In vivo effects of C1-esterase inhibitor on innate immune response during endotoxemia in human.

C1-esterase inhibitor (C1 INH) is a major inactivator of both the complement
and contact system. C1 INH is an acute phase protein, which is normally
excreted during inflammation. C1 INH substitution has shown to reduce
complement and contact activation and, thereby, reducing oedema and
polymorhnuclear leukocyte (PMN) infiltration into tissue. Animal models have
shown that C1 INH improves outcome both given before and shortly after
induction of severe inflammation through sepsis or surgical trauma, but the
underlying mechanism remains to be elucidated. In vitro C1 INH directly
inhibits PMN functions. Since PMN*s are important effector cells in post-injury
immunological pathology, inhibition of postinjury inflammation might be for a
great part due to this entity. We expect to find a C1 INH mediated reduced
systemic inflammation and altered PMN function in volunteers challenged with
LPS.

The primary objective is to investigate the effects of intravenous
administration of C1INH in human volunteers on cytokine release (TNFa) during
endotoxemia. The secondary objective is to determine the effect of
administration of C1 INH on redistribution of neutrophils in the human
endotoxemia model.

Double-blind placebo-controlled randomized cross-over intervention study in
healthy
human volunteers during experimental endotoxemia.

Subjects will be tested in a cross-over design in 2 separate sequential
sessions, 1.5-4 weeks apart. A total of 10 subjects will be randomly assigned
to one of two dosing groups in a 1:1ratio: C1 INH followed by Placebo (n=5),
Placebo followed by C1 INH (n=5).Healthy volunteers will receive 100 U/kg U C1
INH or placebo half an hour after the induction of endotoxemia. Endotoxemia
will be achieved by injection of LPS derived from E coli O:113 (2 ng/kg iv in 1
minute). Before LPS injection, prehydration will be performed by infusion of
1.5 L 2.5% glucose/0.45% saline solution in 1 hour. There will be a 14 day
washout period for patients in both groups.

Approximately 350 ml blood will be withdrawn per LPS experiment and urine will
be collected. A medical interview and physical examination is part of this
study. There will be mild discomfort associated with participation in this
study, as LPS induces flu-like symptoms for approximately 4 hrs.
Administration of high doses C1 INH has been proven to be safe even in pregnant
women.