EXOSOMES: FUTURE MANAGERS OF PREECLAMPSIA ABSTRACT: Preeclampsia (PE) is a pregnancy complication affecting 5-7% pregnant women globally including India and is one of the leading causes of maternal and fetal mortality. The clinical signs usually appear after 20 weeks of gestation, characterized by high blood pressure (≥140/90 mmHg), proteinuria (≥300 mg/24 h) and kidney or liver damage. In mild cases of PE, antihypertensive drugs like aspirin and anti-convulsant MgSO4 are being used as treatment in high-risk patients. However, in severe cases, delivery of the fetus remains the only option. There’s no definite cure for the condition due to lack of clarity in disease pathophysiology and occurrence. Such drawbacks makes this pathological condition highly non manageable leading to worsening of this disease. Exosomes are one type of extracellular vesicles comprising of proteins, RNA and DNA of the source cells/tissues which are reported to modulate the immune system during normal pregnancy. However, little is known about the effect of exosomes in preeclampsia. We believe that inclination of researchers towards exosomes can help us to gain a probable solution towards tracking and treating PE. INTRODUCTION: ISSHP defines preeclampsia as new onset hypertension (systolic >140 mmHg and diastolic >90 mmHg), proteinuria (≥300 mg/24 h), other maternal organ dysfunction (including liver, kidney, neurological), hematological complication, uteroplacental dysfunction such as fetal growth restriction and/or abnormal Doppler ultrasound findings of uteroplacental blood flow. Evidently PE is the cause of approx. 40% premature births delivered before 35 weeks of gestation. Studies have shown that administration of low dose aspirin at early stages in high risk pregnancies can reduce the risk of developing pre-eclampsia. Thus, it becomes necessary to find a novel source of biomarker(s) in order to detect PE as early as possible. Lipid bound nanovesicles called exosomes are considered to be potential biomarkers due to their cargo composition and surface proteins. They are known to have role in pregnancy. Using different approaches, they can be used in managing and diagnosing PE.
Early Onset PE (EOPE)
Late Onset PE (LOPE)
Occurs at less than 34 weeks of gestation and due to alteration in placental development
Occurs at 34 weeks or later and related to placental senescence0
RISK FACTORS OF PE Advanced maternal age (>35 years) Obesity Diabetes Renal diseases
FUNCTION OF EXOSOMES
Multifetal gestation Reproduction
Cell death
Increased shedding of extracellular vesicles
Higher proinflammatory cytokine response
TREATMENT: Clinical examination for treatment involves resting blood pressure measurement, weight gain, edema, complete blood count, 24 hrs. proteinuria and assessment of HELLP syndrome. Electro cardiotocography along with uterine artery Doppler ultrasound can be done for fetal assessment. Antihypertensive drugs like labetalol can be employed. Along with this, two betamethasone injections of 12mg 24 hrs. apart can be given to reduce the risk of neonatal mortality. Effectiveness of magnesium sulphate is well proven treatment for preeclampsia in reducing maternal and neo natal complications. If the conditions get worse, delivery remains the only suitable option.
Immune alteration due to PE
Increased maternal systemic inflammation response
Inflammation
Immune response
Cancer
EXOSOMES AS BIOMARKER FOR PE: Placental type alkaline phosphatase (PLAP) is being extensively used for isolation of placenta-specific exosomes. PE is considered to occur due to altered immune response as a result of increased shedding of placenta. Evidences convey that placenta-specific exosomes could have an important role in the pathogenesis of preeclampsia by means of modulating the maternal immune system as increased exosomal shedding is observed in PE. This theory can be worked upon to find a suitable marker in the form of exosome which can help in understanding disease physiology and its management.
PATHOPHYSIOLOGY Defective trophoblast invasion Impaired spiral artery remodelling Placental Ischaemia Exaggerated Immune response Preeclampsia • • • • • •
High plasma sFLT:VEGF ratio
CONCLUSION: Preeclampsia needs a tracking mechanism and treatment as soon as possible due to its mortality rate in women worldwide and limited treatment due to mis-management. Till now, marker based studies have gained utmost attention. As per our study, placental exosomes can be used to study and diagnose PE. Placenta is required for its study which can be available only after delivery, exosomes can work as non invasive biopsies to understand the nature of placenta during pregnancy. Study of inflammatory and angiogenic markers, in particular can be done to elucidate their role in preeclampsia.
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