Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as preeclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGFß-1 and 5-aza-2’-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56Bright idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56Dim idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immunocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion.

The immune complement system protects against pathogens; however, excess activation results in disease like hemolytic uremic syndrome, a clinical imitator of preeclampsia. Vascular endothelial factor (VEGF) protects against aberrant complement activation and is inhibited by soluble fms-like tyrosine kinase-1 (sFLT1) in other organs. We hypothesize that sFLT1 promotes complement-mediated placental damage through VEGF inhibition in preeclampsia. Objective: Quantify placental complement activity and sFLT1 expression in preeclampsia, and the subgroup of preeclampsia with hemolysis elevated liver enzymes low platelets (HELLP) syndrome. Methods: Placental complement activation marker C4d, membrane attack complex (MAC), and sFLT1 expression was quantified using immunofluores cence microscopy. Results: Placentas from 18 controls, 25 preeclampsia, including 6 cases of HELLP syndrome were identified. Placental C4d expression was greater in PE (median 6.4 [IQR: 5.1, 8.3]) compared to controls (4.4 [3.6, 5.5]; p = 0.003). MAC expression was also increased in preeclampsia compared to controls (6.5 [5.8, 8.7]; 5.4 [2.9, 5.9], p = 0.001). Placental sFLT1 expression was also higher in preeclampsia (p <0.0001). C4d and MAC were strongly correlated with sFLT1 levels in the placenta (R = 0.72; p < 0.0001 and R = 0.59; p = 0.01, respectively). Complement and sFLT1 expression was elevated in HELLP compared to preeclampsia without laboratory abnormalities, but this difference did not reach statistical significance. Conclusion: Increased placental complement activation and damage was seen in preeclampsia and correlates with sFLT1 expression. Our findings support the importance of the complement pathway in preeclampsia.

Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >240 dynes˙s˙cm. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-Whitney U test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls .53], P = 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r = 0.58, P = 0.006) and inversely correlated with cardiac output (r = −0.57, P = 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension.

AKI is a major cause of morbidity and mortality and an important contributor to the development and progression of CKD. Molecular biomarkers that improve the detection and prognostication of AKI are therefore required. We assessed the utility as such of BPI fold-containing family A member 2 (BPIFA2), also known as parotid secretory protein, which we identified a multiplex quantitative proteomics screen of acutely injured murine kidneys. In physiologic conditions, BPIFA2 is expressed specifically in the parotid glands and is abundant in salivary secretions. In our study, AKI induced expression in the kidneys of mice within 3 hours. Furthermore, we detected BPIFA2 protein in plasma and urine in these models as early as 6 hours after injury. However, renal injury did not induce the expression of in mice lacking, an immediate early gene expressed in the kidneys during AKI. Notably, patients with AKI had higher blood and urine levels of BPIFA2 than did healthy individuals. Together, our results reveal that BPIFA2 is a potential early biomarker of AKI.

Expression of sFlt-1 is diminished in villous trophoblasts from patients with placenta increta or percreta. Local depth of invasion was not associated with sFlt-1 expression, suggesting a more global abnormality across the implantation site rather than localized to areas of histologic invasion.

sFlt‐1 is a splice variant of the vascular endothelial growth factor (VEGF) receptor lacking the transmembrane and cytoplasmic domains and acts as a powerful antagonist of VEGF, thereby inhibiting VEGF signaling in the vasculature. Its excess can diminish and alter fenestrated capillary beds and it is considered causal in preeclampsia, but its presence is a physiologically necessity for limiting capillary growth in the vitreous and other compartments within the eye. Plasma sflt1 levels are higher in patients with chronic kidney disease (CKD) and using multivariate regression analysis were exclusively associated with renal function (higher levels correlate with decreasing function) [PMID: 19608702]. The source of this plasma sFlt‐1 is unclear, but circulating monocytes have been considered a possible etiology. 47 renal biopsies were immunostained for sFlt‐1 and evaluated on a 0–4 grading scale of positive cells within inflammatory infiltrates: 4 drug‐induced interstitial nephritis; 12 allografts, 3 with polyomavirus nephritis; 10 diabetes mellitus; 6 lupus glomerulonephritis; 5 ANCA; 5 IgA/HSP nephropathy and 5 miscellaneous chronic kidney diseases. 42 had infiltratory infiltrates of which 31 had sflt positive cells: 3 biopsies had cells which constituted more that 50% of the inflammatory infiltrate (grade 4), 6 biopsies 25–50% (grade 3), 4 biopsies 10–25% (grade 2), 3 biopsies 10% (grade1) and 15 biopsies <10% (grade +/−). The positive cells were generally single but formed clusters that became diffuse. The associated capillary network (immunostaining for CD34) was reduced or had disappeared. This data was supported by RT‐PCR analysis of sFlt‐1 in a subset of frozen biopsy samples. CD68 stains indicated that the positive cells were histiocytes/transitioning myofibroblasts such as seen in [PMID: 28209809]. In general, there was a correlation (r2= 0.89) between degree of inflammation and sFlt‐1 positive cells, but some inflammatory foci were negative; and no correlation was seen between inflammation and fibrotic changes (perhaps indicating that the fibrotic changes might be an ongoing/evolving process). Cases of polyomavirus nephritis (2), drug‐associated interstitial nephritis (3), advanced diabetic kidneys (3) and HSP(1) were the most positive (9/47), but significant (10% or greater) sFlt‐1 positivity was seen in many biopsies (16/47). In conclusion, sFlt‐1 positive cells are generally part of the inflammatory infiltrates in CKD and may be extremely abundant. Their presence promotes an anti‐angiogenic state that could inhibit capillary repair, contribute to peritubular capillary loss and enhance fibrosis in CKD. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No abstract

A school-age boy with a complex medical history underwent a minor elective surgical procedure. Propofol was used for sedation during the procedure. The patient could not be awakened post-operatively. Laboratory findings demonstrated metabolic lactic acidosis, leukocytosis with bandemia, and transaminitis. Neuroimaging demonstrated findings that were consistent with hypoxic-ischemic or toxic-metabolic brain injury involving the bilateral basal ganglia, hippocampi, and cerebellum. The patient's condition progressively worsened over the course of the following few weeks, and brain death was confirmed by scintigraphy seven weeks later. Prompt neuroimaging in unresponsive patients with suspected propofol infusion syndrome (PRIS) is of critical importance in detecting neurologic injuries, excluding alternative diagnoses, and determining prognostication.