Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide.
Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation is not well understood. To determine the role of C6-ceramide in regulating inflammatory responses, human corneal epithelial cells were treated with C6-ceramide in 80 nm diameter nanoliposome bilayer formulation (Lip-C6) prior to stimulation with UV-killed Staphylococcus aureus. Lip-C6 (5 muM) inhibited the phosphorylation of proinflammatory and proapoptotic MAP kinases JNK and p38 and production of neutrophil chemotactic cytokines CXCL1, CXCL5, and CXCL8. Lip-C6 also blocked CXC chemokine production by human and murine neutrophils. To determine the effect of Lip-C6 in vivo, a murine model of corneal inflammation was used in which LPS or S. aureus added to the abraded corneal surface induces neutrophil infiltration to the corneal stroma, resulting in increased corneal haze. Mice were treated topically with 2 nMoles (811 ng) Lip-C6 or with control liposomes prior to, or following, LPS or S. aureus stimulation. We found that corneal inflammation was significantly inhibited by Lip-C6 but not control liposomes given prior to, or following, activation by LPS or S. aureus. Furthermore, Lip-C6 did not induce apoptosis of corneal epithelial cells in vitro or in vivo, nor did it inhibit corneal wound healing. Together, these findings demonstrate a novel, anti-inflammatory, nontoxic, therapeutic role for liposomally delivered short-chain ceramide.
Sun
Yan
Y
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Fox
Todd
T
Adhikary
Gautam
G
Kester
Mark
M
Pearlman
Eric
E
D017209:Apoptosis / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage*; D003315:Cornea / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007634:Keratitis / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D018375:Neutrophil Activation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002518:Ceramides; D008070:Lipopolysaccharides; D008081:Liposomes; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases