Endothelial targeting and enhanced antiinflammatory effects of complement inhibitors possessing sialyl Lewisx moieties.
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.
Mulligan
M S
MS
Department of Surgery and Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Warner
R L
RL
Rittershaus
C W
CW
Thomas
L J
LJ
Ryan
U S
US
Foreman
K E
KE
Crouch
L D
LD
Till
G O
GO
Ward
P A
PA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000627:therapeutic use*; D003169:Complement Inactivator Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D004546:Elapid Venoms / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007105:Immune Complex Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007983:Lewis Blood Group Antigens / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D009844:Oligosaccharides / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D011485:Protein Binding / Q000276:immunology; D017463:Receptors, Complement 3b / Q000235:genetics / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D020449:Repetitive Sequences, Amino Acid; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D000080506:Sialyl Lewis X Antigen
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D007983:Lewis Blood Group Antigens; D009844:Oligosaccharides; D017463:Receptors, Complement 3b; D011994:Recombinant Proteins; D000080506:Sialyl Lewis X Antigen; C016310:cobra venom factor