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30 Cards in this Set
- Front
- Back
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What is Arachidonic Acid synthesized from?
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Essential Fatty Acid Linoleic Acid
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How is Aracidonic Acid released from cellular phospholipids?
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Phospholipase A2
This is the first step in the arachidonic acid cascade and is the overall rate-determining step. |
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What acts to stimulate Phospholipase A2?
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Cytokines such as TNF-alpha, GM-CSF, IFN-gamma,
Growth Factors such as EGF and MAP Kinase Protein C |
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What are the actions of GC's on inhibiting inflammation?
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They induce the synthesis of Lipocortins, a group of proteins that mediate Phospholipase A2.
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Once arachidonic acid is synthesized from linoleic acid via Phospholipase A2, what are the 3 enzyme based pathways and the products of each pathway?
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Cyclooxygenase pathway produces prostaglandins, prostacyclins, and thromboxane
Lipooxygenase pathway produces Leukotrienes and Lipoxins Cytochrome P450 epoxygenase pathway produces epoxyeicosatetraenoic acids |
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COX 1 and COX 2 are needed for these two preliminary conversions.
What activity is unique to each conversion? |
Arachidonic Acid to PGG2
PGG2 to PGH2 The first conversion is due to cyclooxygenase activity, where the second conversion is due to peroxidase activity. |
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What are the 3 main activities of COX1 ?
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Vascular Homeostasis
Renal and GI function (blood flow etc) Platelet Function and antithrombogenesis |
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What are the 5 main activities of COX 2?
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Inflammation, Fever, Pain
Mitogenesis in the GI Renal Adaptation to stresses Deposition of trabecular bone Ovulation, Uterine contraction |
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PGH-2 is considered the critical juncture, because it is the precursor to PGD2, PGE2, PGF2, thromboxane A2 and prostacyclin PGI2
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Prostaglandins have major functions in inflammation and pain as well as a cytoprotective role as vital organs are shielded from ischemia by vasodilation via prostaglandins.
NSAIDs and COX-2 inhibitors are the main drugs that modulate prostaglandins |
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What are the two main effects of Thomboxane A 2
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The chief eicosanoid product of platelets
Vasoconstrictor Platelet adhesion and aggregation |
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What are the two main functions of prostacyclin PGI2?
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Primary eicosanoid of vascular endothelium
Vasodilator (cytoprotective) Inhibitor of platelet aggregation |
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Thromboxane is a relatively stronger vasoconstrictor and platelet activator than PGI2 is a vasodilator and platelet inhibitor. Therefore, imbalances can lead to hypertension, ischemia, thrombosis, MI and stroke.
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In northern latitudes, the incidence of heart disease, stroke and thromboembolic disorders is less. These populations eat a larger portion of fish oils, which contain a smaller portion of arachidonic acid precursors and a great deal of EPA. EPA is converted into Thromboxane A3 and prostacyclin I3, not A 2 and I 2. PGI3 is a stronger vasodilator and platelet inhibitor than TXA3 is a vasoconstrictor and platelet activator.
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Lipooxygenases catalyze the conversion of AA to Leukotrienes and Lipoxins.
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There are 3 major isoforms (5,12,15). They are based upon the portion of AA that they insert an oxygen.
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Describe the Lipooxygenase pathway, the enzymes, the products and what needs to occur for its completion.
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5 - LOX (lipooxygenase 5) needs to be translocated to the nuclear membrane for activity. It then converts AA to HPETEs. HPETEs are then reduced to HETEs by GSP (glutathione peroxidase). HPETE is a precursor for the main Leukotriene precursor LTA4. LTA4 is a precursor for all the leukotrienes, as well as a precursor with HETEs for the lipoxins
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To review, what conversions are lipooxygenases involved in?
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AA to HPETE
HPETE to LTA-4 AA to HETE (which is then converted to lipoxins) HPETE to LTA-4 (which is then converted to lipoxins) |
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Once LTA-4 is made, what two leukotrienes can it be converted to?
Where does this occur? What enzymes are involved? |
LTB-4 - via LTA-4 hydrolase. Occurs in neutrophils and erythrocytes
LTC-4 - via LTC-4 synthase. Occurs in mast cells, eosinophils, basophils and macrophages. |
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What is the role of LTB-4?
What receptors does it bind? |
Acts via BLT-1 and BLT-2 receptors.
Binding to BLT-1 leads to pro-inflammatory consequences and up-regulates neutrophil lysosomal function and free radical production, as well as cytokine production. It also potentiates the actions of NK cells. The role of BLT-2 is unknown. |
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LTC-4 can be converted to LTD-4, LTE-4, LTF-4. What is the role of LTC-4? What receptors does it bind?
What are these molecules responsible for? |
CysLT-1 to cause vasoconstriction, bronchospasm and increased vascular permeability.
Asthma, allergic and hypersensitivity processes |
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What are the two main lipoxins?
What are the two main functions of these lipoxins? |
LXA-4
LXB-4 (1) They modulate the actions of leukotrienes (2) They are important in the resolution of inflammation. It is suggested that they may be counter-regulatory signals of leukotriene action. |
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Name the 5 inflammatory related functions of lipoxins.
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(1) They inhibit neutrophil chemotaxis
(2) They inhibit eosinophil recruitment (3) Inhibit the function of NK cells (4) They inhibit LTB-4 inflammatory effects (5) Mediate the resolution of the inflammatory response |
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Name the 2 vascular related functions of lipoxins.
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(1) They stimulate vasodilation
(2) They inhibit LTC-4 and LTD-4 induced vasoconstriction |
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Cytochrome P450 epoxygenases oxygenate AA to for EET (epoxyeicosatetraenoic acid). What are the 3 main effects of these compounds?
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(1) Modulates vascular tone by inhibiting the Na-K-ATPase in VSMC
(2) Modulates renal function by regulating ion absorption and secretion. (3) They inhibit platelet cyclooxygenases and ICAM expression. |
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How are isoprostanes made?
Name the 2 isoforms. |
Peroxidation of aa
8-epi-PGF-2 alpha 8-epi-PGF-2 |
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How are Prostaglandins, leukotrienes, thromboxanes and lipoxins inactivated?
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Hydroxylation
Beta oxidation Mu oxidation This renders them more hydrophilic and excretable in the urine |
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Describe Transcellular biosynthesis between Platelets, Leukocytes and Endothelial cells.
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Leukocytes obtain AA from EC's and Platelets
Leukocytes use AA to make LTA-4, which they then use to make LTB-4. LTA-4 moves into platelets and EC's EC's use it to make LTC-4 Platelets use it to make LTC-4 as well as LXA-4, LXB-4. |
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Describe what is going on in asthma.
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Allergens stimulate cytokine cascades
LTB-4 and cysteinyl LTC-4, LTD-4 and LTE-4 are involved. LTB-4 = attracts inflammatory cells, activates B-cells and promote the expression of the FC-epsilon-RII receptor on mast cells and basophils which bind IgE released by B-cells LTC-4 and LTD-4 are extremely bronchoconstrictive, cause mucus secretion and inhibit mucus clearing LTD-4 and LTE-4 recruit eosinophils that damage the epithelium. |
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What is the common factor in both UC and CD, the two subgroups of IBD?
What seems to be an effective treatment for these conditions in mouse models? |
Elevated LTB-4 allowing increased infiltration of leukocytes into the parenchyma. This leads to progressive damage.
LXA-4 |
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What causes Rheumatoid Arthritis?
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Chronic, systemic, autoimmune, inflammatory disease primarily attacking the joints but also the skin, CVS, lungs and muscles.
Caused by local release of cytokines, TNF, GFs, and IL's. These all act to induce COX-2 and PGE-2 and pro-inflammatory cells are recruited. Macrophages elaborate collagenases and proteases |
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Describe what generally takes place in glomerularnephritis.
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Complement activation promotes neutrophil and macrophage infiltration.
Leukotrienes are released causing inflammation and vasoconstriction leading to decreased renal blood flow and GFR. |
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What is the potential mechanism for eicosanoids association with cancer?
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Excessive COX-2 produces eicosanoids that flood the RXR (retinoic acid receptor) and provide excessive growth stimuli.
COX-2 inhibitors are associated with reduced colorectal cancer. |
