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Inflammati

Inflammati
on
on
&
&
Pregnancy
Pregnancy
Unit: III Unit: III
Dr: Bashayer A. Saeed Dr: Bashayer A. Saeed
02/18/12
Notes:
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Scope of Presentation
Scope of Presentation
02/18/12
Notes:Humoral immunity B lymphocyte antibodies & complementCell mediated T lymphocyte macrophages, NK, cytotoxic lymphocyte
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Introduction
Introduction
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Notes:
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Introduction
Introduction
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Notes:
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Introduction
Introduction
Inflammatory process (infection) alter the
balance of Th1 and Th2 cytokines
causing a shift toward a Th1
predominance, that initiates and
intensifies the cascade of inflammatory
cytokine production involved in
spontaneous abortion, preterm delivery
or preeclampsia.
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Notes: IL-10 antiinflammatoryMMP-1 & MMP3 degrade fibrillar collagensTLR4 specific receptor for G ve bacteria LPS
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The maternal/placental
The maternal/placental
hormones and the
hormones and the
inflammatory pathways
inflammatory pathways
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Notes:
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The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
Pathologic mechanisms such as
intrauterine
inflammation/infection increase
the proinflammatory cytokines
(IL-1 , TNF-) in amniotic fluid,
fetal membranes, deciduas and
myometrium. This leads to
functional progesterone
withdrawal hence reduced
progesterone function.
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Notes:
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Relaxin
Relaxin is a collagenolytic hormone
involved in uterine growth and
development, myometrial contractility,
and cervical ripening.
It is also involved in 2 inflammatory
pathways by increasing production of
MMPs and proinflammatory cytokine.
May result in preterm premature rupture of
the membranes or preterm delivery
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
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Notes:
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Estrogens
Estrogen play a critical role in some
immune response and immune-
mediated disease
Estrogen have a modulatory effects
on immune function
Inhibits Th1 proinflammatory
cutokines (IL-12, TNF-, INF-
)
Stimulates anti- inflammatory
cytokines ( IL-10, IL-4, TGF-3)
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
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Activin A
Activin A and Activin type II receptors are
expressed by human placenta and fetal
maternal intrauterine membranes
Its levels increase through out pregnancy with
highest levels found at term
Preterm labour is associated with high
concentration of maternal serum Activin A

The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
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Role of activin in inflammation
Promigratory effect on monocytes and
induction of MMP expression by
macrophages, which stimulate their
migration and infiltration through
basement membranes in an
inflammatory state
Induces migration and differentiation of
mast cells
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
12
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
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Oxytocin
Key hormone in stimulating uterine
contraction during parturition
Oxytocin receptor (OTR) is positively
regulated by inflammatory mediators of
parturition
OTR promoter contains several
transcription factor binding sites, which
are activated by cytokines such as IL-1
and IL-6.
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
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Corticotropin releasing factor and
urocortins
Neurohormones expressed by gestational
tissue
They are involved in the mechanisms leading
to preterm delivary
CRF:
Anti- inflammatory effect pt v
r spon to str ss
ort sol ( n
t ol m n s
ro n l mm tor ts
m t R R s
r t p r r n t
on r s nt mmun lls
t s t o n l mm t on
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:
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Urocortin
Urocortin acts as an
endogenous immune
modulatory factor with
predominatly anti-
inflammatory effects
Urocortin and its receptor
(CRFR1 and CRFR2) are
deteced in several immune
cells such as
macrophage/monocyte and T
cells. Their expression with
inflammation
Urocotin is an
immunomodulatory factor:
1.inducing macrophages
apoptosis
2.Suppresses
lipopolysaccharide-
induced TNF-
production
3.Decrease s inflammatory
factors production and
Th1
4.Promote Th2 response(IL-10,
TGF)
production
The maternal/placental
The maternal/placental
hormones and the inflammatory
hormones and the inflammatory
pathways (Continue)
pathways (Continue)
02/18/12
Notes:TLR are transmembrane protiens
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The innate immune system
The innate immune system
response in pregnancy
response in pregnancy
Central to the innate immunity are pattern
recognition receptors (TLRs) that
recognize foreign products
(microorganisms) or endogenous signals
released by tissues.
This receptor system is believed to play a
significant role in infection-mediated
preterm birth
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The innate immune system
The innate immune system
response in pregnancy
response in pregnancy
(Continue)
(Continue)
TLR signaling pathway changes in gene
transcription NF-kB encodes
proinflammatory cytokines (TNF-, IL-
1) induction of effecter molecules
that mediate tissue remodeling (MMPs)
which are implicated in the
pathogenesis of preterm birth or
preeclampsia.
Variation in the intensity of the host
response to challenges that activate
the innate immune system may
contribute to pregnancy outcome.

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The innate immune system in
The innate immune system in
response to Preeclampsia
response to Preeclampsia
Preeclampsia has been characterizes as
an inflammatory state that includes
elevated levels of pro inflammatory
cytokines
Oxidative stress and inflammatory state
are features of PE
Recent studies showed that plasma
concentration of hs-CRP, IL-6, TNF-
and 8-isoprostane are higher in PE than
normal pregnancy
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Reduced tissue perfusion ( O2)
tr ns r pt on tor
pox n u l
tor lp (
tr rs
llul r r spons n
trop o l st lls
pro u t on o v s ul r
n ot l l rowt
tor (V (s LT
s pro oun t
on n ot l l ll
un t on
p rt ns on n
prot nur
n r ul t n s LT
l v ls r n rl
s n o mp n n
nt r t on tw n
ox t v str ss n
n l mm tor r t on
m p rt p t t
p t o n s s o
The innate immune system in
The innate immune system in
response to Preeclampsia
response to Preeclampsia
(Continue)
(Continue)
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Notes:Catechol-o-methyl transferase
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Recent studies suggest that a naturally
occurring inhibitor of HIF-1

(2-
methoxyestradiol) may involved in the
pathophysiology of PE.
2-hydroxyestradiol T
m t ox str ol
n pr n nt m
nt n T
l p not p
v lops pr m tur
l v r
p rt ns on l s ons n
u l v ss ls n
n n
prot nur
n r s umul t on
o n t
pl nt n o s Lt

uppl m nt t on w t
xo nous
m t ox str ol
r v rs s t l
p not p

The innate immune system in


The innate immune system in
response to Preeclampsia
response to Preeclampsia
(Continue)
(Continue)
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Inflammation and preterm
Inflammation and preterm
delivery
delivery
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Inflammation and preterm
Inflammation and preterm
delivery (continue)
delivery (continue)
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Notes:
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Inflammation and preterm
Inflammation and preterm
delivery (continue)
delivery (continue)
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Notes:
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Inflammation and preterm
Inflammation and preterm
delivery (continue)
delivery (continue)
02/18/12
Notes:TLRs recognizes microorganisms Stimulate released of inflammatory chemokines and cytokine PG and matrix degrading enzymes PPROM and /or PTL
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Inflammation and preterm
Inflammation and preterm
delivery (continue)
delivery (continue)
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Notes:Tissue inhibitor metalloproteinase
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Conclusion
Conclusion
Inflammation is involved in
the mechanisms of term
and preterm parturition:
a) Ripening of the cervix:
Cytokines
s X

so t n n n
l t t on
o t rv x
b) Rupture of the membranes:
Cytokines

oll n s s
n
T
w n n
n ruptur
m m r n
c) Myometrial contractility
Cytokines TN
L X

m om tr l
lls
xpr ss on o
TR n
ox to n on
m om tr l
lls
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Clinical implication and
Clinical implication and
future trends
future trends
Understanding physiological inflammatory events
in healthy pregnancy should permit a better
understanding of the pathologiccal process
development , hence leading to the discovery
of novel diagnostic tools or therapeutic
approaches.
Detection of synthetic receptor antagonists for
TLRs or proinflammatory cytokines is a major
goal for the prevention of hypertensive
disturbances of pregnancy, impaired
placentation, PPROM, and preterm uterine
hypercontractility.
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References
References
Challis et al (2009): inflammation and pregnancy. Reproductive
sciences 16(2): 206-213.
Gil Mor (2008): inflammation and pregnancy the role of toll-like
receptors in trophoblast immune interaction. Annals of the New
York Academy of Sciences , 1127:121-128.
Romero R et al (2007): inflammation in pregnancy: its roles in
reproductive physiology, obsetrical complications, and fetal injury.
Yan-Qiong Ouyang et al (2009): interaction between inflammatory and
oxidative stress in preeclampsia. Hypertension in pregnancy 28:56-
62.

The End