Serum developmental endothelial locus-1 is associated with severity of sepsis in animals and humans.

Disruption of the endothelial glycocalyx has a prominent role in the pathophysiology of sepsis. Developmental endothelial locus-1 (Del-1) is an endothelial-derived anti-inflammatory factor. We hypothesized that degradation of the endothelial glycocalyx during sepsis may increase serum Del-1. A mouse model of sepsis was created using cecal ligation and puncture. In septic mice, the endothelial glycocalyx was nearly completely degraded, with less formation of Del-1 in the endothelium and extracellular matrix than in control mice. Serum Del-1 levels were significantly increased in the septic mice with increasing severity of sepsis. Serum Del-1 levels were also measured in 84 patients with sepsis and septic shock and in 20 control subjects. The median serum Del-1 level in patients with sepsis was significantly higher than that in healthy controls. The high Del-1 group had higher illness severity scores and contained more patients with organ dysfunction than the low Del-1 group. The 90-day mortality rate was significantly higher in the high Del-1 group than in the low Del-1 group. Multivariate analysis indicated a tendency for a high serum Del-1 level to be associated with a higher mortality risk. Increased serum Del-1 may be a novel diagnostic biomarker of sepsis and an indicator of disease severity.

The effect of human adipose-derived stem cells on lipopolysaccharide-induced acute respiratory distress syndrome in mice.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of acute respiratory failure in critically ill patients. Recently, several treatment modalities have been proposed for ARDS, but it still has a high mortality rate. In general, the role of mesenchymal stem cells (MSCs) in controlling inflammatory responses has been studied in various immune-associated diseases in humans and animals. However, only a few studies reported adipose-derived stem cells (ASCs), which are easier to isolate, are currently emerging as an attractive treatment option in ARDS. Therefore, in this study, we investigated the therapeutic effects of human ASCs and the regulation of inflammatory responses in an ARDS mouse model. METHODS: In the ARDS model, lipopolysaccharide (LPS) (5 mg/kg) was administered via the intra tracheal injection method. The mice were divided into the following four groups: (I) saline + medium; (II) saline + ASCs (2×105); (III) LPS + medium; (IV) LPS + ASCs. The ARDS observation time was divided into short and long term. LPS administration increased the concentration of proinflammatory cytokines, which was a consistent systemic inflammatory response. RESULTS: LPS/ASC group showed less neutrophil infiltration and less alveolar hemorrhage or congestion than did the LPS group. The lung injury scores of the LPS/ASC group were lower than those of the LPS group (3.8±0.9 vs. 6.8±1.1; P=0.03) at day 2. Compared to the LPS group, LPS/ASC group showed reduced collagen deposition around the vessels and fibrosis accompanied by alveolar septal or interstitial thickening and lower MPO levels than did the LPS group (453.2±26.2 vs. 670.2±65.9 pg/mL; P<0.01) at day 7. CONCLUSIONS: ASC therapy can inhibit neutrophil recruitment, which shows trend of reducing short term lung injury (day 2) and affecting fibrosis in long term (day 7). Further studies are warranted to understand the mechanism and improve the therapeutic effect of ASCs.

Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model.

BACKGROUND: Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses. METHODS: Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury. RESULTS: Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9. CONCLUSIONS: Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPS-induced ALI via immunomodulatory effects.

National trends for open and endovascular repair of aneurysms in Korea: 2004-2013.

The introduction of endovascular aneurysm repair has led to a dramatic decline in open aneurysm repair. The aim of this report was to evaluate Korean national trends for the treatment of aneurysms. A serial, cross-sectional study of time trends of patients who underwent aneurysm repair between 2004 and 2013 was conducted. Data from the Health Insurance Review and Assessment Service were used to evaluate the trends of aneurysm repair in the Korean population and to analyze the trends of open and endovascular aneurysm repair among Medicare beneficiaries. A linear-by-linear association was performed to determine alterations in the rates at which these aneurysm repair techniques were performed. A total of 32,130 patients underwent aneurysm repair between 2004 and 2013. The proportion of patients who underwent open repair decreased from 94.0% in 2004 to 54.9% in 2013; whereas the proportion of patients who underwent endovascular repair increased from 6.0% in 2004 to 45.1% in 2013. During the study period, the number of patients undergoing endovascular repair of aortic aneurysms significantly increased from 82 to 1,396 (relative risk, 16.17; 95% confidence interval: 12.94-20.21). Endovascular repair of abdominal aortic aneurysms (AAAs)overtook open repair between 2010 and 2011. The frequency of open aneurysm repair increased 1.2-fold, with an overall downward trend. The prevalence of endovascular repair markedly increased 15.3-fold. These findings indicated that, in Korea, the endovascular repair of AAAs overtook open repair as the most common technique between 2010 and 2011.

Associations between Single Nucleotide Polymorphisms of High Mobility Group Box 1 Protein and Clinical Outcomes in Korean Sepsis Patients.

PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1ß, IL-6, IL-10, IL-17, and tumor necrosis factor-α] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.

In silico analysis of genomic data for construction of nuclear receptor network.

Availability of genome-wide information in public database provides unprecedented opportunity for developing new strategy to uncover potential interactions of members in large functional family. Here we describe a systematic strategy for constructing and analyzing potential interaction map to uncover novel interaction between nuclear receptors that may play important roles in human disease. This in silico approach can prioritize candidate interactions for further functional validation and assess its clinical relevance.

Impact of serial measurements of lysophosphatidylcholine on 28-day mortality prediction in patients admitted to the intensive care unit with severe sepsis or septic shock.

PURPOSE: The purpose of this study is to investigate the effect of serial lysophosphatidylcholine (LPC) measurement on 28-day mortality prediction in patients with severe sepsis or septic shock admitted to the medical intensive care unit (ICU). METHODS: This is a prospective observational study of 74 ICU patients in a tertiary hospital. Serum LPC, white blood cell, C-reactive protein, and procalcitonin (PCT) levels were measured at baseline (day 1 of enrollment) and day 7. The LPC concentrations were compared with inflammatory markers using their absolute levels and relative changes. RESULTS: The LPC concentration on day 7 was significantly lower in nonsurvivors than in survivors (68.45 ± 42.36 µmol/L and 99.76 ± 73.65 µmol/L; P = .04). A decreased LPC concentration on day 7 to its baseline as well as a sustained high concentration of PCT on day 7 at more than 50% of its baseline value was useful for predicting the 28-day mortality. Prognostic utility was substantially improved when combined LPC and PCT criteria were applied to 28-day mortality outcome predictions. Furthermore, LPC concentrations increased over time in patients with appropriate antibiotics but not in those with inappropriate antibiotics. CONCLUSIONS: Serial measurements of LPC help in the prediction of 28-day mortality in ICU patients with severe sepsis or septic shock.

The atypical orphan nuclear receptor DAX-1 interacts with orphan nuclear receptor Nur77 and represses its transactivation.

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome, gene 1) (NROB1) is an atypical member of the nuclear receptor family, which lacks the classical zinc finger DNA binding domain and acts as a coregulator of a number of nuclear receptors. In this study, we have found that DAX-1 is a novel coregulator of the orphan nuclear receptor Nur77 (NR4A1). We demonstrate that DAX-1 represses the Nur77 transactivation by transient transfection assays. Specific interaction between Nur77 and DAX-1 was detected by coimmunoprecipitation, yeast two-hybrid, and glutathione-S-transferase pull-down assays. The ligand binding domain of DAX-1 and the activation function-2 domain of Nur77 were determined as the direct interaction domains between DAX-1 and Nur77. In vitro competition binding assay showed that DAX-1 repressed Nur77 transactivation through the competition with steroid receptor coactivator-1 for the binding of Nur77. Moreover, DAX-1 repressed Nur77- and LH-dependent increase of cytochrome P450 protein 17 promoter activity in transient transfection assays. Furthermore, Nur77-mediated transactivation was significantly increased by down-regulation of DAX-1 expression with DAX-1 small interfering RNA in testicular Leydig cell line, K28. LH treatment induced a transient increase in Nur77 mRNA, whereas LH repressed DAX-1 expression in a time- and dose-dependent manner in K28 cells. In addition, immunohistochemical analysis showed the expression of Nur77 in mouse testicular Leydig cells. These results suggest that DAX-1 acts as a novel coregulator of the orphan nuclear receptor Nur77, and that the DAX-1 may play a key role in the regulation of Nur77-mediated steroidogenesis in testicular Leydig cells.