Endothelial targeting and enhanced antiinflammatory effects of complement inhibitors possessing sialyl Lewisx moieties
| Autor: | M S, Mulligan, R L, Warner, C W, Rittershaus, L J, Thomas, U S, Ryan, K E, Foreman, L D, Crouch, G O, Till, P A, Ward |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Elapid Venoms
Repetitive Sequences Amino Acid Complement Inactivator Proteins Sequence Homology Amino Acid Anti-Inflammatory Agents Non-Steroidal Oligosaccharides Immunohistochemistry Recombinant Proteins Lewis Blood Group Antigens Receptors Complement 3b Humans Immune Complex Diseases Endothelium Vascular Infusions Intravenous Sialyl Lewis X Antigen Lung Protein Binding Sequence Deletion |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 162(8) |
| ISSN: | 0022-1767 |
| Popis: | The complement inhibitor soluble complement receptor type 1 (sCR1) and a truncated form of sCR1, sCR1[desLHR-A], have been generated with expression of the selectin-reactive oligosaccharide moiety, sialyl Lewisx (sLex), as N-linked oligosaccharide adducts. These modified proteins, sCR1sLex and sCR1[desLHR-A]sLex, were assessed in the L-selectin- and P-selectin-dependent rat model of lung injury following systemic activation of complement by cobra venom factor and in the L-selectin-, P-selectin-, and E-selectin-dependent model of lung injury following intrapulmonary deposition of IgG immune complexes. In the cobra venom factor model, sCR1sLex and sCR1[desLHR-A]sLex caused substantially greater reductions in neutrophil accumulation and in albumin extravasation in lung when compared with the non-sLex-decorated forms. In this model, increased lung vascular binding of sCR1sLex and sCR1[desLHR-A]sLex occurred in a P-selectin-dependent manner, in contrast to the absence of any increased binding of sCR1 or sCR1[desLHR-A]. In the IgG immune complex model, sCR1[desLHR-A]sLex possessed greater protective effects relative to sCR1[desLHR-A], based on albumin extravasation and neutrophil accumulation. Enhanced protective effects correlated with greater lung vascular binding of sCR1[desLHR-A]sLex as compared with the non-sLex-decorated form. In TNF-alpha-activated HUVEC, substantial in vitro binding occurred with sCR1[desLHR-A]sLex (but not with sCR1[desLHR-A]). This endothelial cell binding was blocked by anti-E-selectin but not by anti-P-selectin. These data suggest that sLex-decorated complement inhibitors have enhanced antiinflammatory effects and appear to have enhanced ability to localize to the activated vascular endothelium. |
| Databáze: | OpenAIRE |
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