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Calprotectin europaediatrics 2009
1. CORD BLOOD CALPROTECTIN
CONCENTRATIONS IN FULLTERM PREGNANCIES WITH
NORMAL AND RESTRICTED
FETAL GROWTH
Sofia Liosi 1 , Despina D. Briana 1
Dimitrios Gourgiotis 2 , , Maria Boutsikou 1 , Stavroula
Baka 1 , Antonios Marmarinos , Dimitrios Hassiakos 1 ,
Ariadne Malamitsi-Puchner 1 .
1.Neonatal Division, 2nd Department of Obstetrics and Gynecology, Athens
University Medical School, Athens, Greece
2.Research Laboratories, 2nd Department of Pediatrics, Athens University
Medical School, Athens, Greece
2. Calprotectin
• a 36-kDa calcium and zinc binding
protein
• comprises two heavy chains of 14 kDa
and one light chain of 8 kDa
• constitutes approximately 60% of soluble
cytosol proteins in human neutrophil
granulocytes
3. Calprotectin
• a marker of neutrophil turnover
• immunomodulatory and antimicrobial
effects
• antiproliferative effects (inducing
apoptosis)
4. Intrauterine growth
restriction
(IUGR)
• Failure of the fetus to achieve his/her
intrinsic growth potential
• Consequence of anatomical and/or
functional disorders and diseases in the
feto-placental-maternal unit
• Results to increased morbidity and
mortality in intra- and extra-uterine life
5. Neutrophil activation
is present in preeclampsia and isolated
intrauterine growth restriction
•
•
•
Possible mechanisms may be:
hypoxia
the presence of soluble mediators of
inflammation
endothelial stimulation
6. IUGR
• associated with an increased
incidence of apoptosis in
IUGR-affected fetal membranes
7. Hypothesis
• Umbilical cord blood concentrations of
calprotectin in IUGR cases may differ
from respective concentrations in
appropriate-for-gestational-age (AGA)
controls since the former present
increased neutrophil activation and
excessive apoptosis .
8. Aim
•
Investigate cord blood calprotectin
concentrations in IUGR, and AGA
pregnancies at birth
•
Correlate determined concentrations
with gestational age, gender and mode
of delivery .
9. Subjects
• 160 healthy, singleton full-term
pregnancies
- 1 10 AGA (placental weight: 480-621 g)
- 50 asymmetric IUGR ( placental weight
230 -400g)
• Apgar scores: > 8 in 1 st and 5 th minute
10. Gestation Related Optimal
Weight (GROW) computergenerated programme
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11. Causes of IUGR
•
•
•
•
Preeclampsia ( n=6 )
Pregnancy induced hypertension (n=5 )
Various diseases : severe type I DM
( n=5),iron deficiency anemia (n=3),
hypothyroidism (n=7)
Maternal smoking ( n=24 )
13. Methods
•
•
•
Blood collected from:
Doubly-clamped umbilical cords (m ixed
arteriovenous blood ) – reflecting fetal
state
Determination of plasma calprotectin
concentrations by enzyme immunoassay
( Human Calprotectin ELISA, HBT Hycult
Biotechnology b.v , Uden, The
Netherlands)
Statistical analysis (parametric tests)
14. CALPROTECTIN LEVELS (ng/ml)
Figure 1. Error bars of the concentrations of
Calprotectin in IUGR cases and AGA controls.
320
300
280
260
240
220
0
AGA GROUP
(N=110)
IUGR GROUP
(N=50)
15. Results (1)
• No statistically significant differences in
cord blood calprotectin concentrations
between IUGR and AGA groups .
16. Results (2)
•
•
In a combined group
Cord blood calprotectin concentrations
were significantly decreased in cases of
caesarean section .
• The effect of birthweight, customized
centile, gestational age, gender and
parity on calprotectin concentrations was
not significant .
17. Results (3)
• In the IUGR group
• Calprotectin was significantly elevated
for every week increase in gestational
age.
• Calprotectin was positively correlated
with birthweight.
18. Conclusions (1)
• Cord blood calprotectin concentrations at
term are independent of intrauterine
growth and probably do not reflect the
increased neutrophil activation and
excessive apoptosis expected in IUGR
• P arity, gender and maternal age do not
seem to have any impact on umbilical
cord blood calprotectin concentrations
19. Conclusions (2)
• Calprotectin may have a limited role
during fetal life, possibly due to the
lower degree of neutrophil activation in
the fetus.
• Neutrophil activation and apoptosis seem
to increase with advancing gestational
age in the IUGR group, as indicated by
the increasing calprotectin
concentrations with progressing
pregnancy
20. Conclusions (3)
• Excessive inflammatory response
associated with vaginal delivery may
account for the higher calprotectin
concentrations in the latter
Editor's Notes
Many names=Calprotectin is a suitable descriptive name for this multipotent calcium binding protein with protective properties.'
Neutrophil granulocytes,Monocytes/macrophages,Epithelial cells,Keratinocytes,Pancreatic cell lines,Tracheal gland cells
Skin (epidermis/dermis),Lung,Gut,Oral mucosa,Cervix mucosa,Body fluids
As calprotectin is preformed and ready to be released from activated circulating leucocytes,its concentration in plasma can increase much more rapidly in response to bacteraemia and endotoxaemia than acute phase proteins(CRP) synthesised in the liver.
calprotectin is antiproliferative and can induce apoptosis in human and animal cells, both in normal and transformed cells.these activities can be reversed by the addition of zinc.Calprotectin can inhibit several zinc-dependent metalloproteinases,probably by sequestration of zinc
Calprotectin is a surrogate marker of neutrophil turnover and is elevated in a number of inflammatory conditions
Neutroplil contain a large number of calprotectin which will be released upon their activation
In normal pregnancy there is both a neutrophilia and a mild neutrophil activation. In preeclampsia both direct and indirect evidence supports further marked neutrophil activation. In the pathogenesis of preeclampsia peripheral blood neutrophils may play a vital role in communicating between the preeclamptic placenta and the maternal vascular endothelium and contribute to the endothelial cell dysfunction that characterizesthe maternal syndrome of preeclampsia. Preeclampsia shares many elements with the systemic inflammatory
response syndrome. Neutrophils, key effectors of the systemic inflammatory response syndrome,
Peripheral blood neutrophils are already activated in normal pregnancy..in preeclampsia the neutrophil count is increased relative to pregnancy
Preeclampsia shares many clinical and laboratory characteristics with the systemic inflammatory response syndrome
Activation of peripheral blood neutrophils occuring in isolated IUGR In a manner similar to that seen in preeclampsia
Hypoxia=neutrophils modulate cell adhesion molecule expression when exposed to decreased oxygen tension
Mediators=Neutrophil activation may result from the presence of soluble mediators of inflammation,such TNFα or IL6,which have been reported in the maternal circulation of patients with preeclampsia and in the amniotic fluid of patients with IUGR
Lendothelial=eukocyte activation may be related to endothelial stimulation resulting in overexpression of endothelial cell adhesion molecules and their subsequent shedding.
neutrophil activation is more a consequence of local or systemic inflammatory response than a primary effector of the pathologic hfeatures of the diseases
THE activation might take place during the uteroplacental passage
Calprotectin has apoptosis-inducing activities,and placental apoptosis is augmented in preeclampsia. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that have reduced activity in the invading cytotrophoblasts of preeclamptic patients, possibly contributing to the reduced trophoblast invasion and subsequent dysfunctional uteroplacental circulation in preeclampsia It has been demonstrated that calprotectin inhibits MMPs by the sequestration of zinc.Theoretically,augmented calprotectin concentrations could play a role in the pathophysiology of preeclampsia, for example,through augmented apoptosis and/or reduced trophoblast invasion
A failure of trophoblastic invasionof the spiral arteries which results in placental insufficiency
Protasi apo keimano
Calprotectin elevated in preeclampsia in maternal not fetal
The concentrations of calprotectin in both arterial and venous umbilical plasma were much lower than in maternal plasma in a study AM J OBTSTR GYN BY BRAEKKE(NORWAY)
REASON=low degree of activated neutrophils, low content of calprotectin,or rapid calprotectin turnover in the fetuses
