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61.
Satyan S. Kalkunte Stefan Neubeck Wendy E. Norris Shi-Bin Cheng Stefan Kostadinov Dang Vu Hoang Aftab Ahmed Ferdinand von Eggeling Zahir Shaikh James Padbury Goran Berg Anders Olofsson Udo R. Markert Surendra Sharma 《The American journal of pathology》2013,183(5):1425-1436
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 retinol, 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.Preeclampsia occurs in 5% to 8% of pregnancies worldwide and is a major cause of fetal and maternal morbidity and mortality.1–3 It is a heterogeneous disease with varied presentations from mild self-limited hypertension and proteinuria to severe forms with significant end-organ dysfunction and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).3 Although the cause of preeclampsia and its appropriate treatment remain elusive, this syndrome has been proposed to reflect at least two stages of complications during pregnancy. These begin with preclinical manifestations at the maternal-fetal interface, followed by systemic clinical symptoms.1,2 Hypertension, proteinuria, and edema, with a variable degree of fetal growth restriction, are the cardinal features of preeclampsia.3 Because the placenta is the nutritional and immunological gateway to normal fetal development and pregnancy outcome, placenta-related events are believed to be central to the pathogenesis of this disease. Evidence exists for the release of disease-initiating molecules into maternal circulation that triggers the clinical symptoms.1,4 Placental and systemic anomalies reflected by circulating placental debris, inflammation, impaired remodeling of spiral arteries, placental hypoxia/ischemia, excess production of anti-angiogenic factors [soluble fms-like tyrosine kinase-1 (sFlt-1)], and soluble endoglin (sEng), and angiotensin receptor autoantibodies have all emerged as contributors to the pathophysiological characteristics of preeclampsia.2,4–14Preeclampsia has remained enigmatic because of lack of well-defined etiology and animal models. Although normal mice do not develop preeclampsia spontaneously, mouse models have been judged to be particularly useful to uterine diseases and pregnancy complications because many similarities in female reproduction and placentation have been identified between the two species.15 Moreover, their tractable genetics provide an effective way to probe mechanisms more deeply than many other species.15–17 We recently showed that sera from preeclamptic women could function as a source of novel causative factors that induced hypertension, proteinuria, and kidney pathological characteristics, as well as intrauterine growth restriction (IUGR), in IL-10−/− mice in a pregnancy-specific manner.18 IL-10 functions as a potent vascular and anti-inflammatory cytokine and has been shown to be present at significantly reduced levels in preeclampsia placental tissue.19,20 Preeclampsia serum (PES) was found to disrupt endovascular cross talk between trophoblasts and endothelial cells and to induce placental hypoxia and excess production of sFlt-1 and sEng,18 soluble factors known to precipitate maternal symptoms.21,22 These results from our serum-based humanized mouse model suggest that the pathophysiological characteristics of preeclampsia are more complex than previously thought and are likely to involve interactions and dysregulation of multiple factors. By using serum proteomic screening by surface-enhanced laser-desorption ionization-time-of-flight (SELDI-TOF), our results suggest that PES contains a reduced abundance of transthyretin, a plasma transport protein for the thyroid hormone, thyroxine, and retinol-binding protein.23 More important, transthyretin has been widely studied for its role in amyloid diseases associated with protein misfolding and aggregation, resulting in deposits of toxic, fibrillar aggregates in specific organs.24–26 Dysregulated or reduced transthyretin has also been implicated in Alzheimer disease, and overexpression of a wild-type human transthyretin transgene has been shown to ameliorate the disease in the transgenic murine model of human Alzheimer disease.27,28 Transthyretin in its native form assumes a homotetrameric quaternary configuration (approximately 14 kDa per monomer). Post-translational modifications of the monomer result in detection of several isoforms.29 Circulating transthyretin is also a validated marker of malnutrition and has a putative role in oocyte maturation and inflammation.30–32 Although the presence of transthyretin during implantation in mice and in the placenta and trophoblasts in humans has been reported,33,34 its functional role in normal pregnancy or adverse pregnancy outcomes has not been recognized. We hypothesize that transthyretin in preeclampsia is structurally and functionally dysregulated and contributes to the onset of this serious pregnancy complication. Herein, we present complementary in vitro and in vivo approaches, which show that endogenously altered transthyretin is a preeclampsia-causing agent and that native transthyretin has the ability to block the onset of preeclampsia-like features. 相似文献
62.
Influence of oxygen tension on the viscoelastic behavior of red blood cells in sickle cell disease 总被引:2,自引:0,他引:2
Although the rheological behavior of sickle cell suspensions and of hemoglobin S solutions is known to be strongly dependent on oxygen tension (PO2), little data exist concerning the influence of PO2 on the viscoelasticity of individual HbSS RBC. We have used micropipette aspiration techniques to test the deformation response of both HbSS and control HbAA RBC over a wide range of PO2 at 23 degrees C. Sickled, spiculed HbSS cells were present for PO2 approximately less than 35 mm Hg; for a number of these cells, the deformation response was essentially elastic and an effective membrane rigidity (EMR) was calculated. EMR increased with decreasing PO2 and was approximately 5 to 50 times higher than the equivalent rigidity of oxygenated HbSS RBC. In addition, the rate of membrane deformation was very slow for sickled cells; the half-time for the deformation process increased as PO2 was lowered and was about two orders of magnitude longer than the equivalent time for normal RBC. Other sickled cells exhibited plastic deformation when subjected to comparable deforming forces and experienced irreversible membrane deformation and budding. At all PO2 levels tested, some HbSS RBC remained as discocytes; these cells had normal membrane elasticity and membrane viscosity. Furthermore, changes in PO2 did not affect the membrane properties of HbAA RBC. Thus, gross abnormalities in the deformation response of HbSS RBC were only detected after morphological sickling had occurred. These abnormalities most likely arose from changes in the cytoplasmic HbS viscoelasticity and, if present in vivo, would be expected to impair the flow of HbSS cells in the microcirculation. 相似文献
63.
Alloimmunization to platelets in heavily transfused patients with sickle cell disease 总被引:2,自引:0,他引:2
Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization. 相似文献
64.
65.
Simone CS Wolfkamp Caroline Verseyden Esther WM Vogels Sander Meisner Kirsten Boonstra Charlotte P Peters Pieter CF Stokkers Anje A te Velde 《World journal of gastroenterology : WJG》2014,20(10):2664-2672
AIM:To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease(CD).METHODS:In this study,we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls.As both autophagy related like 1(ATG16L1)and immunityrelated guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleo-tide-binding ligomerization domain-containing protein2(NOD2)has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction.The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo?Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.RESULTS:In this study,we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity(ratio of mean fluorescence intensity)between the patient groups and the healthy controls.CD patients show a significantly higher phagocytic capacity(ratio mean percentage of phagocytic cells)compared to healthy controls(51.91%±2.85%vs 37.67%±7.06%,P=0.05).The extend of disease was not of influence.However,variants of ATG16L1(WT:2.03±0.19 vs homozygoot variant:4.38±0.37,P<0.009)as well as NOD2(C-ins)(heterozygous variant:42.08±2.94 vs homozygous variant:75.58±4.34(P=0.05)are associated with the phagocytic activity in patients with CD.CONCLUSION:Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants.This could be part of the pathophysiological mechanism resulting in the disease. 相似文献
66.
Giuseppe Bellelli MD Paolo Mazzola MD Alessandro Morandi MD MPH Adriana Bruni MD Lucio Carnevali MD Maurizio Corsi MD Giovanni Zatti MD Antonella Zambon PhD Giovanni Corrao PhD Birgitta Olofsson RN PhD Yngve Gustafson MD PhD Giorgio Annoni MD 《Journal of the American Geriatrics Society》2014,62(7):1335-1340
67.
68.
Jay R Shapiro Caressa Lietman Monica Grover James T Lu Sandesh CS Nagamani Brian C Dawson Dustin M Baldridge Matthew N Bainbridge Dan H Cohn Maria Blazo Timothy T Roberts Feng‐Shu Brennen Yimei Wu Richard A Gibbs Pamela Melvin Philippe M Campeau Brendan H Lee 《Journal of bone and mineral research》2013,28(7):1523-1530
69.
70.
R. Wiklund A. Toots M. Conradsson B. Olofsson H. Holmberg E. Rosendahl Y. Gustafson H. Littbrand 《Osteoporosis international》2016,27(3):923-931