Association of IL-13 rs20541 and rs1295686 variants with symptomatic asthma in a Saudi Arabian population.

Objective: Interleukin 13 (IL-13) plays a critical pro-inflammatory role in asthma. Several single nucleotide polymorphisms (SNPs) are associated with asthma susceptibility in specific populations; however, further replicative studies in other ethnic groups are mandatory.

Methods: The association between IL-13 SNPs rs762534, rs20541, rs1295686, and rs1800925 (risk alleles A, A, T, and A, respectively) and asthma predisposition in a Saudi Arabian cohort was examined via a case-control cross-sectional study.

Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.

Background: In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22).

Risk factors hindering asthma symptom control in Saudi children and adolescents.

Background: Maintaining good control of asthma symptoms can help to prevent exacerbations and its associated complications. The Asthma Control Test (ACT) can rapidly assess the effectiveness of asthma management plan and therapy. The aim of this study was therefore to identify risk factors associated with uncontrolled asthma symptoms in young Saudi asthmatic children (3-17 years old).

Th-17 regulatory cytokines inhibit corticosteroid induced airway structural cells apoptosis.

Background: Although corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells.

Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children.

Background: Acute exacerbations of bronchial asthma remain a major cause of frequent Emergency Department (ED) visits by pediatric patients. However, other factors including psychosocial, behavioural and educational, are also reportedly associated with repetitive ED visits. Therefore, it is necessary to determine whether such visits are justifiable.

IL-17 Enhances Chemotaxis of Primary Human B Cells during Asthma.

IL-17 is a pro-inflammatory mediator that is believed to play a critical role in regulating tissue inflammation during asthma, COPD, as well as other inflammatory disorders. The level of expression of IL-17 has been shown to be upregulated in lung bronchial tissue of asthmatic patients. Several reports have provided further evidence that this cytokine could play a key role in enhancing the migration of inflammatory as well as structural cells of the bronchial lung tissue during asthma and COPD.

Rs37972 and rs37973 single-nucleotide polymorphisms in the glucocorticoid-inducible 1 gene are not associated with asthma risk in a Saudi Arabian population.

Objective: Rs37972 and rs37973 variants in the glucocorticoid-induced transcript 1 gene have been associated with inhaled glucocorticosteroid responsiveness in asthmatics; however, some discrepancies have been also reported. This study aims to determine whether rs37972 and rs37973 SNPs are associated with asthma risk in Saudi Arabian asthmatics.

Methods: Two-hundred seventy-one diagnosed asthmatics (3-65 years old) and 387 healthy control subjects of equivalent age were recruited.

Association of the STAT-6 rs324011 (C2892T) variant but not rs324015 (G2964A), with atopic asthma in a Saudi Arabian population.

Background: The signal transducer and activator of transcription 6 (STAT6) transduces signals in response to IL-4 and IL-13 cytokine stimulations, resulting in many cell-specific responses. Some common STAT6 SNPs were associated with asthma predisposition and/or IgE levels, although discrepancies have also been reported.

Objective: To determine whether STAT6 rs324011 and rs324015 polymorphisms are associated with atopic asthma in Saudi Arabian patients.

Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils.

Background: Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood.

Objective: In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines.

Eosinophils induce airway smooth muscle cell proliferation.

Asthma is characterized by eosinophilic airway inflammation and remodeling of the airway wall. Features of airway remodeling include increased airway smooth muscle (ASM) mass. However, little is known about the interaction between inflammatory eosinophils and ASM cells.

Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells.

Purpose: Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation.

Methods: GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR.

T1 and T2 ADAM33 single nucleotide polymorphisms and the risk of childhood asthma in a Saudi Arabian population: a pilot study.

Background And Objectives: Genetic association studies have demonstrated that over 100 variants in target genes (including ADAM33) are associated with airway remodeling and hyper-responsiveness in different ethnic groups; however, this has never been evaluated in Arabic populations. The objective of this study was to determine whether ADAM33 polymorphisms that are associated with asthma in a population of asthmatic children from Saudi Arabia.

Design And Setting: A cross-sectional pilot study comparing the polymorphisms of normal subjects and asthmatic patients from Saudi Arabia over a period of 1 year.

IL-17A and IL-17F expression in B lymphocytes.

Background: Recent evidence suggests that cells other than Th-17 lymphocytes express interleukin (IL)-17A and IL-17F and contribute to the production of these cytokines in immunologically mediated diseases. B lymphocytes are known to be an important source of cytokines in chronic inflammatory diseases. We therefore investigated the potential of human B lymphocytes to produce IL-17A and IL-17F.

Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines.

Background: Corticosteroid insensitivity in asthmatics is associated with an increased expression of glucocorticoid receptor-beta (GR-beta) in many cell types. T-helper type 17 (Th17) cytokine (IL-17A and F) expressions increase in mild and in difficult-to-treat asthma. We hypothesize that IL-17A and F cytokines alone or in combination, induce the expression of GR-beta in bronchial epithelial cells.

Intracrine signaling through lipid mediators and their cognate nuclear G-protein-coupled receptors: a paradigm based on PGE2, PAF, and LPA1 receptors.

Prostaglandins (PGs), platelet-activating factor (PAF), and lysophosphatidic acid (LPA) are ubiquitous lipid mediators that play important roles in inflammation, cardiovascular homeostasis, and immunity and are also known to modulate gene expression of specific pro-inflammatory genes. The mechanism of action of these lipids is thought to be primarily dependent on their specific plasma membrane receptors belonging to the superfamily of G-protein-coupled receptors (GPCR). Increasing evidence suggests the existence of a functional intracellular GPCR population.

Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1.

Stimulation of freshly isolated rat hepatocytes with lysophosphatidic acid (LPA) resulted in LPA1 receptor-mediated and nitricoxide-dependent up-regulation of the immediate early genes iNOS (inducible nitric-oxide synthase (NOS)) and mPGES-1 (microsomal prostaglandin E synthase-1). Because LPA is a ligand for both cell surface and intracellular receptor sites and a potent endothelial NOS (eNOS) activator, we hypothesized that NO derived from activated nuclearized eNOS might participate in gene regulation. Herein we show, by confocal microscopy performed on porcine cerebral endothelial cells expressing native LPA1-receptor and eNOS and on HTC4 rat hepatoma cells co-transfected with recombinant human LPA1-receptor and fused eNOS-GFP cDNA, a dynamic eNOS translocation from peripheral to nuclear regions upon stimulation with LPA.

Prostaglandin E2--mediated relaxation of the ductus arteriosus: effects of gestational age on g protein-coupled receptor expression, signaling, and vasomotor control.

Background: In the preterm newborn, a patent ductus arteriosus is in large part a result of the increased sensitivity of the immature ductus to prostaglandin E2 (PGE2). PGE2 acts through 3 G protein-coupled receptors (EP2, EP3, and EP4) that activate both adenyl cyclase and K(ATP) channels. We explored these pathways to identify the mechanisms responsible for the increased sensitivity of the immature ductus to PGE2.

Intracellular-specific colocalization of prostaglandin E2 synthases and cyclooxygenases in the brain.

Prostaglandin E2 (PGE2) is the major primary prostaglandin generated by brain cells. However, the coordination and intracellular localization of the cyclooxygenases (COXs) and prostaglandin E synthases (PGESs) that convert arachidonic acid to PGE2 in brain tissue are not known. We aimed to determine whether microsomal and cytosolic PGES (mPGES-1 and cPGES) colocalize and coordinate activity with either COX-1 or COX-2 in brain tissue, particularly during development.

Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1.

Lysophosphatidic acid (LPA) is a bioactive molecule involved in inflammation, immunity, wound healing, and neoplasia. Its pleiotropic actions arise presumably by interaction with their cell surface G protein-coupled receptors. Herein, the presence of the specific nuclear lysophosphatidic acid receptor-1 (LPA1R) was revealed in unstimulated porcine cerebral microvascular endothelial cells (pCMVECs), LPA1R stably transfected HTC4 rat hepatoma cells, and rat liver tissue using complementary approaches, including radioligand binding experiments, electron- and cryomicroscopy, cell fractionation, and immunoblotting with three distinct antibodies.

Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy.

Background: Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy.

Methods And Results: We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro.

Nuclear prostaglandin signaling system: biogenesis and actions via heptahelical receptors.

Prostaglandins are ubiquitous lipid mediators that play pivotal roles in cardiovascular homeostasis, reproduction, and inflammation, as well as in many important cellular processes including gene expression and cell proliferation. The mechanism of action of these lipid messengers is thought to be primarily dependent on their interaction with specific cell surface receptors that belong to the heptahelical transmembrane spanning G protein-coupled receptor superfamily. Accumulating evidence suggests that these receptors may co-localize at the cell nucleus where they can modulate gene expression through a series of biochemical events.