Preeclampsia is a prevalent and potentially devastating disorder of pregnancy. Characterized by a sudden spike in blood pressure and urinary protein levels, it is associated with significant obstetric complications. BPH/5 is an inbred mouse model of preeclampsia with borderline hypertension before pregnancy. BPH/5 mice develop hypertension, proteinuria, and endothelial dysfunction during late gestation (after E14.5). We hypothesized that BPH/5 mice might exhibit early feto-placental abnormalities before the onset of maternal disease. All placental cell lineages were present in BPH/5 mice. However, the fetal and placental weights were reduced, with abnormalities in all the placental zones observed starting early in gestation (E9.5-E12.5). The fractional area occupied by the junctional zone was significantly reduced at all gestational timepoints. Markedly fewer CDKN1C-stained trophoblasts were seen invading the proximal decidual zone, and this was accompanied by reductions in Cdkn1c gene expression. Trophoblast giant cell morphology and cytokeratin staining were not altered, although the mRNA levels of several giant cell-specific markers were significantly downregulated. The labyrinth layer displayed decreased branching morphogenesis of endothelial cells, with electron microscopy evidence of attenuated trophoblast layers. The maternal decidual arteries showed increased wall-to-lumen ratios with persistence of actin-positive smooth muscle cells. These changes translated into dramatically increased vascular resistance in the uterine arteries, as measured by pulse-wave Doppler. Collectively, these results support the hypothesis that defects at the maternal-fetal interface are primary causal events in preeclampsia, and further suggest the BPH/5 model is important for investigations of the underlying pathogenic mechanisms in preeclampsia.
Abstract-Recently we described a mouse model, BPH/5, that spontaneously develops the hallmark clinical features of preeclampsia. BPH/5 exhibit impaired placentation before the onset of hypertension and proteinuria, supporting a causal role for the placenta in the pathogenesis of preeclampsia. Here we tested the hypothesis that an increase in reactive oxygen species (ROS) early in pregnancy results in placental abnormalities leading to the maternal symptoms of preeclampsia. We further hypothesized that chronic antioxidant therapy would ameliorate both feto-placental abnormalities and maternal symptoms. ROS levels measured by dihydroethidium revealed significant increases in oxidative stress in BPH/5 placentas at midgestation compared with C57 controls. This increase in ROS was correlated with reduced expression and activity of cytoplasmic superoxide dismutase in early and midgestation BPH/5 placentas. These abnormalities in placental oxidant factors occurred before the onset of maternal symptoms, suggesting a possible causal link between increased ROS and maternal and feto-placental pathology in this model. In support of this, chronic treatment of BPH/5 with the superoxide dismutase-mimetic Tempol throughout gestation significantly improved fetal growth and survival. Furthermore, Tempol ameliorated pregnancy-induced increases in blood pressure and proteinuria in BPH/5 mothers. We confirmed that Tempol radical was present in plasma, and it normalized ROS levels in all placental zones in BPH/5. These data for the first time demonstrate an important causative role for increased ROS in the placenta in the pathogenesis of preeclampsia in a model that spontaneously develops the disease. The results also strongly suggest the potential utility of antioxidant therapy in treating preeclampsia. (Hypertension. 2008;51:1058-1065.)
Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1α (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1α stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for β2 integrins. SDF-1α also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-α, IL-1β, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the β2 integrin LFA-1 by SDF-1α. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1α-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1α-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier.
Objectives: While most pediatric coronavirus disease 2019 cases are not life threatening, some children have severe disease requiring emergent resuscitative interventions. Resuscitation events present risks to healthcare provider safety and the potential for compromised patient care. Current resuscitation practices and policies for children with suspected/confirmed coronavirus disease 2019 are unknown. Design: Multi-institutional survey regarding inpatient resuscitation practices during the coronavirus disease 2019 pandemic. Setting: Internet-based survey. Subjects: U.S. PICU representatives (one per institution) involved in resuscitation system planning and oversight. Interventions: None. Measurements and Main Results: Of 130 institutions surveyed, 78 (60%) responded. Forty-eight centers (62%) had admitted coronavirus disease 2019 patients; 26 (33%) reported code team activation for patients with suspected/confirmed coronavirus disease 2019. Sixty-seven respondents (86%) implemented changes to inpatient emergency response systems. The most common changes were as follows: limited number of personnel entering patient rooms (75; 96%), limited resident involvement (71; 91%), and new or refined team roles (74; 95%). New or adapted technology is being used for coronavirus disease 2019 resuscitations in 58 centers (74%). Most institutions (57; 73%) are using enhanced personal protective equipment for all coronavirus disease 2019 resuscitation events; 18 (23%) have personal protective equipment policies dependent on the performance of aerosol generating procedures. Due to coronavirus disease 2019, most respondents are intubating earlier during cardiopulmonary resuscitation (56; 72%), utilizing video laryngoscopy (67; 86%), pausing chest compressions during laryngoscopy (56; 72%), and leaving patients connected to the ventilator during cardiopulmonary resuscitation (56; 72%). Responses were varied regarding airway personnel, prone cardiopulmonary resuscitation, ventilation strategy during cardiopulmonary resuscitation without an airway in place, and extracorporeal cardiopulmonary resuscitation. Most institutions (46; 59%) do not have policies regarding limitations of resuscitation efforts in coronavirus disease 2019 patients. Conclusions: Most U.S. pediatric institutions rapidly adapted their resuscitation systems and practices in response to the coronavirus disease 2019 pandemic. Changes were commonly related to team members and roles, personal protective equipment, and airway and breathing management, reflecting attempts to balance quality resuscitation with healthcare provider safety.
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