Inflammation and pre-eclampsia

doi:10.1016/j.siny.2006.04.001

Seminars in Fetal and Neonatal Medicine

Volume 11, Issue 5, October 2006, Pages 309-316

https://doi.org/10.1016/j.siny.2006.04.001 Get rights and content

Summary

Pre-eclampsia is a common and potentially dangerous disorder of human pregnancy. The maternal syndrome of hypertension, proteinuria and oedema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress. This results in the excess release of placental factors, such as syncytiotrophoblast debris or soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF), into the maternal circulation, where they trigger an inflammatory response and endothelial dysfunction. Alternatively, pre-eclampsia can develop in the presence of a normal placenta in women that are susceptible to systemic inflammation, such as with chronic cardiovascular disease or diabetes. While clinical management of pre-eclampsia does not currently include anti-inflammatory agents, current research is focusing on ways to reduce inflammation and oxidative stress.

Introduction

Pre-eclampsia is a widespread and potentially dangerous disorder of the second half of pregnancy. It is characterised by polymorphic, maternal systemic disturbances and clinical features. However, pre-eclampsia is currently impossible to predict or prevent as its precise causes are unknown. The signs that are used for clinical screening are new hypertension and proteinuria, which regress after delivery, but there is no specific diagnostic feature that, on its own, allows unequivocal recognition.

It seems clear that pre-eclampsia originates in the placenta as the presence of a placenta is necessary to cause the disorder.¹ A fetus is not required as pre-eclampsia can occur with hydatidiform mole, a complication of pregnancy characterised by dysregulated trophoblast proliferation without a fetus. Furthermore, the only cure for pre-eclampsia is delivery, which removes the placenta. However, the placenta does not need to be abnormal to induce pre-eclampsia.

The disease constitutes a spectrum that includes so-called ‘maternal’ and ‘placental’ pre-eclampsia.² With placental pre-eclampsia, there is an abnormal placenta in a normal woman. With maternal pre-eclampsia, there is a normal placenta within a woman who suffers from a pre-existing problem, such as cardiovascular disease or diabetes. In practice, many women with pre-eclampsia have both types in varying degrees.

The placental problem is principally one of oxidative stress, resulting from a poorly developed uteroplacental blood supply. The maternal problem results from a systemic inflammatory response that involves the entire inflammatory network of the circulation, including the endothelium. While the first stage (placental) is difficult to detect clinically, the second (maternal) stage is the clinical syndrome. The sequence of events has been highlighted by the two stage hypothesis for pre-eclampsia (Fig. 1).¹

Section snippets

Innate and adaptive immunity

Inflammatory (innate) responses evolved before adaptive immune responses. The innate system responds quickly to stimuli and is relatively non-specific, while the adaptive system develops slowly but has a precise mode of action as it delivers antigen-specific responses with immunological ‘memory’. The innate system can interact with the adaptive immune system but does not require this interaction to function, whereas, the adaptive system cannot function without signals from the innate system.

Systemic inflammatory responses

A systemic inflammatory response differs from local inflammatory responses, which are confined to specific tissues. Rather, a systemic response is diffuse, involving all cells and protein systems within the blood and, by secondary extension, affecting inflammatory networks outside the circulation in target organs.

The primary inflammatory cells are the phagocytes (monocytes and granulocytes), dendritic cells and NK cells. Endothelial cells are involved and produce a range of pro-inflammatory

Systemic inflammatory response and pregnancy

Normal pregnancy is characterised by a mild systemic inflammatory response, which becomes apparent during the luteal phase of the menstrual cycle before implantation occurs and develops as pregnancy progresses. In pre-eclampsia, a similar response occurs, but is of greater intensity.¹⁰

During normal pregnancy, the mild inflammatory changes do not indicate illness. Rather, many physiological features of pregnancy are indicators of the associated acute phase response, such as increased plasma

Conclusions

Pregnancy is a systemic inflammatory stress for women, particularly during the second half of gestation, to which both endocrine and placental factors probably contribute. The placental stimulus may comprise sFlt-1 and/or debris released into the maternal circulation from the syncytiotrophoblast, signalling danger to the maternal innate immune system. Pre-eclampsia ensues when the threshold for sustaining homeostasis is reached and excessive involvement of maternal endothelial integrity occurs.

References (63)

C.W. Redman
Current topic: pre-eclampsia and the placenta
Placenta
(1991)
R.B. Ness et al.
Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications
Am J Obstet Gynecol
(1996)
J.K. Sethi et al.
The role of TNF alpha in adipocyte metabolism
Semin Cell Dev Biol
(1999)
B. Isomaa
A major health hazard: the metabolic syndrome
Life Sci
(2003)
C.W. Redman et al.
Preeclampsia: an excessive maternal inflammatory response to pregnancy
Am J Obstet Gynecol
(1999)
C. Barriga et al.
Increased phagocytic activity of polymorphonuclear leukocytes during pregnancy
Eur J Obstet Gynecol Reprod Biol
(1994)
G.P. Sacks et al.
Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis
Am J Obstet Gynecol
(1998)
R. Austgulen et al.
Increased levels of cytokines and cytokine activity modifiers in normal pregnancy
Eur J Obstet Gynecol Reprod Biol
(1994)
L.A. Barbour et al.
Human placental growth hormone causes severe insulin resistance in transgenic mice
Am J Obstet Gynecol
(2002)
J.M. Roberts et al.
Pre-eclampsia: an endothelial cell disorder
Am J Obstet Gynecol
(1989)

A. Mantovani et al.

Cytokines as communication signals between leukocytes and endothelial cells

Immunol Today

(1989)

M.M. Faas et al.

A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats

Am J Obstet Gynecol

(1994)

B.T. Alexander et al.

Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression

Am J Hypertens

(2002)

B.M. Sibai et al.

Dexamethasone to improve maternal outcome in women with hemolysis, elevated liver enzymes, and low platelets syndrome

Am J Obstet Gynecol

(2005)

A. Konijnenberg et al.

Extensive platelet activation in preeclampsia compared with normal pregnancy: enhanced expression of cell adhesion molecules

Am J Obstet Gynecol

(1997)

R.N. Taylor et al.

High plasma cellular fibronectin levels correlate with biochemical and clinical features of preeclampsia but cannot be attributed to hypertension alone

Am J Obstet Gynecol

(1991)

E. Gratacos et al.

Lipid peroxide and vitamin E patterns in pregnant women with different types of hypertension in pregnancy

Am J Obstet Gynecol

(1998)

L.C. Chappell et al.

Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial

Lancet

(1999)

N. Vitoratos et al.

Defective antioxidant mechanisms via changes in serum ceruloplasmin and total iron binding capacity of serum in women with pre-eclampsia

Eur J Obstet Gynecol Reprod Biol

(1999)

E. Teran et al.

Elevated C-reactive protein and pro-inflammatory cytokines in Andean women with pre-eclampsia

Int J Gynaecol Obstet

(2001)

H. Li et al.

Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta

Placenta

(2005)

D.C. Felmeden et al.

Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management

Am J Hypertens

(2003)

N. Ishihara et al.

Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation

Am J Obstet Gynecol

(2002)

V.A. Rodie et al.

Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy?

Atherosclerosis

(2004)

A. Moffett-King

Natural killer cells and pregnancy

Nat Rev Immunol

(2002)

C. Gabay et al.

Acute-phase proteins and other systemic responses to inflammation

N Engl J Med

(1999)

M.B. Pepys et al.

C-reactive protein: a critical update

J Clin Invest

(2003)

J.S. Yudkin et al.

C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?

Arterioscler Thromb Vasc Biol

(1999)

G.K. Hansson et al.

Innate and adaptive immunity in the pathogenesis of atherosclerosis

Circ Res

(2002)

L. Gatti et al.

Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study

Int J Clin Lab Res

(1994)

A. Halligan et al.

Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia

Br J Obstet Gynaecol

(1994)

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Inflammation and acidosis are two stress stimuli that correspond to pathophysiological processes occurring in placental-mediated vascular disorders. We aimed to investigate the effects of these stimuli on placental chorionic blood vessels reactivity using the ex-vivo placental perfusion model.
Term placentas were obtained immediately after cesarean deliveries, and selected cotyledons were cannulated and dually perfused ex-vivo. Placentas were perfused with three different protocols: culture medium (M199-controls, n = 5), culture medium with lipopolysaccharide (inflammatory stimuli) (LPS,1 μg/ml, n = 7), and acidotic culture medium (M − 199, pH: 6.9–7, n = 6). Each perfusion experiment was maintained for 180 min. Fetal perfusion pressure was continuously measured. Measurements in response to angiotensin II (AT II) at the end of the perfusion were compared between the treatment groups, including amplitude of the contraction response, relaxation factor, time to maximal constriction and the area under the pressure curve (AUC).
In response to ATII there was a significant difference in the amplitude of the contraction and the AUC between the treatment groups, (p = 0.049, p = 0.015, respectively). As compared with control perfused cotyledon, the inflammatory stimuli significantly increased the vasoconstriction response to ATII in fetal placental blood vessels, as expressed by increased AUC - median (IQR): 555 (235–1184) vs. 133 (118–207), respectively, p = 0.017. The time to maximal constriction and the relaxation factor did not differ between the groups.
Inflammatory stimuli but not acidosis impact fetal-placental vasculature in response to ATII, suggesting that inflammation can compromise vascular function.
PINK1-mediated mitophagy induction protects against preeclampsia by decreasing ROS and trophoblast pyroptosis
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Preeclampsia (PE) is a multisystemic disorder attributed to the excessive presentation of placenta-derived immunoinflammatory factors. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy participates in the development and persistence of the inflammation. We hypothesized that dysregulated mitophagy might be involved in the pathogenesis of PE by promoting the activation of trophoblast pyroptosis that augment inflammation.
The morphology of mitochondrial in placenta were observed by transmission electron microscopy. The localization of PINK1 in the placenta was determined by immunohistochemistry. The expression levels of PINK1, PARKIN, LC3B, and SQSTM1 and pyroptosis-related molecules were compared between normal pregnancies and PE. We used hypoxia/reoxygenation (H/R) to stimulate the trophoblast hypoxia environment. HTR-8/SVneo cells were transfected with PINK1 plasmid and si-PINK1, respectively, and then were treated with H/R, to determine whether PINK1 regulated ROS and HTR-8/Svneo pyroptosis. Finally, ROS production was inhibited by MitoTEMPO to observe whether the pro-pyroptosis effect of PINK1 knockdown is alleviated.
Swollen mitochondrial were accumulated in the PE placentae. PINK1 is localized on villus trophoblast (VTs) and extravillous trophoblast (EVTs). PINK1-mediated mitophagy was abolished in the PE placenta, while the levels of pyroptosis were induced. H/R stimulation aggravated the downregulation of mitophagy and the up-regulation of pyroptosis. Overexpression of PINK1 mitigated H/R-induced upregulation of ROS and pyroptosis while silencing PINK1 did the opposite. Reducing ROS production can effectively resist the pro-pyroptosis effect of PINK1 knockdown.
This study demonstrated that PINK1-mediated mitophagy might played a protective role in PE by reducing ROS and trophoblast pyroptosis.
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An imbalanced redox homeostasis resulting in oxidative stress is present in preeclampsia. Peroxiredoxin-1 (PRDX1) and thioredoxin-1 (TRX1) regulatory enzymes are also contributing to the redox homeostasis, but were not investigated so far in preeclampsia. Thus, we have aimed to characterize PRDX1, TRX1 and oxidative stress biomarkers in blood samples of pregnant women with preeclampsia.
Twelve patients with preeclampsia (PE) were enrolled into the study. Seven third trimester healthy pregnant women (HP) were accepted as control group.
Peripheral venous blood samples of healthy and preeclamptic pregnant women were analyzed. Plasma level of advanced oxidation protein products (AOPP) was determined by spectrophotometry. The exofacial PRDX1 and TRX1 expression of lymphocytes and monocytes was detected by flow cytometry.
The plasma AOPP level was significantly higher in preeclampsia compared to the healthy pregnant group. Significantly higher percentage of PRDX1 and TRX1 expressing lymphocytes and monocytes were detected in the blood samples of preeclamptic women compared to healthy pregnant controls. The ratio of circulating PRDX1 and TRX1 expressing lymphocytes and monocytes showed a significant inverse correlation with the birth weight of newborns.
We have revealed that the level of advanced oxidation protein products is increased and the exofacial peroxiredoxin-1 and thioredoxin-1 system in lymphocytes and monocytes is upregulated in preeclampsia. In addition, the ratio of peroxiredoxin-1 and thioredoxin-1 positive circulating lymphocytes and monocytes correlates inversely with the neonatal birth weight, which finding indicates that pregnancies complicated by intrauterine growth restriction are accompanied by a higher level of oxidative stress.
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Citation Excerpt :
Very few women were on 150 mg of aspirin daily which prevented an analysis of a dose related effect. With inflammation as a possible driver of placental endothelial dysfunction in women in SLE [11], the effect of aspirin on preeclampsia may be less marked than in other high-risk obstetric populations. This relationship warrants further prospective investigation.
Systemic lupus erythematosus is associated with increased rates of preeclampsia. Both aspirin and hydroxychloroquine are recommended for preeclampsia prophylaxis in women with lupus but there are no studies examining related outcomes in an Australian cohort. This was a single centre retrospective study of lupus affected pregnancies. The association between hydroxychloroquine, aspirin and preeclampsia was examined using adjusted logistic regression models. In 95 pregnancies, hydroxychloroquine was associated with a significantly lower risk of preeclampsia (adjusted OR 0.16, 95 % CI 0.04–0.64) but there was no association between aspirin and preeclampsia (adjusted OR 1.34, 95 % CI 0.33–5.40).
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The pathogenesis of hypertensive disorder of pregnancy (HDP), which affects about 10% of pregnant women, is still incompletely understood. Our previous study showed that endoplasmic reticulum (ER) stress influences high-temperature requirement A serine peptidase 1 (HTRA1) expression and trophoblast invasion. However, the involvement of ER stress in the regulation of HTRA subtype expression and pathophysiology of HDP has not been characterized in extravillous trophoblasts (EVTs). To investigate this, HTR8/SVneo EVTs cell line was treated with the ER stress inducers Thapsigargin (Thap) or Tunicamycin (Tuni). Treatment with either Thap or Tuni inhibited trophoblast invasion, reduced HTRA1 and HTRA3 expression, but did not alter HTRA2 or HTRA4 expression. Knockdown of HTRA1 or HTRA3 also inhibited trophoblast invasion. Furthermore, treatment with either ER stress inducer or HTRA1 silencing increased the ratio of soluble fms-like tyrosine kinase-1/placental growth factor (sFLT1/PlGF), which is a marker of HDP. Immunohistochemical analysis revealed that HTRA1 is localized to EVTs and the endometrial decidua in the placenta of patients with HDP. These results suggest that factors that cause ER stress could result in the inhibition of EVTs invasion via HTRA1.

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Inflammation and pre-eclampsia

Summary

Introduction

Section snippets

Innate and adaptive immunity

Systemic inflammatory responses

Systemic inflammatory response and pregnancy

Conclusions

Placenta

Am J Obstet Gynecol

Semin Cell Dev Biol

Life Sci

Am J Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

Am J Obstet Gynecol

Immunol Today

Am J Obstet Gynecol

Am J Hypertens

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Lancet

Eur J Obstet Gynecol Reprod Biol

Int J Gynaecol Obstet

Placenta

Am J Hypertens

Am J Obstet Gynecol

Atherosclerosis

Natural killer cells and pregnancy

Nat Rev Immunol

Acute-phase proteins and other systemic responses to inflammation

N Engl J Med

C-reactive protein: a critical update

J Clin Invest

C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?

Arterioscler Thromb Vasc Biol

Innate and adaptive immunity in the pathogenesis of atherosclerosis

Circ Res

Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study

Int J Clin Lab Res

Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia

Br J Obstet Gynaecol