition of macrophages and the PI3K/Akt pathway in vitro. Furthermore, simultaneous injection of an EP4 antagonist and doxycycline significantly blocked the doxycycline-mediated attenuation of EIU.CONCLUSIONS. Doxycycline can ameliorate EIU, and PGE2-EP4 signaling is essential for the antiinflammatory effects of doxycycline in vitro and in vivo.