Postreceptor Mechanisms of Growth Factor Action
Enrique Pimentel in Handbook of Growth Factors, 2017
The leukotrienes are noncyclized metabolites of arachidonic acid and their biosynthesis is catalyzed by a lipoxygenase specific for C-5 position. These lipid mediators have 20 carbons and 3 conjugated double bonds. The leukotriene A is an unstable epoxide that can be hydrolyzed to generate leukotriene B (LTB) or the peptido-leukotrienes C, D, and E by addition of a peptide group in position C. These peptido-leukotrienes are the bioactive components of the slow-reacting substance or anaphylaxis. Leukotrienes display many biological effects and may have a crucial role in inflammatory and hypersensitivity reactions. LTB stimulates polymorphonuclear leukocytes and leads to their aggregation and degranulation. LTB is also a potent chemotactic and chemokinetic agent for polymorphonuclear leukocytes, eosinophils, and monocytes. LTB can stimulate suppressor T lymphocytes and can enhance natural cytotoxic cell activity. It is also a potent bronchoconstrictor. Bioactive leukotrienes induce vasoconstriction of vascular beds and can produce a negative inotropic effect on cardiac muscle fibers. The precise role of leukotrienes in the mechanisms of action of hormones and growth factors is not clear, but they are members of the eicosanoid family of lipids and have numerous interactions with the prostaglandins. The effects of LTB on leukocyte function are probably mediated by the synthesis of diverse cytokines. There is evidence that the physiological actions of leukotrienes are mediated by a specific receptor located on the cell surface and that the LTB transduction mechanism involves changes in G proteins and alterations in phosphatidylinositol turnover. LTB may regulate the production of different cytokines by modulating the yield or the function of transcription factors such as the Fos and Jun proteins, which recognize AP-1-containing target genes.
Genetic Diversity
Peter Donaldson, Ann Daly, Luca Ermini, Debra Bevitt in Genetics of Complex Disease, 2015
(s) — the space between the protein-coding regions of the DNA sequences (known as exons). Intronic sequences have a range of roles, not all of which are fully understood. Invariant chain — polypeptide that associates with HLA class II molecules in the endo-plasmic reticulum where it acts as a molecular chaperone to prevent inappropriate peptide binding until the HLA molecule can be transported to the endosomes where it is degraded and peptides can compete for binding. Inversions — a re-arrangement where a segment of a chromosome is reversed from end to end. Killer cell immunoglobulin-like receptor (KIR) — family of receptors on natural killer cells that bind HLA class I on target cells and either activate or downregulate the natural killer cell. Kinship coefficients — a measure of consanguinity between individuals in complex disease studies; this can be used to estimate bias. Least-squares criterion — statistical method of looking for errors in a study and corresponds with the maximum-likelihood ratios if the experimental error has a normal distribution. Leber hereditary optic neuropathy — disorder inherited from the mitochondrial DNA causing degeneration of retinal ganglia cells and their axons. Leukocyte (antigens, typing, antibodies) — white cells. Antigens refers to proteins on white cells; typing refers to phenotyping using serological testing; antibodies refers to the agents required to perform phenotyping. Leukotriene — a family of inflammatory mediators produced by leukocytes and possibly some other cells. They are involved in immune inflammation and vascular adhesion. Linear regression model — mathematical model used in statistical analysis to define a relationship between a dependent variable (on the y-axis) and one or more other explanatory variables (on the x-axis). Linkage — a physical link between two or markers on a chromosome (see Linkage analysis). It can also refer to a link between a genetic marker and disease or disease trait. Linkage analysis — one of two major strategies for identifying "disease alleles" based on the likelihood of the marker alleles, mutations, copy number variants of a gene or genes being inherited with the trait. Linkage analysis is mostly based on informative families, though occasionally sibling pairs are used, and it works well for diseases that present in early life, have high penetrance, and a near-Mendelian pattern of inheritance. It does not work in diseases that are transmitted horizontally through the population, such as infectious diseases. Linkage disequilibrium (LD) — the co-occurrence of alleles from two or more gene loci more often than expected by chance [see also Ancestral haplotype (HLA 7.2 and 8.1)]. For example, two alleles each present at 10% in a population should be found together at a frequency of 1% if there is equilibrium. However, when there is "disequilibrium the alleles are likely to be found together more often (or less often) than expected by chance.
The Role of the Clinical Laboratory in Nutritional Assessment
Aruna Bakhru in Nutrition and Integrative Medicine, 2018
Allergies and asthma can make those affected feel terrible, both directly and through medications used to treat them. Asthma is often an allergic-based lung disorder in which spasms and inflammation of the bronchial passages restrict the flow of air in and out of the lungs. Difficulty breathing can affect appetite, which can in turn have negative effects on diet, mood, and general well-being. Leukotrienes contribute to the allergic and inflammatory reactions in asthma. Because leukotrienes are derived from arachidonic acid, which is unique to animal products, a vegetarian diet is often helpful by reducing leukotriene formation. When such a diet was followed for 1 year in conjunction with many specific dietary changes (such as avoidance of caffeine, sugar, salt, and chlorinated tap water) and combined with a variety of herbs and supplements, significant improvements were reported in one group of asthmatics. Magnesium, vitamin B6, and omega-3 fatty acids also play a role in asthma. Magnesium levels are often low in patients with asthma. Small studies suggest short-term benefit with magnesium supplements. Likewise, vitamin B6 levels are often low in patients with asthma. This deficiency may relate to the asthma itself or to certain asthma drugs (such as theophylline and aminophylline) that deplete vitamin B6. Clinical studies suggest patients taking supplements of vitamin B6 have fewer and less severe asthmatic attacks. Finally, fish oils contain the essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which block the production of leukotrienes. Research shows that fish oil supplements reduce reactions to allergens that can trigger attacks in some patients with asthma.
The role of leukotrienes in immunopathogenesis of rheumatoid arthritis
Published in Modern Rheumatology, 2014
Bahman Yousefi, Farhad Jadidi-Niaragh, Gholamreza Azizi, Fatemeh Hajighasemi, Abbas Mirshafiey
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. However, conventional medications can reduce inflammation, relieve pain, and slow joint damage. Leukotrienes are a family of paracrine agents derived from oxidative metabolism of arachidonic acid. Synthesis of lipid mediators and subsequent induction of receptor activity are tightly regulated under normal physiological conditions, so that enzyme and/or receptor dysfunction can lead to a variety of clinical signs and symptoms of disease, such as local pain and tissue edema. In these tissues, immunocompetent cells accumulate at the site of injury, contributing to tissue damage and perpetuation of the disease process. Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies.
The potential link between atherosclerosis and the 5-lipoxygenase pathway: investigational agents with new implications for the cardiovascular field
Published in Expert Opinion on Investigational Drugs, 2007
Carl Whatling, William McPheat, Margareta Herslöf
The 5-lipoxygenase pathway is responsible for the production of leukotrienes – inflammatory lipid mediators that have a role in innate immunity, but that can also have pathological effects in inflammatory diseases. Recently, a potential link between leukotriene production and atherosclerosis has been proposed. The expression of leukotriene biosynthetic enzymes and leukotriene receptors has been identified in coronary and carotid atherosclerotic plaques, and the levels of biosynthetic enzymes have been correlated with the clinical symptoms of unstable plaques. Genetic variants in 5-lipoxygenase pathway genes have also been associated with a relative risk of developing myocardial infarction and stroke. On the basis of these discoveries, antileukotriene compounds are now being evaluated for the treatment of cardiovascular disease. Several tool compounds have been shown to limit the progression of lesion development in preclinical models of atherosclerosis, and three compounds, including two drugs previously developed for asthma, are undergoing clinical trials in patients with acute coronary syndromes.
Leukotriene pathway in sickle cell disease: a potential target for directed therapy
Published in Expert Review of Hematology, 2009
Jessica Knight-Perry, Michael R DeBaun, Robert C Strunk, Joshua J Field
Sickle cell disease (SCD) is characterized by recurrent episodes of vaso-occlusion, resulting in tissue ischemia and end-organ damage. Inflammation is critical to the pathogenesis of vaso-occlusion and has been associated with SCD-related morbidity and mortality. Despite the impact of inflammation, no directed anti-inflammatory therapies for the treatment or prevention of vaso-occlusive events currently exist. Among individuals with SCD, asthma is a comorbid inflammatory condition that increases the risk of pain episodes, acute chest syndrome and death. Inflammation associated with asthma could augment the proinflammatory state of SCD, increasing episodes of vaso-occlusion. Leukotrienes are inflammatory mediators that play a prominent role in the pathogenesis of asthma and have been associated with SCD-related morbidity. Targeting inflammatory mediators, such as leukotrienes, is a promising approach for the development of novel therapies for the treatment of SCD. This review will examine the relationship between inflammation and vaso-occlusion, with particular focus on the leukotriene pathway.
Related Knowledge Centers
- Inflammation
- Anaphylaxis
- Hypersensitivity
- Uv
- Eicosanoic Acids
- Arachidonic Acids
- Ltc