Eicosanoid receptors as therapeutic targets for asthma

2021 ◽  
Vol 135 (16) ◽  
pp. 1945-1980
Author(s):  
William S. Powell
Keyword(s):  
Inflammatory Cells ◽  
G Protein Coupled Receptors ◽  
Oxidation Products ◽  
Eicosatetraenoic Acid ◽  
Lipoxin A4 ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Combined Actions ◽  
G Protein Coupled ◽  
Eicosanoid Formation

Abstract Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.

scholarly journals Hypertonic Saline in Treatment of Pulmonary Disease in Cystic Fibrosis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Emer P. Reeves ◽  
Kevin Molloy ◽  
Kerstin Pohl ◽  
Noel G. McElvaney
Keyword(s):  
Cystic Fibrosis ◽  
Hypertonic Saline ◽  
Mucociliary Clearance ◽  
Inflammatory Cells ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Surface Liquid ◽  
Subsequent Failure

The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

scholarly journals 5-Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity

2004 ◽  
Vol 2004 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Harizi Hedi ◽  
Gualde Norbert
Keyword(s):  
Dendritic Cells ◽  
Adaptive Immunity ◽  
Inflammatory Cells ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Lipoxygenase Pathway ◽  
Innate And Adaptive Immunity ◽  
Paracrine Signalling ◽  
Signalling Molecules ◽  
G Protein Coupled

5-lipoxygenase (5-LO) pathway is the major source of potent proinflammatory leukotrienes (LTs) issued from the metabolism of arachidonic acid (AA), and best known for their roles in the pathogenesis of asthma. These lipid mediators are mainly released from myeloid cells and may act as physiological autocrine and paracrine signalling molecules, and play a central role in regulating the interaction between innate and adaptive immunity. The biological actions of LTs including their immunoregulatory and proinflammatory effects are mediated through extracellular specific G-protein-coupled receptors. Despite their role in inflammatory cells, such as neutrophils and macrophages, LTs may have important effects on dendritic cells (DC)-mediated adaptive immunity. Several lines of evidence show that DC not only are important source of LTs, but also become targets of their actions by producing other lipid mediators and proinflammatory molecules. This review focuses on advances in 5-LO pathway biology, the production of LTs from DC and their role on various cells of immune system and in adaptive immunity.

scholarly journals The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis

2018 ◽  
Vol 98 (2) ◽  
pp. 1055-1082 ◽  
Author(s):  
Lucia Negri ◽  
Napoleone Ferrara
Keyword(s):  
Cancer Progression ◽  
Developmental Disorder ◽  
Tissue Injury ◽  
Myeloid Cell ◽  
Inflammatory Cells ◽  
G Protein Coupled Receptors ◽  
Mediators Of Inflammation ◽  
Motility Regulation ◽  
G Protein Coupled ◽  
Stimulating Factor

The mammalian prokineticins family comprises two conserved proteins, EG-VEGF/PROK1 and Bv8/PROK2, and their two highly related G protein-coupled receptors, PKR1 and PKR2. This signaling system has been linked to several important biological functions, including gastrointestinal tract motility, regulation of circadian rhythms, neurogenesis, angiogenesis and cancer progression, hematopoiesis, and nociception. Mutations in PKR2 or Bv8/PROK2 have been associated with Kallmann syndrome, a developmental disorder characterized by defective olfactory bulb neurogenesis, impaired development of gonadotropin-releasing hormone neurons, and infertility. Also, Bv8/PROK2 is strongly upregulated in neutrophils and other inflammatory cells in response to granulocyte-colony stimulating factor or other myeloid growth factors and functions as a pronociceptive mediator in inflamed tissues as well as a regulator of myeloid cell-dependent tumor angiogenesis. Bv8/PROK2 has been also implicated in neuropathic pain. Anti-Bv8/PROK2 antibodies or small molecule PKR inhibitors ameliorate pain arising from tissue injury and inhibit angiogenesis and inflammation associated with tumors or some autoimmune disorders.

scholarly journals Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1033 ◽  
Author(s):  
Farjana Afrin ◽  
Mengna Chi ◽  
Andrew L. Eamens ◽  
Ryan J. Duchatel ◽  
Alicia M. Douglas ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Cannabinoid Receptors ◽  
Redox Homeostasis ◽  
G Protein Coupled Receptors ◽  
Therapeutic Benefits ◽  
Potential Efficacy ◽  
Anti Cancer ◽  
Potential Benefits ◽  
G Protein Coupled ◽  
Cancerous Cells

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.

Protease-activated receptor 2: activation, signalling and function

2003 ◽  
Vol 31 (6) ◽  
pp. 1191-1197 ◽  
Author(s):  
G.S. Cottrell ◽  
S. Amadesi ◽  
F. Schmidlin ◽  
N. Bunnett
Keyword(s):  
Inflammatory Cells ◽  
Coagulation Factors ◽  
G Protein Coupled Receptors ◽  
Protease Activated Receptors ◽  
Mitogen Activated Protein ◽  
Tethered Ligand ◽  
And Function ◽  
Protease Activated Receptor 2 ◽  
G Protein Coupled ◽  
Deficient Mice

PARs (protease-activated receptors) are a family of four G-protein-coupled receptors for proteases from the circulation, inflammatory cells and epithelial tissues. This report focuses on PAR2, which plays an important role in inflammation and pain. Pancreatic (trypsin I and II) and extrapancreatic (trypsin IV) trypsins, mast cell tryptase and coagulation factors VIIa and Xa cleave and activate PAR2. Proteases cleave PAR2 to expose a tethered ligand that binds to the cleaved receptor. Despite this irreversible activation, PAR2 signalling is attenuated by β-arrestin-mediated desensitization and endocytosis, and by lysosomal targeting and degradation, which requires ubiquitination of PAR2. β-Arrestins also act as scaffolds for the assembly of multi-protein signalling complexes that determine the location and function of activated mitogen-activated protein kinases. Observations of PAR2-deficient mice support a role for PAR2 in inflammation, and many of the effects of PAR2 activators promote inflammation. Inflammation is mediated in part by activation of PAR2 in the peripheral nervous system, which results in neurogenic inflammation and hyperalgesia.

scholarly journals Anti-Atherosclerotic Potential of Free Fatty Acid Receptor 4 (FFAR4)

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 467
Author(s):  
Anna Kiepura ◽  
Kamila Stachyra ◽  
Rafał Olszanecki
Keyword(s):  
Fatty Acids ◽  
G Protein Coupled Receptors ◽  
Long Chain Fatty Acids ◽  
Inflammatory Reactions ◽  
Beneficial Effects ◽  
Promising Strategy ◽  
The Family ◽  
Free Fatty Acid Receptor ◽  
G Protein Coupled ◽  
Stimulation Of

Fatty acids (FAs) are considered not only as a basic nutrient, but are also recognized as signaling molecules acting on various types of receptors. The receptors activated by FAs include the family of rhodopsin-like receptors: GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR120 (FFAR4), and several other, less characterized G-protein coupled receptors (GPR84, GPR109A, GPR170, GPR31, GPR132, GPR119, and Olfr78). The ubiquitously distributed FFAR4 can be activated by saturated and unsaturated medium- and long-chain fatty acids (MCFAs and LCFAs), as well as by several synthetic agonists (e.g., TUG-891). The stimulation of FFAR4 using selective synthetic agonists proved to be promising strategy of reduction of inflammatory reactions in various tissues. In this paper, we summarize the evidence showing the mechanisms of the potential beneficial effects of FFAR4 stimulation in atherosclerosis. Based partly on our own results, we also suggest that an important mechanism of such activity may be the modulatory influence of FFAR4 on the phenotype of macrophage involved in atherogenesis.

Mineralocorticoid receptor actions in cardiovascular development and disease

2021 ◽  
Author(s):  
Morag J. Young ◽  
Colin D. Clyne
Keyword(s):  
Dna Binding ◽  
Hormone Receptors ◽  
Inflammatory Cells ◽  
Steroid Hormone Receptors ◽  
Cardiovascular Development ◽  
Epithelial Tissues ◽  
Therapeutic Benefits ◽  
Corticosteroid Hormones ◽  
Health And Disease ◽  
G Protein Coupled

Abstract Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol. The pathology of inappropriate MR activation in non-epithelial tissues are well-described, and steroidal antagonists of the MR have been clinically beneficial in the management of heart failure and blood pressure for decades. However, the role of cortisol-dependent MR activation in the physiological setting is less well defined. Like other steroid hormone receptors, the MR also regulates non-DNA-binding pathways including MAPK pathways and G protein coupled receptors to provide diversity to MR signaling. Whether nonDNA binding pathways are more relevant for MR activation in non-epithelial, versus epithelial, tissues remain unclear. This review will focus on molecular regulation of ligand-dependent MR activation and the physiology and pathophysiology of MR actions in the heart with a focus on the cardiomyocyte and provide a discussion of relevant genomic and non-genomic MR pathways and potential new transcriptional partners for the MR and their relevance for health and disease. Understanding MR actions in the heart will provide new insights into cell-selective mechanisms that underpin the therapeutic benefits of MRAs, and are a critical step towards developing next-generation tissue selective MR modulators with improved safety profiles.

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