sphingosine-phosphorylcholine and Disease-Models--Animal

Sjögren syndrome (SS) is an autoimmune disease in which immune cells infiltrate the exocrine gland. Since SS is caused by a disorder of the immune system, treatments should regulate the immune response. Sphingosylphosphorylcholine (SPC) is a sphingolipid that mediates cellular signaling. In immune cells, SPC has several immunomodulatory functions. Accordingly, this study verifies the immunomodulatory ability and therapeutic effect of SPC in SS. To understand the function of SPC in SS, we treated SPC in female NOD/ShiJcl (NOD) mice. The mice were monitored for 10 weeks, and inflammation in the salivary glands was checked. After SPC treatment, we detected the expression of regulatory B (B

Topics: Animals; B-Lymphocytes, Regulatory; Disease Models, Animal; Female; Humans; Inflammation; Mice; Mice, Inbred NOD; Phosphorylcholine; Sialadenitis; Sjogren's Syndrome; Sphingosine

To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5-lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis.

Topics: Administration, Topical; Animals; Arachidonate 5-Lipoxygenase; Dermatitis, Atopic; Disease Models, Animal; Leukotriene B4; Mice; Phenylpropionates; Phosphorylcholine; Pruritus; Receptors, Leukotriene B4; Skin; Sphingosine

The goal of this study was to evaluate the possible protective effects of sphingosylphosphorylcholine (SPC) against cholestatic oxidative stress and liver damage in the common bile duct ligated rats. Fifty-six animals were included in each of the following 7 groups: control, SPC control, phosphate-buffered solution control, sham operated, bile duct ligation (BDL), BDL plus phosphate-buffered solution, and BDL plus SPC. Sphingosylphosphorylcholine was administered 14 days at a daily dose of 2 microm/mL intraperitoneally. The severity of cholestasis and hepatic injury was determined by changes in the plasma enzyme activities of aspartate aminotransferase, alanine aminotransferase, gama glutamin transferase, and levels of total bilirubin and direct bilirubin. Malondialdehyde, nitric oxide, and superoxide dismutase were determined to evaluate the oxidative status in the liver tissue. Myeloperoxidase activity and levels of tissue hydroxyproline were determined to assess neutrophil activation and collagen accumulation, respectively. Treatment with SPC markedly reduced serum transaminase activities as compared to BDL rats. Sphingosylphosphorylcholine also inhibited the increase in liver malondialdehyde; nitric oxide levels significantly and also attenuated the depletion of superoxide dismutase in the liver after BDL. Similarly, the increase in tissue myeloperoxidase activity and hydroxyproline owing to BDL was also attenuated by the SPC treatment. These data were supported by histopathologic findings. The alpha-smooth muscle actin-positive cells in the BDL were observed to be reduced with the SPC treatment. In conclusion, these findings suggested that SPC can attenuate hepatic damage in extrahepatic cholestasis by prevention of oxidative stress, and inflammatory process. All these findings suggest that SPC may be a promising new therapeutic agent for cholestatic liver injury.

Topics: Analysis of Variance; Animals; Cholestasis, Extrahepatic; Common Bile Duct; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Immunohistochemistry; Ligation; Lipid Peroxidation; Liver Diseases; Liver Function Tests; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Phosphorylcholine; Probability; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Sphingosine

Rho-kinase (ROK)-mediated Ca2+ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca2+ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca2+ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH).. Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated.. At cerebrospinal fluid concentrations of 100 and 300 micromol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 micromol/l): 61.8 +/- 8.2%), which was markedly reversed by Y27632 (96.3 +/- 4.4%) or EPA (92.6 +/- 12.8%). SAH caused severe vasospasm on day 7 (67.6 +/- 7.8%), which was significantly blocked by Y27632 (95.5 +/- 10.6%) or EPA (90.0 +/- 4.4%).. SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV.

Topics: Animals; Basilar Artery; Benzopyrans; Cerebral Angiography; Cisterna Magna; Disease Models, Animal; Dogs; Eicosapentaenoic Acid; Female; Injections; Male; Phosphorylcholine; Protein Kinase Inhibitors; rho-Associated Kinases; Signal Transduction; Sphingosine; Subarachnoid Hemorrhage; Time Factors; Vasoconstriction; Vasodilator Agents; Vasospasm, Intracranial

Using a new class of intracellular 2nd messengers to prevent stricture formation after caustic ingestion, sphingosylphosphorylcholine (SPC) has a wide spectrum of activity in cell growth regulation and signal transduction. Caustic esophageal burns were created with 15% NaOH in an experimental rat model. Control group animals (n = 10) had esophageal burns with no treatment, whereas the SPC group (n = 10) had esophageal burns gavaged with SPC for 7 days. Efficacy of treatment was assessed in 28 days by contrast esophagograms, histopathologic evaluation, and biochemically by tissue hydroxyproline (OHP) content. Contrast esophagograms demonstrated that SPC significantly prevented stricture formation. Obvious collagen deposition was present in submucosa, muscularis mucosa, and muscular layers in the control group compared with the SPC group. The damage to the esophageal wall on histopathologic examination was significantly lower in the SPC group (p < 0.05). Tissue OHP contents were significantly lower in the SPC-treated group (3.0 +/- 0.1 microg/mg) compared with the control group (4.3 +/- 0.2 microg/mg) (p < 0.05). We conclude that SPC improves healing following caustic esophageal burns. Furthermore, SPC is effective in preventing caustic esophageal strictures. These effects of SPC occur through its proliferative and specifically its remodeling effects on wound healing.

Topics: Animals; Burns, Chemical; Caustics; Collagen; Contrast Media; Disease Models, Animal; Esophageal Stenosis; Esophagus; Female; Hydroxyproline; Mucous Membrane; Muscle, Smooth; Phosphorylcholine; Radiography; Rats; Rats, Wistar; Second Messenger Systems; Sodium Hydroxide; Sphingosine; Treatment Outcome; Wound Healing