Eicosanoids are a diverse group of bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs). They play a crucial role in various physiological and pathological processes, including inflammation, immune response, pain perception, and cardiovascular regulation. Eicosanoids exert their effects locally in a paracrine or autocrine manner. They are derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA), which are omega-6 and omega-3 PUFAs, respectively. The term "eicosanoid" encompasses several subclasses of compounds, including prostaglandins, thromboxanes, leukotrienes, lipoxins, and epoxyeicosatrienoic acids (EETs).
Biosynthesis of Eicosanoids
Eicosanoids are synthesized through the enzymatic oxidation of polyunsaturated fatty acids (PUFAs), primarily arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The key enzymes involved in eicosanoid biosynthesis are cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP) enzymes.
Cyclooxygenase (COX) Pathway
The COX pathway is responsible for the production of prostaglandins (PGs) and thromboxanes (TXs) from AA. This pathway is initiated by the enzyme phospholipase A2 (PLA2), which cleaves AA from the phospholipid membrane. The free AA is then converted into prostaglandin G2 (PGG2) through a series of enzymatic reactions.
The key enzyme in this pathway is cyclooxygenase (COX), also known as prostaglandin-endoperoxide synthase. COX catalyzes the oxygenation of AA to prostaglandin H2 (PGH2). There are two isoforms of COX: COX-1 and COX-2.
COX-1 is constitutively expressed in most tissues and plays a role in maintaining homeostatic functions, such as gastric cytoprotection and platelet aggregation. In contrast, COX-2 is inducible and upregulated during inflammation and other pathological conditions. It is primarily responsible for the production of prostaglandins involved in pain, inflammation, and fever.
PGH2, the common precursor, is further converted into various prostaglandins by specific synthases, such as prostaglandin E synthase (PGES) and prostaglandin F synthase (PGFS). These prostaglandins have diverse functions in the body, including regulation of inflammation, vascular tone, and reproductive processes.
Lipoxygenase (LOX) Pathway
The LOX pathway involves the enzymatic oxidation of AA, EPA, or DHA by lipoxygenase enzymes. LOX enzymes are classified based on their positional specificity of oxygenation on the fatty acid chain. For example, 5-lipoxygenase (5-LOX) primarily acts on AA, while 15-lipoxygenase (15-LOX) acts on both AA and EPA.
In the LOX pathway, the fatty acid is converted into hydroperoxyeicosatetraenoic acids (HPETEs), which serve as intermediates for the synthesis of leukotrienes and lipoxins. 5-LOX converts AA to 5-HPETE, which is further metabolized into leukotriene A4 (LTA4). LTA4 can be enzymatically converted into various leukotrienes, such as leukotriene B4 (LTB4), leukotriene C4 (LTC4), and leukotriene D4 (LTD4).
Leukotrienes are potent mediators of inflammation and immune response. They play important roles in allergic reactions, asthma, and other inflammatory diseases. Lipoxins, on the other hand, are anti-inflammatory in nature and contribute to the resolution of inflammation.
Cytochrome P450 (CYP) Pathway
The CYP route entails the cytochrome P450 enzymes' metabolism of PUFAs, mainly AA. In order to create epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), these enzymes catalyze the oxygenation of AA.
EETs have a significant role in controlling inflammation and vascular tone. They influence blood pressure regulation and have vasodilatory effects. On the other hand, HETEs display a variety of actions based on the particular metabolite and its site of action. While some HETEs have a role in the control of vascular tone and immune response, others have pro-inflammatory characteristics.
The CYP enzymes CYP2C, CYP2J, and CYP2E are in charge of AA metabolism. These enzymes have tissue-specific expression patterns and help produce a variety of eicosanoids that are obtained from CYP.
Eicosanoid biosynthesis and receptor signalling (Dennis et al., 2015).
Metabolism of Eicosanoids
Eicosanoids are rapidly metabolized to ensure the tight control of their signaling and biological activities. Several enzymatic pathways are involved in the metabolism of eicosanoids, including β-oxidation, ω-oxidation, and conjugation with glutathione or glucuronic acid.
β-oxidation is a major pathway responsible for the degradation of eicosanoids. It involves sequential oxidation of the fatty acid chain, leading to the generation of shorter-chain metabolites. This process occurs in peroxisomes and mitochondria and ultimately results in the production of water-soluble metabolites that are easily eliminated from the body.
ω-oxidation is another important pathway involved in the metabolism of eicosanoids. It primarily occurs in the endoplasmic reticulum and involves the oxidation of the terminal carbon of the fatty acid chain. ω-oxidation leads to the formation of dicarboxylic acids, which are further metabolized or excreted.
Conjugation reactions, such as glutathione and glucuronic acid conjugation, play a role in the detoxification and elimination of eicosanoids. These reactions enhance the water solubility of eicosanoids, facilitating their excretion through the urine or bile.
Dysregulated Eicosanoid Signaling and Diseases
Dysregulated eicosanoid signaling has been implicated in a wide range of diseases, contributing to their pathogenesis and progression. Imbalances in the production, metabolism, and signaling of eicosanoids can have profound effects on cellular processes, inflammation, immune responses, and tissue homeostasis. Here, we delve into the details of some key diseases associated with dysregulated eicosanoid signaling:
Inflammatory Disorders
Inflammatory illnesses such as rheumatoid arthritis, inflammatory bowel disease (IBD), and asthma are all caused by dysregulated eicosanoid signaling. Pro-inflammatory eicosanoids, particularly prostaglandins and leukotrienes, are overproduced in certain circumstances.
The COX pathway produces prostaglandins, which enhance inflammation by producing vasodilation, increasing vascular permeability, and drawing inflammatory cells to the site of inflammation. Prostaglandins like PGE2 and PGD2 have been related to the pathogenesis of rheumatoid arthritis and IBD, respectively, through contributing to joint deterioration and intestinal inflammation.
Leukotrienes, derived from the LOX pathway, are potent mediators of inflammation and immune responses. Leukotriene B4 (LTB4) is a chemoattractant for immune cells, promoting their recruitment to inflamed tissues. Cysteinyl leukotrienes, including leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4), contribute to airway inflammation, bronchoconstriction, and mucus production in asthma.
Therapeutics targeting eicosanoid pathways (Dennis et al., 2015).
Cardiovascular Diseases
Eicosanoids play a significant role in cardiovascular physiology and are involved in the development and progression of cardiovascular diseases such as atherosclerosis, hypertension, and thrombosis.
Prostaglandins, particularly prostacyclin (PGI2) and thromboxane A2 (TXA2), have opposing effects on platelet aggregation and vascular tone. PGI2 is a potent vasodilator and inhibitor of platelet aggregation, while TXA2 promotes vasoconstriction and platelet activation. Imbalances in the levels of these eicosanoids can disrupt vascular homeostasis and contribute to the development of atherosclerosis and thrombosis.
Furthermore, the dysregulation of other eicosanoids, such as leukotrienes, can also influence cardiovascular health. Leukotrienes, especially LTB4 and cysteinyl leukotrienes, have been implicated in promoting inflammation, vascular remodeling, and atherogenesis.
Cancer
Eicosanoid signaling that is dysregulated can encourage angiogenesis, immune evasion, tumor growth, and metastatic spread. Prostaglandins, notably PGE2, have been linked to immunological suppression, angiogenesis, and tumor cell growth. PGE2 works by attaching to immune cells' and tumor cells' EP receptors, which activates signaling pathways that promote the survival and growth of tumors. By encouraging tumor cell invasion, migration, and angiogenesis, leukotrienes, particularly LTB4, also advance malignancy. In order to encourage tumor growth and metastasis, LTB4 increases the recruitment of immune cells to the tumor microenvironment, such as neutrophils and macrophages.
Cell-specific production of eicosanoids in the tumor microenvironment (Johnson et al., 2020)
MS-Based Eicosanoid Analysis
Mass spectrometry (MS) has revolutionized the field of lipidomics, enabling the sensitive and accurate analysis of eicosanoids. MS-based approaches allow for the identification, quantification, and structural characterization of eicosanoids, providing valuable insights into their roles in health and disease.
Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is commonly employed for eicosanoid analysis. It offers high sensitivity, selectivity, and the ability to analyze multiple eicosanoids simultaneously. Isotope-labeled internal standards are used for quantification, ensuring accurate measurements of eicosanoid concentrations.
Advanced MS techniques, such as high-resolution mass spectrometry (HRMS) and imaging mass spectrometry (IMS), further expand the capabilities of eicosanoid analysis. HRMS enables the identification of unknown eicosanoids and the elucidation of their structures. IMS allows for the spatial visualization of eicosanoid distribution within tissues, providing valuable insights into their localizations and roles in specific physiological processes or disease states.
MS-based eicosanoid analysis facilitates the discovery of novel eicosanoids, the investigation of their biosynthesis and metabolism, and the assessment of their perturbations in various diseases. It serves as a powerful tool for researchers and clinicians aiming to understand the complex interplay of eicosanoids and develop targeted interventions for eicosanoid-related disorders.
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References
- Mosaad, Eman, et al. "The role (s) of eicosanoids and exosomes in human parturition." Frontiers in Physiology 11 (2020): 594313.
- Dennis, Edward A., and Paul C. Norris. "Eicosanoid storm in infection and inflammation." Nature Reviews Immunology 15.8 (2015): 511-523.
- Johnson, Amber M., Emily K. Kleczko, and Raphael A. Nemenoff. "Eicosanoids in cancer: new roles in immunoregulation." Frontiers in pharmacology 11 (2020): 595498.
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