Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease

© 2018 Elsevier Ltd Arachidonic acid is metabolized by cyclooxygenases (COX-1 and COX-2) into various prostanoids which exert different functions in mammalian physiology. One of these prostanoids, prostaglandin E 2 (PGE 2 ), interacts with four different G protein-coupled receptors, named EP 1 , EP 2 , EP 3 and EP 4 , to initiate different downstream signalling pathways. Prostanoid receptors are diversely expressed throughout different tissues all over the body and PGE 2 is responsible for a large variety of beneficial and disadvantageous effects. We have recently achieved a greater understanding of the biology of prostanoid E receptors and the potential for specific drug targeting with the advent of potent and selective EP receptor agonists and antagonists. This has important implications for lung health and disease as PGE 2 -mediated EP receptor activation impacts upon migration of airway smooth muscle cells, airway microvascular leak, tone regulation of pulmonary blood vessels, mast cell degranulation, bronchodilatation, cough, angiogenesis and airway inflammation, to name a few. In this review, we overview the EP receptor family and the related signalling pathways, summarize a variety of EP 1-4 receptor agonists and antagonists, provide an overview of pharmacological tools used to implicate EP receptor function in the context of respiratory health and disease and finally highlight some of the more selective pharmacological reagents that have recently been developed. The availability of selective pharmacological agonists and antagonists for the distinct EP receptors, as well as the development of specific prostanoid receptor knock-out mice, offer hitherto unattainable opportunities for achieving an in depth understanding of the role and function of PGE 2 in respiratory disease and the exciting potential of targeting EP receptors more broadly

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism

Alcoholic liver disease and bilateral multifocal central serous retinopathy:a case report

INTRODUCTION: We present a unique case of a patient with bilateral, multifocal central serous retinopathy in a patient with alcoholic liver disease. CASE PRESENTATION: A 58-year-old Caucasian man with alcoholic liver disease, liver cirrhosis and ascites presented to the eye clinic. The ophthalmoscopic examination of both eyes revealed a symmetrical pattern of variably sized, slightly yellowish, translucent, raised lesions throughout the fundi which were confirmed to be caused by multifocal central serous retinopathy after optical coherence tomography and autofluoresence tests. CONCLUSION: This case highlights the possible link between central serous retinopathy and end-stage liver disease, with potential implications for the pathogenesis of central serous retinopathy in these patients

SAR imaging from incomplete data using elastic net regularisation

Synthetic aperture radar imaging suffers significantly from incomplete datasets, where whole pulses are missing. In this Letter, the author introduces an elastic net regularisation to imaging, reducing those artefacts and improving the signal to noise ratio of the image at the same time

Detection of Moving Targets Using Off-Grid Compressed Sensing

Detection of moving targets using M P ≈ 100 pulses from an airborne radar with multiple receive channels is a crucial point of Earth surveillance. Compressed sensing (CS) has been proven to be applicable to this problem in several publications. Nevertheless, the position of scatterers and the computational grid points for CS differ in general regardless of the scatterers' motion. Hence, we introduce in this paper a method for moving target detection using off-grid CS by reconstructing angle-Doppler diagrams

Application of distributed compressed sensing for GMTI purposes

The first step of ground moving target indication is the differentiation between moving and nonmoving objects. Using sparsity based methods for this purpose is often constrained by the nonsparse characteristic of the nonmoving clutter. In this paper we present a new approach for moving target indication based on distributed compressed sensing, a variant of the well known compressed sensing, thus allowing nonsparse background data

Compressed sensing for the detection of moving targets from short sequences of pulses: Special section "sparse reconstruction in remote sensing"

The detection of ground moving targets from Mp ≈ 100 pulses of multichannel radar data allows the surveilance of wide areas. In this paper, their sparse distribution is utilized to produce a reconstruction of an angle-Doppler matrix using two different compressed sensing approaches - ℓ1-relaxation and smoothed L0. For an exemplary set of real data, the targets are detected and presented in a map of the scenery

Elastic net regularization for SAR imaging from incomplete data

Missing radar pulses cause severe artifacts in common synthetic aperture radar images. In this paper, the SAR processor is regularized using the elastic net approach - an additive combination of1- and2-norm - for reducing those artifacts and the noise level. Real data examples show the effectiveness of this approach. © VDE VERLAG GMBH à Berlin à Offenbach