Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Intravenous fluid restriction after major abdominal surgery: a randomized blinded clinical trial

Background: Intravenous (IV) fluid administration is an essential part of postoperative care. Some studies suggest that a restricted post-operative fluid regime reduces complications and postoperative hospital stay after surgery. We investigated the effects of postoperative fluid restriction in surgical patients undergoing major abdominal surgery. Methods: In a blinded randomized trial, 62 patients (ASA I-III) undergoing elective major abdominal surgical procedures in a university hospital were allocated either to a restricted (1.5 L/24 h) or a standard postoperative IV fluid regime (2.5 L/24 h). Primary endpoint was length of postoperative hospital stay (PHS). Secondary endpoints included postoperative complications and time to restore gastric functions. Results: After a 1-year inclusion period, an unplanned interim analysis was made because of many protocol violations due to patient deterioration. In the group with the restricted regime we found a significantly increased PHS (12.3 vs. 8.3 days; p = 0.049) and significantly more major complications: 12 in 30 (40%) vs. 5 in 32 (16%) patients (Absolute Risk Increase: 0.24 [95%CI: 0.03 to 0.46], i.e. a number needed to harm of 4 [95%CI: 2-33]). Therefore, the trial was stopped prematurely. Intention to treat analysis showed no differences in time to restore gastric functions between the groups. Conclusion: Restricted postoperative IV fluid management, as performed in this trial, in patients undergoing major abdominal surgery appears harmful as it is accompanied by an increased risk of major postoperative complications and a prolonged postoperative hospital stay

Patients with migraine with aura have increased flow mediated dilation

<p>Abstract</p> <p>Background</p> <p>Endothelium-derived nitric oxide (NO) mediates the arterial dilation following a flow increase (i.e. flow-mediated dilation, FMD), easily assessed in the brachial artery. NO is also involved in cerebral hemodynamics and it is supposed to trigger vascular changes occurring during migraine. This study aimed at investigating whether migraine patients present an altered response to NO also in the peripheral artery system.</p> <p>Methods</p> <p>We enrolled 21 migraineurs (10 with aura [MwA], 11 without aura [MwoA]), and 13 controls. FMD was evaluated with ultrasound in all subjects by measuring the percentage increase of the brachial artery diameter induced by hyperaemia reactive to sustained cuff inflation around the arm above systolic pressure. FMD values were then normalized for shear stress.</p> <p>Results</p> <p>Normalized FMD values were higher in patients with MwA (28.5 10^-2%.s) than in controls (9.0 10^-2%.s) and patients with MwoA (13.7 10^-2%.s) (p < 0.001). FMD was over the median value (19%) in 23.1% of controls, in 45.5% of the MwoA patients, and in 90% of the MwA patients.</p> <p>Conclusions</p> <p>Migraineurs with aura present an excessive arterial response to hyperaemia, likely as an effect of an increased sensitivity to endothelium-derived nitric oxide. This phenomenon observed peripherally might reflect similar characteristics in the cerebral circulation.</p

Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC

Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression

Post-transcriptional regulation of HIV-1 gene expression is mediated by interactions between viral transcripts and viral/cellular proteins. For HIV-1, post-transcriptional nuclear control allows for the export of intron-containing RNAs which are normally retained in the nucleus. Specific signals on the viral RNAs, such as instability sequences (INS) and Rev responsive element (RRE), are binding sites for viral and cellular factors that serve to regulate RNA-export. The HIV-1 encoded viral Rev protein binds to the RRE found on unspliced and incompletely spliced viral RNAs. Binding by Rev directs the export of these RNAs from the nucleus to the cytoplasm. Previously, Rev co-factors have been found to include cellular factors such as CRM1, DDX3, PIMT and others. In this work, the nuclear matrix protein Matrin 3 is shown to bind Rev/RRE-containing viral RNA. This binding interaction stabilizes unspliced and partially spliced HIV-1 transcripts leading to increased cytoplasmic expression of these viral RNAs

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain

ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators