-
Allergy Aug 2022
Topics: Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cysteine; Humans; Hypersensitivity; Leukotrienes; Prostaglandins; Therapeutic Irrigation
PubMed: 35451080
DOI: 10.1111/all.15319 -
BioMed Research International 2015Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to... (Review)
Review
Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1 receptor (cysLT1R) and cysLT2 receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.
Topics: Animals; Autocrine Communication; Cell Membrane; Eosinophils; Gene Expression Regulation; Humans; Leukotrienes; Paracrine Communication; Receptors, Leukotriene; Secretory Vesicles
PubMed: 25866815
DOI: 10.1155/2015/848762 -
Polskie Archiwum Medycyny Wewnetrznej Dec 2011Asthma is a chronic and heterogeneous inflammatory disorder of the airways defined by its clinical, physiological and pathological characteristics. Accordingly to... (Review)
Review
Asthma is a chronic and heterogeneous inflammatory disorder of the airways defined by its clinical, physiological and pathological characteristics. Accordingly to currently available guidelines inhaled glucocorticosteroids (ICS) represent the most effective anti-inflammatory medication for the treatment of persistent asthma, and this class of drugs is recommended as the first-line controller therapy both in children and adults. Leukotriene modifiers (LTRAs) are usually used as a second line of add-on therapy, although they may be regarded as the first-line therapy in exercise induced bronchoconstriction, in patients with comorbid allergic rhinitis and in children with asthma and frequent viral infections. A recently published pragmatic (real-life) study showed that LTRAs provide an alternative treatment for asthma, which, at least for the evaluated endpoints, may be as effective as ICS in our every-day practice. To assess how the recent data may affect our every-day practice and current guidelines for clinical management of asthma, it needs to be clearly understood what pragmatic trials add to our knowledge. In our opinion, it is premature to change current guidelines. However, pragmatic and observational studies are clearly needed as they provide additional information to randomized controlled trials. The main goal of all those efforts is to improve asthma control and decrease the burden of the disease for patients and societies. It may be that the future approach will introduce several new strategies based on system biology studies for the treatment of asthma guided in a personalized medicine approach.
Topics: Administration, Inhalation; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Humans; Leukotrienes
PubMed: 22210376
DOI: No ID Found -
Pharmacology 2010The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells,... (Review)
Review
The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C(4) (LTC(4)), leukotriene D(4) (LTD(4)) and leukotriene E(4) (LTE(4)), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT(1) and CysLT(2). The CysLT(1) receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT(2) receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT(1)-receptor-mediated effects, and the role of the CysLT(2) receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT(2)-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.
Topics: Animals; Cardiovascular Diseases; Cysteine; Female; Gene Expression Regulation; Humans; Leukotrienes; Male; Neoplasms; Neurosecretory Systems; Protein Conformation; Receptors, Leukotriene; Respiratory Hypersensitivity; Signal Transduction
PubMed: 20516735
DOI: 10.1159/000312669 -
Clinical and Experimental Allergy :... Dec 2010Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor... (Review)
Review
Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT(1) and CysLT(2) , have been identified. The activation of the CysLT(1) receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB(4) might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT(1) receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT(1) receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT(1) receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT(1) receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.
Topics: Anti-Asthmatic Agents; Asthma; Humans; Leukotriene Antagonists; Leukotrienes; Receptors, Leukotriene
PubMed: 21059119
DOI: 10.1111/j.1365-2222.2010.03630.x -
International Journal of Molecular... Jul 2019Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to... (Review)
Review
Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various allergic diseases, including asthma (neutrophilic asthma and aspirin-sensitive asthma), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and anaphylaxis. This review summarizes the biology of LTs and their receptors, recent developments in the area of anti-LT strategies (in settings such as ongoing clinical studies), and prospects for future therapeutic applications.
Topics: Animals; Biomarkers; Disease Susceptibility; Gene Expression Regulation; Humans; Hypersensitivity; Leukotriene Antagonists; Leukotrienes; Metabolic Networks and Pathways; Molecular Targeted Therapy; Receptors, Leukotriene; Signal Transduction
PubMed: 31336653
DOI: 10.3390/ijms20143580 -
American Journal of Physiology. Lung... Sep 2002Mechanical forces affect both the function and phenotype of cells in the lung. In this symposium, recent studies were presented that examined several aspects of... (Review)
Review
Mechanical forces affect both the function and phenotype of cells in the lung. In this symposium, recent studies were presented that examined several aspects of biomechanics in lung cells and their relationship to disease. Wound healing and recovery from injury in the airways involve epithelial cell spreading and migration on a substrate that undergoes cyclic mechanical deformation; enhanced green fluorescent protein-actin was used in a stable cell line to examine cytoskeletal changes in airway epithelial cells during wound healing. Eosinophils migrate into the airways during asthmatic attacks and can also be exposed to cyclic mechanical deformation; cyclic mechanical stretch caused a decrease in leukotriene C(4) synthesis that may be dependent on mechanotransduction mechanisms involving the production of reactive oxygen species. Recent studies have suggested that proinflammatory cytokines are increased in ventilator-induced lung injury and may be elevated by overdistention of the lung tissue; microarray analysis of human lung epithelial cells demonstrated that cyclic mechanical stretch alone profoundly affects gene expression. Finally, airway hyperresponsiveness is a basic feature of asthma, but the relationship between airway hyperresponsiveness and changes in airway smooth muscle (ASM) function remain unclear. New analysis of the behavior of the ASM cytoskeleton (CSK) suggests, however, that the CSK may behave as a glassy material and that glassy behavior may account for the extensive ASM plasticity and remodeling that contribute to airway hyperresponsiveness. Together, the presentations at this symposium demonstrated the remarkable and varied roles that mechanical forces may play in both normal lung physiology as well as pathophysiology.
Topics: Cytokines; Eosinophils; Epithelial Cells; Humans; Leukotrienes; Lung; Stress, Mechanical; Wound Healing
PubMed: 12169567
DOI: 10.1152/ajplung.00141.2002 -
Biological & Pharmaceutical Bulletin 2011The purpose of this review is to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their... (Review)
Review
The purpose of this review is to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions. LTs belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are known to be important factors in a variety of local and systemic diseases and allergic/inflammatory diseases. We examined whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, we investigated the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors. We found the expression of 5-lipoxygenase (5-LO), FLAP and the cysteinyl leukotrienes (CysLT1) mRNAs in spinal microglia, LTA4h and LTC4s mRNAs in both spinal neurons and microglia, and BLT1 mRNA in spinal neurons. Administration of the 5-LO inhibitor or the receptor antagonists suppressed mechanical allodynia. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation. This review summarizes the hypothesis that LTs might work in the spinal cord and primary afferent in pathological pain conditions.
Topics: Animals; Ganglia, Spinal; Hyperalgesia; Inflammation; Inflammation Mediators; Leukotrienes; Neuralgia; Peripheral Nervous System; Peripheral Nervous System Diseases; RNA, Messenger; Receptors, Leukotriene; Spinal Cord; p38 Mitogen-Activated Protein Kinases
PubMed: 21804200
DOI: 10.1248/bpb.34.1163 -
Frontiers in Immunology 2022The pathological implications of tumor-associated macrophages in the glioma microenvironment have been highlighted, while there lacks a gene signature to characterize...
Integrated genomic, transcriptomic, and epigenetic analyses identify a leukotriene synthesis-related M2 macrophage gene signature that predicts prognosis and treatment vulnerability in gliomas.
The pathological implications of tumor-associated macrophages in the glioma microenvironment have been highlighted, while there lacks a gene signature to characterize the functional status and clinical implications of these cells. Comprehensive bioinformatics approaches were employed to develop an M2 macrophage-associated gene signature at bulk-tumor and single-cell levels and explore immunological and metabolic features. Consequently, the PI3K pathway and fatty acid metabolism were correlated with the M2 fraction. Further distilling the pathway members resulted in a leukotriene synthesis-related gene signature (Macro index), including PIK3R5, PIK3R6, ALOX5, ALOX5AP, and ALOX15B, that was primarily expressed by monocytes/macrophages. Increased Macro index predicted IL13-induced macrophages, and was associated with T-cell dysfunction at both transcriptional and epigenetic levels and predicted an unfavorable outcome. Besides, the Macro index was proportional with PAI1 at the protein level, with high levels of the latter suggesting a decreased progression-free interval of glioblastoma. Notably, the monocytes/macrophages in the glioma environment contribute to the expression of immune checkpoints and the Macro index predicts glioma responsiveness to anti-PD1 treatment. Together, our study proposed a leukotriene synthesis-related M2 macrophage gene signature, which may provide insights into the role of these cells in the glioma microenvironment and facilitate individually tailored therapeutic strategies for the disease.
Topics: Brain Neoplasms; Epigenesis, Genetic; Fatty Acids; Genomics; Glioma; Humans; Interleukin-13; Leukotrienes; Macrophages; Phosphatidylinositol 3-Kinases; Prognosis; Transcriptome; Tumor Microenvironment
PubMed: 36159811
DOI: 10.3389/fimmu.2022.970702 -
The Journal of Allergy and Clinical... Sep 2009The intracellular parent of the cysteinyl leukotrienes (cysLTs), leukotriene (LT) C(4), is formed by conjugation of LTA(4) and reduced glutathione by LTC(4) synthase in... (Review)
Review
The intracellular parent of the cysteinyl leukotrienes (cysLTs), leukotriene (LT) C(4), is formed by conjugation of LTA(4) and reduced glutathione by LTC(4) synthase in mast cells, eosinophils, basophils, and macrophages. After extracellular export, LTC(4) is converted to LTD(4) and LTE(4) through sequential enzymatic removal of glutamic acid and then glycine. Only LTE(4) is sufficiently stable to be prominent in biologic fluids, such as urine or bronchoalveolar lavage fluid, of asthmatic individuals and at sites of inflammation in animal models. LTE(4) has received little attention because it binds poorly to the classical type 1 and 2 cysLT receptors and is much less active on normal airways than LTC(4) or LTD(4). However, early studies indicated that LTE(4) caused skin swelling in human subjects as potently as LTC(4) and LTD(4), that airways of asthmatic subjects (particularly those that were aspirin sensitive) were selectively hyperresponsive to LTE(4), and that a potential distinct LTE(4) receptor was present in guinea pig trachea. Recent studies have begun to uncover receptors selective for LTE(4): P2Y(12), an adenosine diphosphate receptor, and CysLT(E)R, which was observed functionally in the skin of mice lacking the type 1 and 2 cysLT receptors. These findings prompt a renewed focus on LTE(4) receptors as therapeutic targets that are not currently addressed by available receptor antagonists.
Topics: Animals; Asthma; Guinea Pigs; Humans; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Mice; Receptors, Leukotriene; Receptors, Purinergic P2; Skin
PubMed: 19647860
DOI: 10.1016/j.jaci.2009.05.046