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Departments of
*
Surgery and
Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
Department of Physiology, University of Nebraska School of Dentistry, Lincoln, NB 68583;
§
Avant Immunotherapeutics, Inc., Needham, MA 02494; and
¶
Department of Pathology, Loyola University School of Medicine, Maywood, IL 60153
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-
-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.
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