vb-201 and Inflammation

Oxidized phospholipids (OxPLs) are abundantly found at sites of inflammation and are considered to play an active role in the modulation of the immune response. Whereas most studies attributed a proinflammatory role to OxPLs, recent studies demonstrate that some products of phospholipid oxidation may in fact exhibit anti-inflammatory properties. This study summarizes the proinflammatory and anti-inflammatory properties of OxPLs and sheds light on the therapeutic potential of OxPL derivatives or analogs for treatment of chronic inflammatory disorders.. OxPLs may inhibit activation of several Toll-like receptors and can epigenetically reduce the capacity of dendritic cells to function as mature, fully functional immunostimulatory cells. These data demonstrate that OxPLs can induce anti-inflammatory effects. Moreover, VB-201, an orally available synthetic phospholipid analog of the Lecinoxoid family, was found to attenuate inflammation in various preclinical animal models and is currently employed in a phase II clinical trial in psoriasis.. Chemical or biological modifications of phospholipids yield various products, some of which may exhibit anti-inflammatory properties. Identification of such species and generation of more stable/potent anti-inflammatory OxPL variants may represent a novel approach for the treatment of immune-mediated diseases such as psoriasis, atherosclerosis, multiple sclerosis and rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Atherosclerosis; Dendritic Cells; Disease Models, Animal; Epigenesis, Genetic; Glycerylphosphorylcholine; Humans; Inflammation; Mice; Multiple Sclerosis; Oxidation-Reduction; Phospholipids; Psoriasis; Rabbits; Signal Transduction; Toll-Like Receptors

Previous studies demonstrated that toll-like receptors 4 and 2 (TLR-4 and TLR-2), which are expressed on liver-resident Kupffer, hepatic stellate cells, and circulating monocytes, play a role in nonalcoholic fatty liver disease. Lecinoxoids are oxidized phospholipids that antagonize TLR-2- and TLR-4-mediated activation of innate immune cells and inhibit monocyte migration. In this study, we tested the effect of two functionally different lecinoxoids on the development of nonalcoholic steatohepatitis and liver fibrosis in a mouse model.. Two-day-old C57BL/6 mice were injected with streptozotocin and fed a high-fat diet from Week 4 after birth. At Week 6 post-birth, lecinoxoids VB-201 or VB-703 were given orally, once daily, for 3 weeks. Telmisartan was administered orally, once daily, for 3 weeks, as positive control. At experiment conclusion, biochemical indices were evaluated. HE stain and quantitative PCR were used to determine the extent of steatosis and steatohepatitis, and Sirius red stain was used to assess liver fibrosis.. Treatment with lecinoxoids did not alter the concentration of blood glucose, liver triglycerides, or steatosis compared with solvent-treated mice. However, whereas VB-201 inhibited the development of fibrosis and, to some extent, liver inflammation, VB-703 significantly lessened both liver inflammation and fibrosis.. This study indicates that using lecinoxoids to antagonize TLR-2, and more prominently TLR-4, is sufficient to significantly inhibit nonalcoholic steatohepatitis and liver fibrosis. Inhibiting monocyte migration with lecinoxoids that are relatively weak TLR-4 antagonists may alter liver fibrosis and to some extent nonalcoholic steatohepatitis.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Glucose; Blotting, Western; Cell Movement; Cytokines; Dendritic Cells; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glycerophosphates; Glycerylphosphorylcholine; Hepatic Stellate Cells; Humans; Inflammation; Kupffer Cells; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Monocytes; Non-alcoholic Fatty Liver Disease; Phospholipids; Pyridinium Compounds; Real-Time Polymerase Chain Reaction; Telmisartan; Toll-Like Receptor 2; Toll-Like Receptor 4; Triglycerides