| 1. |
- Kalkunte, Satyan S., et al.
(author)
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Transthyretin Is Dysregulated in Preeclampsia, and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model
- 2013
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In: American Journal of Pathology. - : ELSEVIER SCIENCE INC, 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA. - 0002-9440 .- 1525-2191. ; 183:5, s. 1425-1436
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Journal article (peer-reviewed)abstract
- Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinal, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.
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| 2. |
- Kalkunte, Satyan, et al.
(author)
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Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
- 2010
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In: AMERICAN JOURNAL OF PATHOLOGY. - : American Society for Investigative Pathology (ASIP). - 0002-9440. ; 177:5, s. 2387-2398
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Journal article (peer-reviewed)abstract
- Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.
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| 3. |
- Matthiesen, Leif, et al.
(author)
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Multiple pregnancy failures: an immunological paradigm.
- 2012
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In: American Journal of Reproductive Immunology. - : Wiley. - 1600-0897 .- 1046-7408. ; 67:4, s. 334-340
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Journal article (peer-reviewed)abstract
- Recurrent spontaneous abortion (RSA), three or more pregnancy losses prior to 20 weeks, occurs in about 1% of all pregnancies, 50% of RSA cases remain unexplained and unresolved. Recently, immune pathways have been implicated in the pathophysiology of RSA. Immune tolerance of the fetal-placental unit and placental angiogenesis are mandatory for a successful pregnancy outcome. Unscheduled dysregulation of the placental vasculature is thought to be the pathophysiologic mechanisms underlying an array of pregnancy complications like infertility, miscarriage, pre-eclampsia, and fetal growth restriction and death. Investigations on mechanisms and management of RSA are mired by substandard design and lack of optimal randomized clinical trials and have resulted in disagreement on guidelines for evaluation and treatments for patients with multiple pregnancy losses of unknown etiology. The present review focuses on evidence-based research discussion with immunologic causes, and immune-regulatory therapies recommended for helping patients with a history of RSA. We highlight data that might support revalidation of low molecular weight heparin as a protective therapy in RSA. Newly launched growth factors, GM-CSF, and potentially novel agents to suppress inflammatory rejection, including regulatory T cells, human chorionic gonadotropin, and M-CSF/IL-10, may work in concert with tender-loving-care therapy and give hope to couples with multiple pregnancy losses.
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