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Three-dimensional PCA score scatter plots. Three-dimensional PCA score scatter plots obtained for 37 septic shock patients (red) and 20 ICU controls (green) based on the (A) metabolic data and (B) cytokine/chemokine data. The groups are well clustered along the axes of the three principal components. One septic shock sample is placed outside the sphere that describes the 95% confidence interval of the Hotelling’s T-squared distribution.

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery., Abdominal surgery can often lead to complications including the formation of peritoneal adhesions and the molecular mechanisms underlying this process are still unknown. Here, the authors suggest that bacterial contamination drives adhesion formation through mesothelial EGFR signalling.

The receiver operating characteristic (ROC) curves plotted with a decimal logarithmic scale for the horizontal axes. The ROC plots for (A) septic shock patients vs. ICU controls and (B) septic shock nonsurvivors vs. septic shock survivors models based on the metabolomics data, cytokine/chemokine data and the combined dataset (metabolites together with inflammatory mediators), APACHE (acute physiology and chronic health evaluation) and SOFA (sequential organ failure assessment) scores. Black line - fit line, red dashed line - the chance curve (that is the diagonal of the ROC curve when plotted in linear scale).

The OPLS-DA regression coefficient plot. Positive values of coefficients (the upper part of the diagram) indicates increased metabolite or inflammatory mediator concentrations in septic shock nonsurvivor samples while negative values (the lower part of diagram) present a decrease in metabolite or inflammatory mediator concentrations, as compared to the age-sex-matched septic shock survivors. Only significant metabolites are shown (P

The receiver operating characteristic (ROC) curves plotted with a decimal logarithmic scale for the horizontal axes. The ROC plots for (A) septic shock patients vs. ICU controls and (B) septic shock nonsurvivors vs. septic shock survivors models based on the metabolomics data, cytokine/chemokine data and the combined dataset (metabolites together with inflammatory mediators), APACHE (acute physiology and chronic health evaluation) and SOFA (sequential organ failure assessment) scores. Black line - fit line, red dashed line - the chance curve (that is the diagonal of the ROC curve when plotted in linear scale).

The summary table. Comparison of statistical measures calculated for the supervised OPLS-DA models without excluding outliers to the results presented in the manuscript.

Background—Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal diseases. Because Ang II may contribute to the leukocyte recruitment associated with these pathological states, the aim of the present study was to assess the role of Ang II in leukocyte–endothelial cell interactions in vivo. Methods and Results—Intravital microscopy of the rat mesenteric postcapillary venules was used. Sixty minutes of superfusion with 1 nmol/L Ang II induced a significant increase in leukocyte rolling flux (83.8±20.7 versus 16.4±3.1 cells/min), adhesion (11.4±1.0 versus 0.8±0.5 cells/100 µm), and emigration (4.0±0.7 versus 0.2±0.2 cells/field) without any vasoconstrictor activity. These effects were not mediated by mast cell activation. Intravenous pretreatment with AT1 (losartan) or AT2 (PD123,319) receptor antagonists significantly reduced Ang II–induced responses. A combination of both receptor antagonists inhibited the leukocyte rolling flux, adhesion, and extravasation elicited by Ang II at 60 minutes. Pretreatment of animals with fucoidin or an adhesion-blocking anti–rat P-selectin monoclonal antibody abolished Ang II–induced leukocyte responses. Furthermore, rat platelet P-selectin expression was not affected by Ang II stimulation. Conclusions—Ang II induces significant leukocyte rolling, adhesion, and emigration, which may contribute not only to hypertension but also to the onset and progression of the vascular damage associated with disease states in which plasma levels of this peptide are elevated. Piqueras Ruiz, Laura, Laura.Piqueras@uv.es ; Alvarez Ribelles, Angeles, Angeles.Alvarez@uv.es ; Esplugues Mota, Juan Vicente, Juan.V.Esplugues@uv.es ; Sanz Ferrando, Maria Jesus, Maria.J.Sanz@uv.es

Item does not contain fulltext Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.