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Eicosanoids

Eicosanoids are cell-signaling molecules produced from arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs). With the action of phospholipase A2 Phospholipase A2 Phospholipases that hydrolyze the Acyl group attached to the 2-position of phosphoglycerides. Nephrotic Syndrome, arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) is released from the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin ( PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. The LTs and LXs are products of the lipoxygenase (LOX) pathway. The remaining eicosanoids are produced from the cyclooxygenase Cyclooxygenase Nonsteroidal Antiinflammatory Drugs (NSAIDs) (COX) pathway, which involves 2 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, COX-1 and COX-2. Eicosanoids are involved in various physiological and pathological processes. Thromboxanes cause platelet aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies and are potent vasoconstrictors. Leukotrienes mediate allergic responses, while LXs have anti-inflammatory activities. Principal actions of PGs include vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs, smooth muscle contraction Smooth muscle contraction Smooth muscle is primarily found in the walls of hollow structures and some visceral organs, including the walls of the vasculature, GI, respiratory, and genitourinary tracts. Smooth muscle contracts more slowly and is regulated differently than skeletal muscle. Smooth muscle can be stimulated by nerve impulses, hormones, metabolic factors (like pH, CO2 or O2 levels), its own intrinsic pacemaker ability, or even mechanical stretch. Smooth Muscle Contraction, and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation. Prostacyclin, a member of the PG family, has a potent vasodilatory effect. Both biologic actions and inhibitions of eicosanoids are mechanisms used in pharmacologic agents for various medical conditions and desired clinical effects.

Last updated: Oct 17, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Eicosanoids

  • Cell-signaling molecules
  • Produced from arachidonic acid (an abundant 20-carbon polyunsaturated fatty acid released from the plasma membrane through the activity of phospholipase A2)
  • Major families of eicosanoids: 
    • Prostanoids:
      • Thromboxanes (TXA2s)
      • Prostaglandins (PGs)
      • Prostacyclin (PGI2)
    • Leukotrienes (LTs) and lipoxins (LXs)
  • Receptor names: Receptor classification system uses the distinguishing letter of the prostanoid (e.g., “E” in prostaglandin E) and combines it with the letter “P” for prostanoid. (e.g., PGE has EP EP Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy  receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors). Subscript numerals represent the subtypes (e.g., PGE2 EP EP Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy2). 

Biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology

  • Eicosanoids are typically not stored within cells.
  • Synthesis Synthesis Polymerase Chain Reaction (PCR) is on-demand and is affected by physical, chemical, and hormonal stimuli.
  • With proper stimuli, specific pathways are triggered to produce different eicosanoid families.
  • Stimuli → phospholipases activated → arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) is released
  • Arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) is metabolized by different enzyme pathways:
    • LOX → LT and LX
    • COX → cyclization to PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis2, PG, or TXA2
      • COX-1: enzyme constitutively expressed in many tissues
      • COX-2: enzyme induced by pro-inflammatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response and found in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, kidney, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types, and female reproductive system
Schematic overview of eicosanoids biosynthesis

Schematic overview of eicosanoid biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology:
Arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) released from membrane phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism by cytosolic phospholipase A2 Phospholipase A2 Phospholipases that hydrolyze the Acyl group attached to the 2-position of phosphoglycerides. Nephrotic Syndrome can be enzymatically converted either to prostaglandins (PGs) and thromboxane (TXA2) by COX enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes or to leukotrienes (LTs) and lipoxins (LXA4s) by lipoxygenases (LOXs).
5-LOX: 5-lipoxygenase
12/15-LOX: 12/15-lipoxygenase
LTC4S: LTC4 synthase
PGIS: PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis or prostacyclin synthase
PGDS: PGD PGD Determination of the nature of a pathological condition or disease in the ovum; zygote; or blastocyst prior to implantation. Cytogenetic analysis is performed to determine the presence or absence of genetic disease. Reproductive Ethical Issues2 synthase
PGFS: PGF synthase
PGES: PGE synthase
TXAS: TXA2 synthase

Image: “Schematic overview of eicosanoid biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology” by Debeuf N et al AL Amyloidosis. License: CC BY 4.0

Thromboxanes

Description

  • Metabolite of arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) synthesized in platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology 
  • Generated through the following process:
    • Arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) → prostaglandin H2 (PGH2) via enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes COX-1/COX-2 
    • TXA2 is predominantly COX-1 derived.
    • PGH2→ TXA2 via the action of TXA2 synthase (TXAS) 
  • Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: TPɑ and β (expressed in different tissues and cells including platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology, vascular endothelial cells, lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy, heart, thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy)

Effects

  • Activates phospholipase A2 Phospholipase A2 Phospholipases that hydrolyze the Acyl group attached to the 2-position of phosphoglycerides. Nephrotic Syndrome
  • Platelet activation Platelet activation A series of progressive, overlapping events, triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. Hemostasis:
  • Vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure

Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability

Inflammatory effects of TXA2 in some conditions:

  • Thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus:
    • Increased levels of TXA2 are noted in injury and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation.
    • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology activation, aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies, and vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
    • Conditions related to thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus:
      • Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction and angina
      • Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
  • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma: TXA2 is related to bronchoconstriction and airway Airway ABCDE Assessment remodeling.

Prostaglandins

Description

  • Produced from arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) via COX:
    • Basal amounts of PGs are produced through the action of COX-1.
    • Mediators (e.g., cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response) induce the COX-2 isoform → ↑ PG production
  • Arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) → PGH2 (common substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes for TXA2 and PGs)
  • From PGH2, different enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes produce varying PGs:
    • Names of PGs are based on structural features, coded by a letter (e.g., PGD PGD Determination of the nature of a pathological condition or disease in the ovum; zygote; or blastocyst prior to implantation. Cytogenetic analysis is performed to determine the presence or absence of genetic disease. Reproductive Ethical Issues, PGE, PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis).
    • Subscript numeral indicates the number of double bonds (e.g., PGE1, PGE2).
  • Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Prostaglandin E (PGE): E-type prostanoid ( EP EP Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy) 1–4 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Prostaglandin D2 ( PGD PGD Determination of the nature of a pathological condition or disease in the ovum; zygote; or blastocyst prior to implantation. Cytogenetic analysis is performed to determine the presence or absence of genetic disease. Reproductive Ethical Issues2): D-type prostanoid (DP) 1 and 2 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Prostaglandin F2ɑ (PGF2ɑ): F-type prostanoid ( FP FP An FP test result indicates that a person has the disease when they do not. Epidemiological Values of Diagnostic Tests) receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis2: I-type prostanoid (IP) receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Effects

Table: Effects of prostaglandins
Prostaglandins Effects
PGD PGD Determination of the nature of a pathological condition or disease in the ovum; zygote; or blastocyst prior to implantation. Cytogenetic analysis is performed to determine the presence or absence of genetic disease. Reproductive Ethical Issues2 (made predominantly by mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation)
PGE1
PGE2
  • Vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
  • Uterine contraction (↑ tone in low concentrations)
PGF2ɑ
  • Uterine contraction (↑ tone)
  • Relaxation of ciliary muscle
PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis2 (produced by vascular wall endothelial cells)
  • Vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • Inhibitor of platelet aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies
  • Potentiates effects (↑ permeability and chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1) of other mediators

Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability

With multiple biologic effects, several PGs have clinical uses:

  • PGE1 ( alprostadil Alprostadil Coarctation of the Aorta) has smooth muscle relaxing effects utilized in:
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction 
    • Preventing closure of patent ductus arteriosus Ductus arteriosus A fetal blood vessel connecting the pulmonary artery with the descending aorta. Patent Ductus Arteriosus (PDA) in neonates with congenital Congenital Chorioretinitis heart disease awaiting corrective cardiac surgery Cardiac surgery Cardiac surgery is the surgical management of cardiac abnormalities and of the great vessels of the thorax. In general terms, surgical intervention of the heart is performed to directly restore adequate pump function, correct inherent structural issues, and reestablish proper blood supply via the coronary circulation. Cardiac Surgery
  • PGE1 (misoprostol):
    • Cytoprotective effect used in preventing peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease
    • Labor induction 
    • Termination of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (combined with mifepristone Mifepristone A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary Cushing syndrome. Antiprogestins and Selective Progesterone Modulators (RU-486))
    • Side effect: diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • PGE2 (dinoprostone):
    •  Labor induction (cervical ripening)
    • Termination of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • PGF2α:
    • Carboprost (PGF2α analog)
      • Termination of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
      • Oxytocic effect used in refractory postpartum hemorrhage Postpartum hemorrhage Postpartum hemorrhage is one of the most common and deadly obstetric complications. Since 2017, postpartum hemorrhage has been defined as blood loss greater than 1,000 mL for both cesarean and vaginal deliveries, or excessive blood loss with signs of hemodynamic instability. Postpartum Hemorrhage
    • Latanoprost (topically active PGF2α analog): ↓ intraocular pressure Intraocular Pressure The pressure of the fluids in the eye. Ophthalmic Exam in open-angle glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma or ocular hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis2 (with powerful vasodilating effect): Epoprostenol Epoprostenol A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Hemostasis, treprostinil Treprostinil Pulmonary Hypertension Drugs, iloprost Iloprost An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. Pulmonary Hypertension Drugs are used for pulmonary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension.

Leukotrienes and Lipoxins

Description

  • End-products of the LOX pathway
  • Arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) is converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by 5-LOX:
    • 5-HPETE → 5-hydroxyeicosatetraenoic acid (5-HETE) → leukotriene Leukotriene Asthma Drugs A4 (LTA4)
    • By the action of LOX, LTA4 is converted to LTB4, cysteinyl LTs (LTC4, LTD4, LTE4) or LX.
    • In some cells utilizing different LOX pathways, arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) can be converted to LXs without conversion to LTA4.
  • Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Cysteinyl leukotrienes: CysLT receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • LTB4: leukotriene Leukotriene Asthma Drugs B (BLT) receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Effects

Leukotrienes mediate allergic and inflammatory responses with release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology stimulated by allergens.

Table: Effects of eicosanoids
Eicosanoids Effects
LTC4, LTD4, LTE4
LTB4 (and HETE)
LXs A4 and B4
  • Anti-inflammatory
  • Inhibit leukocyte adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies and chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1

Clinical correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability

Leukotrienes are released from cells and their Inflammatory effects are seen in asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma and allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency.

  • Cysteinyl LTs:
    • Formed from eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation and mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation, which are commonly associated with asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
    • ↑ Mucus production
    • Bronchoconstriction ( smooth muscle contraction Smooth muscle contraction Smooth muscle is primarily found in the walls of hollow structures and some visceral organs, including the walls of the vasculature, GI, respiratory, and genitourinary tracts. Smooth muscle contracts more slowly and is regulated differently than skeletal muscle. Smooth muscle can be stimulated by nerve impulses, hormones, metabolic factors (like pH, CO2 or O2 levels), its own intrinsic pacemaker ability, or even mechanical stretch. Smooth Muscle Contraction)
  • While less well-defined in asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma, LTB4 is a chemoattractant for both neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation.

Inhibitors of the Arachidonic Pathway

Inhibition of the pathways, which reduces the production of eicosanoids, also has clinical uses.

  • Corticosteroids Corticosteroids Chorioretinitis: exert anti-inflammatory effects by inhibiting phospholipase A2 Phospholipase A2 Phospholipases that hydrolyze the Acyl group attached to the 2-position of phosphoglycerides. Nephrotic Syndrome, blocking the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
  • Non-selective COX inhibitors: 
    • ↓ Eicosanoid synthesis Synthesis Polymerase Chain Reaction (PCR) → ↓ pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation 
    • Interferes with gastroduodenal protection (which occurs through COX-1)
    • + Risk of bleeding (due to inhibition of thromboxane synthesis Synthesis Polymerase Chain Reaction (PCR) → ↓ platelet aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies)
    • Include:
      • NSAIDs NSAIDS Primary vs Secondary Headaches: reversibly bind BIND Hyperbilirubinemia of the Newborn COX 
      • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs): irreversibly binds COX and is used against vascular thrombotic events due to its role in reducing TXA2 
    • COX-2 inhibitors:
      • Minimal platelet effects (as the TXA2 pathway is not affected)
      • Fewer GI complications compared with non-selective COX inhibitors
  • LT receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonists
    • Inhibit leukotriene Leukotriene Asthma Drugs (LT) D4 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and LTE4 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Zafirlukast Zafirlukast Asthma Drugs, montelukast Montelukast Asthma Drugs 
    • Used in exercised-induced bronchospasm Bronchospasm Asthma Drugs, asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma, and allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency
  • LT synthesis Synthesis Polymerase Chain Reaction (PCR) inhibitor or 5-LOX inhibitor ( zileuton Zileuton Asthma Drugs)
    • Selective inhibition of 5-LOX (thus preventing conversion of  arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) to LTs)
    • Used in exercised-induced bronchospasm Bronchospasm Asthma Drugs, asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma, and allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency

References

  1. Botham K. M., & Mayes P. A. (2018). Biosynthesis of fatty acids & eicosanoids. Harper’s Illustrated Biochemistry, 31e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2386&sectionid=187837307
  2. Chandrasekharan, J. A., & Sharma-Walia, N. (2015). Lipoxins: nature’s way to resolve inflammation. Journal of inflammation research, 8, 181–192. https://doi.org/10.2147/JIR.S90380
  3. Chung, K., Barnes, P. (2009). Mediator Antagonists. Asthma and COPD (Second Edition, pp.655–662), Academic Press. https://doi.org/10.1016/B978-0-12-374001-4.00052-3
  4. Goodman, S. (2021). General Modes of Intercellular Signaling. Goodman’s Medical Cell Biology (Fourth Edition, Pages 249-270), Academic Press. https://doi.org/10.1016/B978-0-12-817927-7.00008-9
  5. Kumar, V., Abbas, A., Aster, J. (2021). Robbins and Cotran Pathologic Basis of Disease (10th edition, pp. 86–88). Elsevier, Inc.
  6. Malik, K., Dua, A. (2021). Prostaglandins. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK553155/
  7. Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis, thrombosis, and vascular biology, 31(5), 986–1000. https://doi.org/10.1161/ATVBAHA.110.207449
  8. Rucker, D., Dhamoon, A. S. (2020). Physiology, Thromboxane A2. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK539817/
  9. Trevor A. J., & Katzung B. G., & Kruidering-Hall M. (2015). Prostaglandins & other eicosanoids. Katzung & Trevor’s Pharmacology: Examination & Board Review, 11e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1568&sectionid=95702090
  10. Undas, A., Brummel-Ziedins, K. E., & Mann, K. G. (2007). Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood, 109(6), 2285–2292. https://doi.org/10.1182/blood-2006-01-010645
  11. Yui, K., Imataka, G., Nakamura, H., Ohara, N., & Naito, Y. (2015). Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders. Current neuropharmacology, 13(6), 776–785. https://doi.org/10.2174/1570159×13666151102103305

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