Fingolimod Suppresses a Cascade of Core Vicious Cycle in Dry Eye NOD Mouse Model: Involvement of Sphingosine-1-Phosphate Receptors in Infiltrating Leukocytes.

摘要: Purpose The purpose of this study was to evaluate the inhibitory mechanism fingolimod and involvement sphingosine-1-phosphate receptors (S1PRs) cytokines-matrix metalloproteinases (MMPs)/MAP kinases (MAPKs) signaling in a dry eye disease (DED) mouse model. Methods Sixty-four male NOD mice (DED model) 16 age-matched BALB/c were used. In preliminary experiment, randomly divided into positive control group fingolimod-treated groups, with 8 serving as wild-type control. subsequent, separate study, 48 6 groups: groups at three different concentrations (0.05%, 0.005%, 0.001%), normal saline group, untreated fingolimod+W146 group. Animals received or eyedrops times daily until euthanasia 2 months later. Mice intraperitoneal injections W146 (0.1 mg/kg/day). Proinflammatory mediators assessed by protein array. Activities MMP-2 MMP-9 evaluated zymography. MAPKs S1PRs examined Western blots immunohistochemistry. Infiltrating cells mechanisms assessed. Results levels inflammatory upregulated. By comparison, treatment significantly suppressed such markers which reversed (P < 0.01). Importantly, double immunofluorescence staining, leukocytes confirmed involved DED Conclusions Leukocytes are therapeutic may be associated roles "cytokines-MMPs/MAPKs" cycle ocular surface tissues mediating infiltrating leukocytes.