i(3)so3-galactosylceramide and Reperfusion-Injury

Mixed cryoglobulinemia (MC) is an immunological disorder characterized by immune-complex-mediated systemic vasculitis involving small vessels, which may present with renal, cutaneous, rheumatologic, and/or neurological manifestations. Until recently, the possible appearance of anti-neuronal autoantibodies in peripheral neuropathy occurring in the context of hepatitis C virus (HCV)-associated IgMk/IgG MC has not been extensively addressed. Therefore, a sample of these patients were evaluated by means of immuno-enzyme methods of anti-neuronal autoantibody detection. A significant increase in plasma titers of both anti-GM1 ganglioside and anti-sulfatide was observed. Abnormal titers were associated with evidence of active neuropathy as assessed by electrophysiologic studies. While peripheral neuropathy was traditionally thought to result from axonal ischemic damage caused by deposits of cryoprecipitable immune complexes in the vasa nervorum, a significant association between anti-GM1 and anti-sulfatide antibodies and involvement of the peripheral nervous system was observed in HCV-associated mixed IgMk/IgG cryoglobulinemia. Anti-neuronal reactivity could be a direct trigger of neurologic injury in this disorder.

Topics: Aged; Antigen-Antibody Complex; Autoantibodies; Cryoglobulinemia; Female; Ganglioside Galactosyltransferase; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Paresthesia; Reperfusion Injury; Sulfoglycosphingolipids; Vasculitis

Hepatic ischemic reperfusion injury (IRI) is a major complication of liver transplantation and resectional hepatic surgeries. Natural killer T (NKT) cells predominate in liver, where they recognize lipid antigens bound to CD1d molecules. Type I NKT cells use a semi-invariant T-cell receptor and react with α-galactosylceramide; type II NKT cells use diverse T-cell receptors. Some type II NKT cells recognize the self-glycolipid sulfatide. It is not clear whether or how these distinct NKT cell subsets mediate hepatocellular damage after IRI.. We examined the roles of type I and type II NKT cells in mice with partial hepatic, warm ischemia, and reperfusion injury.. Mice that lack type I NKT cells (Jα18-/-) were protected from hepatic IRI, indicated by reduced hepatocellular necrosis and serum levels of alanine aminotransferase. Sulfatide-mediated activation of type II NKT cells reduced interferon-γ secretion by type I NKT cells and prevented IRI. Protection from hepatic IRI by sulfatide-mediated inactivation of type I NKT cells was associated with significant reductions in hepatic recruitment of myeloid cell subsets, especially the CD11b(+)Gr-1(int), Gr-1(-), and NK cells.. In mice, subsets of NKT cells have opposing roles in hepatic IRI: type I NKT cells promote injury whereas sulfatide-reactive type II NKT cells protect against injury. CD1d activation of NKT cells is conserved from mice to human beings, so strategies to modify these processes might be developed to treat patients with hepatic reperfusion injury.

Topics: Animals; CD11b Antigen; Female; Interferon-gamma; Liver; Mice; Mice, Inbred C57BL; Myeloid Cells; Natural Killer T-Cells; Necrosis; Receptors, Chemokine; Reperfusion Injury; Sulfoglycosphingolipids

There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d(-/-)) or type I NKT cells (Jα18(-/-)). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubulointerstitium, which is the primary area of injury. Sulfatide-induced activation of type II NKT cells protected kidneys from IRI, but inhibition of NKT cell recruitment enhanced injury. In co-culture experiments, sulfatide-induced activation of NKT cells from either mice or humans attenuated apoptosis of renal tubular cells after transient hypoxia via hypoxia-inducible factor (HIF)-1α and IL-10 pathways. Renal tissue of patients with acute tubular necrosis (ATN) frequently contained NKT cells, and the number of these cells tended to negatively correlate with ATN severity. In summary, sulfatide-reactive type II NKT cells are renoprotective in IRI, suggesting that pharmacologic modulation of NKT cells may protect against ischemic injury.

Topics: Acute Kidney Injury; Animals; Cytokines; Epithelial Cells; Hypoxia; Hypoxia-Inducible Factor 1; Interleukin-10; Kidney Tubules; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Reperfusion Injury; Sulfoglycosphingolipids

Sulfatide binds to P- and L-selectin, which play important roles in the initiation of neutrophil-endothelial interactions. Sulfatide protects skin flaps from ischemia-reperfusion injury. The purpose of this study was to evaluate the augmented protection when anti-rat ICAM-1 and anti-rat LFA-1 antibodies are combined with sulfatide in the ischemia-reperfusion model of rat skin flaps. Sulfatide was administered intravenously just before elevation of the right abdominal epigastric flap, and monoclonal antibodies were injected 30 min before clamp release. The femoral artery and vein were clamped above and below the epigastric vessels for 11 h and then the clamp was released. The administration of both sulfatide and monoclonal antibodies significantly increased the flap surviving area (6.58 +/- 0.61 cm(2) versus the group with monoclonal antibodies alone, 4.43 +/- 0.32 cm(2), P = 0.01). In the untreated rats the area was 1.86 +/- 0.36 cm(2). Histological examination 24 h after reperfusion in the group treated with sulfatide and monoclonal antibodies showed only slight leukocyte invasion into the flap, and myeloperoxidase activity 24 h after reperfusion was significantly reduced. This study indicates that both sulfatide and monoclonal antibodies protect rat skin flaps from ischemia-reperfusion injury.

Topics: Animals; Antibodies, Monoclonal; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Male; Peroxidase; Rats; Rats, Inbred Lew; Reperfusion Injury; Sulfoglycosphingolipids; Surgical Flaps

Monoclonal antibodies to adhesive molecules have been used in many trials to decrease ischemia-reperfusion injury, which is considered to occur in areas such as the distal region of the random pattern flap. The monoclonal antibody to the primary neutrophil adherence-mediating glycoprotein CD18 improves the survival length of the random pattern flap. Sulfatide binds strongly with L- and P-selectin. We found that sulfatide has a protective effect against ischemia-reperfusion injury. The purpose of this study was to evaluate the effect of sulfatide on the survival length of the random pattern flap in rats. Sulfatide was administered intravenously just before elevation of the cranially based dorsal skin flap. Administration of sulfatide significantly augmented flap survival length (49.5 +/- 1.7 mm vs control 41.5 +/- 2.1 mm, P = 0. 01). Flap survival length was significantly longer than dye distance (49.1 +/- 2.0 mm vs 39.7 +/- 1.1 mm, P = 0.01). In the control flap, no significant difference between survival length and dye distance was detected. Histological examination 48 h after flap elevation showed leukocyte invasion in the dermal layer of control flaps, whereas little leukocyte invasion was observed in the flaps of rats administered sulfatide.

Topics: Animals; Dermatologic Surgical Procedures; L-Selectin; Leukocytes; Male; P-Selectin; Rats; Rats, Inbred Lew; Reperfusion Injury; Skin; Sulfoglycosphingolipids; Surgical Flaps

It has been demonstrated that ischemic preconditioning (IPC) affords protection against the post-ischemic endothelial dysfunction. Here, a hypothesis was tested that IPC, by protecting the endothelium, prevents also the adherence of granulocytes (PMNs) in the post-ischemic heart. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/30 min reperfusion (IR) and peritoneal PMNs were infused between 15 and 25 min of the reperfusion. Acetylcholine (ACh)-induced coronary vasodilatation and nitrite outflow were used to measure endothelial function and coronary flow response to sodium nitroprusside (SNP) served as a measure of endothelium-independent vascular function. The endothelial adherence of PMNs to the coronary microvessels was assessed in histological preparation of the myocardium. In the hearts subjected to IR, ACh-induced vasodilatation and nitrite outflow were reduced by 55% and 69%, respectively, SNP response remained unaltered, and 22% of microvessels were occupied by PMNs, as compared to 2% in the sheam perfused hearts. These alterations were attenuated by IPC (3 x 5 min ischemia). A selectin blocker, sulfatide, prevented IR-induced PMNs adherence and did not affect the responses to ACh and SNP. These data demonstrate that IR leads to the endothelial dysfunction and to the selectin-mediated PMNs adhesion in the isolated guinea-pig and that IPC attenuates both alterations. We speculate that the pro-adhesive effect of IR is secondary to the endothelial injury and that the anti-PMNs action represents a novel cardioprotective mechanism of IPC.

Topics: Acetylcholine; Animals; Cell Adhesion; Coronary Vessels; Drug Interactions; Endothelium, Vascular; Female; Granulocytes; Guinea Pigs; Hemodynamics; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Male; Microcirculation; Nitric Oxide; Nitrites; Nitroprusside; Perfusion; Reperfusion Injury; Selectins; Sulfoglycosphingolipids; Time Factors; Vasodilator Agents

Monoclonal antibodies to adhesion molecules have been used in many trials to prevent ischemia-reperfusion injury. Sulfatide reacts strongly with P- and L-selectin, which play an important role in the initiation of neutrophil-endothelial interactions occurring in injured or inflamed tissues. The purpose of this study was to evaluate the effect of sulfatide on ischemia-reperfusion injury of the rat skin flap. Sulfatide was administered intravenously just before elevation of the right abdominal epigastric flap. The femoral artery and vein were clamped above and below the epigastric vessels for 10 or 11 h and then the clamp was released. Administration of sulfatide augmented significantly the flap area surviving in the 10-h ischemic model (7.18 +/- 0.47 cm2 versus control 5.15 +/- 0.39 cm2. P = 0.01). In the 11-h ischemic model the area was 4.59 +/- 0. 36 cm2 versus control 1.73 +/- 0.31 cm2 (P = 0.001). The ATP levels in the flap gradually increased after release of the clamp in the rat administered sulfatide, and the increase was significant at 48 h (P = 0.006). Histological examination 48 h after surgery showed greater leukocyte invasion into the control flap than into the flap of the rat administered sulfatide. Myeloperoxidase activity was significantly reduced 48 h after reperfusion in the 11-h ischemic model. This study indicates that sulfatide has a significant protective effect against ischemia and reperfusion in rat epigastric flaps.

Topics: Adenosine Triphosphate; Animals; L-Selectin; Male; P-Selectin; Peroxidase; Rats; Rats, Inbred Lew; Reperfusion Injury; Skin; Sulfoglycosphingolipids; Surgical Flaps; Time Factors