Block 3 - Bsf: Eicosanoids And Platelet Aggregation

Front 1

How many carbons are in eicosanoids?

Back 1

20 (“eicosa” Greek for 20)

Front 2

What are eicosanoids primarily produced from?

Back 2

Arachidonic acid

Front 3

T/F

Eicosanoids are local mediators that act where synthesized or in adjacent cells.

Back 3

True!

Front 4

T/F

Eicosanoids are transported in the blood.

Back 4

False!

Unlike hormones, they are not transported in the blood

Front 5

What are the 3 classes of eicosanoids?

Back 5

Prostaglandins, leukotrienes and lipoxins.

Front 6

T/F

Eicosanoids exert control over only a few physiological processes.

Back 6

False!

They exert control over a wide range of physiological processes.

Front 7

Many of the effects of eicosanoids are mediated by what (2 answers)?

Back 7

Cyclic AMP or calcium second messengers

Front 8

Name the 20-carbon ω-6 FA.

Back 8

Arachidonic acid (AA)

Front 9

Most arachidonic acid (AA) in the human body is synthesized from what?

Back 9

Dietary linoleic acid (essential FA, 18:3 ω-6)

Front 10

What is linoleic FA present in?

Back 10

Vegetable oils and animal fats

Front 11

When does arachidonic acid become essential?

Back 11

If linoleic FA is absent from the diet.

Front 12

What enzyme frees arachidonic acid from phospholipid molecule?

Back 12

Phospholipase A2

Front 13

alpha-Linolenic acid (ALA) is a omega-____ fatty acid.

Back 13

3

Front 14

Which is more stable: alpha-linolenic acid (ALA) or linoleic acid?

Back 14

Linoleic acid (omega-6 more stable than omega-3)

Front 15

Which FA is converted in the body to EPA (eicosapentaenoic acid) then to DHA (docosahexaenoic acid)?

Back 15

alpha-Linolenic acid (ALA)

Front 16

What are some dietary sources of linoleic acid (LA)?

Back 16

Seed oils, lard, and egg yolk.

Front 17

What are some dietary sources of alpha-linolenic acid (ALA)?

Back 17

Seed oils and green leafs.

Front 18

What are some dietary sources of EPA and DHA?

Back 18

Cold water oily fish and breast milk.

Front 19

Which metabolites are more inflammatory: metabolites of omega-6 FAs or omega-3 FAs?

Back 19

Metabolites of omega-6 FAs

Front 20

What is the range for the healthy ratios of omega6/omega3?

What types of oil have a healthy ratio in this this range?

Back 20

From 1:1 to 4:1

Canola and sometimes olive oil.

Front 21

What factors can activate phospholipase A2?

Back 21

Mechanical trauma, histamine, cytokines, and growth factors.

Front 22

What factors can inhibit phospholipase A2?

Back 22

Anti-inflammatories, glucocorticoids, and cortisone.

Front 23

T/F

Glucocorticoids' effect on phospholipase A2 will cause release of arachidonic acid from membrane lipids.

Back 23

False!

This would actually inhibit phospholipase A2, thereby inhibiting release of AA from lipids.

Front 24

What are the enzymes in the 3 pathways that free arachidonic acid is converted to eicosanoids?

Back 24

COX isozymes (constitutive COX-1 and inducible COX-2)

LOX enzymes (5-LO, 12-LO, 15-LO)

P-450 epoxygenase

Front 25

a) Which enzyme(s) catalyze(s) the formation of PGH2?

b) Then, cell-specific PG synthases convert PGH2 to what compounds?

Back 25

a) COX isozymes (constitutive COX-1 and inducible COX-2)

b) Prostaglandins, prostacyclin and thromboxanes.

Front 26

Which enzyme(s) catalyze(s) the formation of:
a) LTs
b) 12-HETEs
c) Lipoxins (LXs)

Back 26

LOX enzymes
a) 5-LO
b) 12-LO
c) 15-LO

Front 27

Which enzyme(s) catalyze(s) the formation of hydroxyeicosatetraenoic acids (HETEs) and epoxides?

Back 27

P-450 epoxygenase

Front 28

What is the longest amino acids that the body can synthesize?

Back 28

Palmitate (16 carbons)

Front 29

Prostaglandins can be produced from ___(how many?)____ different precursors, but the major pathway uses what as a precursor?

Back 29

3

Arachidonic acid

Front 30

a) In the synthesis of prostoglandins and thromboxanes from arachidonic acid, what enzyme is the inital step (AA --> PGG2) catalyzed by?

b) What change is occuring at this step? (think organic chem)

c) The next step is ______-specific.

Back 30

a) Cyclo-oxygenase

b) Hydroperoxy group is reduced to hydroxyl group

c) Tissue

Front 31

Which prostaglandin is involved in vasodilation and platelet declumping?

Back 31

PGI2

Front 32

What are the actions of TxA2.

Back 32

Vasoconstriction, platelet aggregation, lymphocyte proliferation, and bronchoconstriction.

Front 33

Which prostaglandin is involved in uterine smooth muscle contraction and parturition, and also increases vasoconstriction, bronchoconstriction, and smooth muscle contraction?

Back 33

PGF2a

Front 34

Which prostaglandin is involved in chemotaxis (Th2 lymphocytes) and allergic asthma (lung epithelial cell)?

Back 34

PGD2

Front 35

Which prostaglandin is involved in bone resorption (osteoclasts), fever generation (neurons of OVLT in POA), maturation for ovulation and fertilization (ovarian CO cells), and pain response (spinal neurons)?

Back 35

PGE2

Front 36

NSAIDs inhibit what enzymes?

Back 36

Cyclooxygenases

Front 37

Aspirin is a(n) (reversible/irreversible) inhibitor of COX-1 and COX-2.

Back 37

Irreversible

Front 38

T/F

Platelets are able to produce cyclooxygenases de novo.

Back 38

False!

Platelets cannot produce cyclooxygenases de novo.

Front 39

____________ of the active site of COX-2 changes its catalytic activity.

Back 39

Acetylation

Front 40

When COX-2 is modified by acetylation, it converts arachidonic acid to what?

Back 40

15R-HETE

Front 41

What enzyme converts 15R-HETE to LXA4 and LXB4?

Back 41

Leukocyte 5-LOX

Front 42

Aspirin inhibits the production of (pro/anti)-inflammatory eicosanoids, but stimulates synthesis of (pro/anti)-inflammatory eicosanoids.

Back 42

Anti, pro

Front 43

Acetaminophen and ibuprofen are (reversible/irreversible) inhibitors of COX-1 and COX-2.

Back 43

Reversible

Front 44

Salicylate is the same thing as:

Back 44

Aspirin
(Excedrin, Alka-Seltzer)

Front 45

Para-aminophenol is the same thing as:

Back 45

Acetaminophen
(Tylenol)

Front 46

Aryl-proprionic acid is the same thing as:

Back 46

Ibuprofen (Advil, Motrin)

Naproxen (Aleve)

Front 47

What effect does aspirin have on COX-1?

Back 47

Reduces platelet aggregation (TxA2).

Front 48

What effect does aspirin have on COX-2?

Back 48

Reduces inflammation.

Front 49

What is a side effect due to COX-1 inhibition?

Back 49

Stomach irritation

Because the prostaglandins produced in COX-1 pathway are important in production of gastric acid and gastric mucosa (overproduction of gastric acid, higher acidity, irritation)

Front 50

What are a couple examples of specific COX-2 inhibitors?

Back 50

Celebrex/Vioxx

Front 51

What is the benefit to celebrex/vioxx over aspirin?

Back 51

They target the inflammatory response, but there is no COX-1 inhibition to produce aspirin-induced side effects (stomach irritation).

Front 52

PGI2, PGE2, and PGD2 (decrease/increase) vasodilation and cAMP while they (decrease/increase) platelet aggregation, leukocyte aggregation, IL-1 and IL-2, T-cell proliferation, and lymphocyte migration.

Back 52

Increase, decrease

Front 53

Prostaglandins and thromboxanes are inactivated (slowly/rapidly).

Back 53

Rapidly

Half-lives range from seconds to minutes.

Front 54

a) What are prostaglandins inactivated by (2 things)?

b) What gets excreted in the urine?

Back 54

a) Oxidation of 15-hydroxyl group to a ketone
Reduction of double bond at carbon 13

b) Subsequent beta- and omega-oxidation of nonring portion results in dicarboxylic acid excreted in urine?

Front 55

TxA2 is metabolized to what by cleavage of the oxygen bridge between carbons 9 and 11?

Back 55

TxB2

TxB2 does not have any biological activity.

Front 56

a) Which prostaglandin or thromboxane causes platelet aggregation and vasoconstriction?

b) It is converted in the _________ via ___________.

Back 56

a) TXA2 (Thrombus)

b) Platelets, thromboxane synthase

Front 57

a) Which prostaglandin or thromboxane is involved with sleep?

b) It is converted from PGH2 in the ___________ via _________.

Back 57

a) PGD2 (Drowsy)

b) CNS, mast and fat cells; isomerase

Front 58

a) Which prostaglandin or thromboxane is involved with wakefulness, pain, fever, inflammation, and renal arteriolar dilation?

b) It is converted from PGH2 in _________ via __________.

Back 58

a) PGE2 (Eye opener)

b) Many cells, isomerase

Front 59

a) Which prostaglandin or thromboxane is involved with platelet disaggregation, vasodilation, and decreased stomach acid secretion?

b) It is converted from PGH2 in ____________ via _________.

Back 59

a) PGI2 (Inhibits aggregation)

b) Endothelial cells, prostacyclin synthase

Front 60

a) Which prostaglandin or thromboxane is involved with labor induction?

b) It is converted from _______ via __________.

Back 60

a) PGF2a (Fetus)

b) PGE2, reductase

Front 61

Which prostaglandin that we learned is the only one that isn't converted directly from PGH2?

Back 61

PGF2a

Front 62

Which prostaglandin or thromboxane is the central intermediate?

Back 62

PGH2 (Head of pathway)

Front 63

What are the fatty compounds the contribute to the inflammatory response in asthma?

Back 63

Leukotrienes

Front 64

Leukotrienes contain what typical structure?

Back 64

Triene structure - three double bonds in series

Front 65

a) What are formed by the incorporation of an O2 molecule onto a carbon of a double bond of arachidonic acid?

b) This results in formation of a ______________ group and rearrangement of the ______________.

Back 65

a) HPETEs and HETEs

b) Hydroperoxy, double bond

Front 66

Lipoxygenases can act on which carbons of arachidonic acid?

Back 66

5, 12, or 15

Front 67

What lipoxygenase is found in polymorphonuclear leukocytes?

Back 67

5-lipoxygenase

Front 68

What lipoxygenase is found in platelets?

Back 68

12-lipoxygenase

Front 69

What lipoxygenase is found in eosinophilic leukocytes?

Back 69

15-lipoxygenase

Front 70

What is occuring (think o chem) in the conversion of HPETE to HETE?

Back 70

The unstable hydroperoxy group is being converted to a more stable hydroxyl group.

Front 71

Which enzyme produces the major leukotrienes?

Back 71

5-lipoxygenase

Front 72

Which leukotrienes is 5-HPETE converted to? And where?

Back 72

To LTA4, which can then be converted to LTC4 or LTB4.
In leukocytes and mast cells

Front 73

What does zyflo inhibit?

Back 73

5-lipoxygenase, and therefore leukotriene synthesis

Front 74

Which leukotriene(s) increase(s) vascular permeability, T-cell proliferation, lymphocyte aggregation, INF-y, IL-1 and IL-2?

Back 74

LTB4

Front 75

Which leukotriene(s) increase(s) bronchoconstriction, vascular permeability, and INF-y?

Back 75

LTC4 and LTD4

Front 76

Name the series of anti-inflammatory mediators that are short-lived nonclassic eicosanoids.

Back 76

Lipoxins

Front 77

Which 2 enzymes help form lipoxins?

Back 77

15-LOX and 5-LOX

Front 78

Which lipoxin acts to oppose some leukocyte responses to leukotrienes?

Back 78

LXA4

Front 79

a) Which action(s) of LTB4 does LXA4 inhibit?

b) Which action(s) of LTD4 does LXA4 inhibit?

Back 79

a) Chemotaxis and degranulation of polymorphonuclear leukocytes.

b) Vasoconstriction

Front 80

Lipoxins can be used to prevent what?

Back 80

Constriction of the airways

Front 81

What are produced from arachidonic acid by peroxidation?

Back 81

Isoprostanes

Front 82

What enzyme is used to convert arachidonic acid to isoprostanes?

Back 82

Trick question! This is not an enzymatic process. It's caused by the action free-radical.

Front 83

a) What is used to measure oxidative stress?

b) The increase in reactive oxygen results in modifications of what?

Back 83

a) Urine level of isoprostanes

b) DNA, proteins and lipids

Front 84

Many ______________ diseases have in common increased oxidative stress.

Back 84

Neurodegenerative

Front 85

Increased oxidative stress can be caused by what 2 problems?

Back 85

Overproduction of reactive oxigen species
Not sufficient neutralization by antioxidants

Front 86

The biological function of isoprostanes, measured on cultured cells, is similar to what prostaglandin?

What are isoprostane's actions?

Back 86

PGF2a

Increases bronchoconstriction, vasoconstriction, and smooth muscle contraction.

Front 87

What is zyflo used to treat?

Back 87

Asthma

Front 88

T/F

Isoprostanes can covalently modify a variety of proteins.

Back 88

True!

Front 89

Some isoprostanes have anti-____________ and anti-_________ effects (DHA).

Back 89

Inflammatory, cancer

Front 90

Anandamine is produced from:

Back 90

Phosphatidylethanolamine

AA is transferred to amino group of ethanolamine

Front 91

What enzyme releases anandamine?

Back 91

Phospholipase D

Front 92

Anandamine promotes what type of an effect?

Back 92

Analgesis effect

Front 93

What enzyme degrades anandamine?

Back 93

Hydrolase

Front 94

Which eicosanoids are increased in chronic inflammatory conditions?

Back 94

PGs and LTs

Front 95

Granulocytes, macrophages, neutrophils, platelets, mast cells and endothelial cells are involved in eicosanoid production during what?

Back 95

Inflammation

Front 96

What 5 things do eicosanoids act as during inflammation? (also, for each one, what is the eicosanoid(s) performing the action)

Back 96

Proinflammatory molecules (PGH2)
Chemoatractants (LTB4)
Platelet aggregating factors (TXA2)
Contractors of smooth muscle (CysLTs)
Modifiers of vascular permeability (LTs)

Front 97

Which eicosanoids can act as both proinflammatory and anti-inflammatory mediators depending on the array of EP (E-prostanoid) receptors with different signal transduction pathways?

Back 97

PGs

Front 98

Which eicosanoids play an active part in controlling the resolution of inflammation by stimulating endogenous anti-inflammatory pathways?

Back 98

LXs

Front 99

Which eicosanoids might be worth investigating as an approach for the treatment of inflammatory diseases?

Back 99

LXs

Front 100

Which eicosanoids are important mediators of acute or chronic joint inflammation?

Back 100

LTs

Front 101

Recent studies in mouse models have suggested that LTB4 and its receptors play crucial role in the development of what?

Back 101

Inflammatory arthritis

Front 102

Inhibitors of _________ biosynthesis and its receptor function are protective in mouse models of rheumatoid arthritis.

Back 102

LTB4

Mice deficient in LTB4 biosynthetic enzymes or LTB4 receptors are resistant to RA development.

Front 103

T/F

Clinical and pharmacological studies demonstrated the importance of eicosanoids in the development of many cancers.

Back 103

True!

Front 104

Overexpression of _______ and its major metabolite ______ has been found in breast, colon and prostate cancers.

Back 104

COX-2, PGE2

Front 105

In relation to cancer...
COX-2-derived PGE2 can do what 4 things?

Back 105

Reduce apoptosis
Inhibit immune surveillance
Stimulate cellular proliferation and angiogenesis
Enhance cellular invasiveness

it "RISEs" cancer rates

Front 106

A key mechanism involved in cancer-associated immunosuppression is PGE2's inhibition of what?

Back 106

Inhibition of dendritic cells (DC) differentiation and function

Reduced T-cell and DC function is related to COX-2 overexpression and PGE2 production in patients with breast cancer.

Front 107

The omega-3 and omega-6 PUFAs are very important constituents of what?

Back 107

Neuronal cell membranes

Front 108

In the adult cerebral cortex, how do the omega3 and omega6 contents compare?

Back 108

The omega-3 (DHA) content of the adult cerebral cortex is similar to that of omega-6 or ~ 3% of the dry weight

Front 109

In (white/gray) matter, there is a higher proportion of omega-6 than omega-3 PUFAs.

Back 109

White

Front 110

What symptoms can occur due to a deficiency in omega3 in the diet?

Back 110

Affect learning and memory
Alter olfactory and auditory responses to stimuli
Lead to increased depression and aggression

Front 111

8.04(b) Duress

Back 111

In a prosecution for an offense that does not constitute a felony, it is an affirmative defense to prosecution that the actor engaged in the proscribed conduct because he was compelled to do so by force or threat of force

Front 112

How are the effects of depression similar to an omega3 deficiency? These are the effects of omega3 deficiency:

a) Decreased levels of dopamine and D2 receptor.
b) Reduced glucose uptake via glucose transporter.
c) Increased AA turnover and metabolism.
d) Decreased BDNF levels in brain.

Back 112

a) Depression treatment helps maintain neurotransmitter levels.
b) Reduced metabolism, which is increased by treatment with lithium.
c) Treatment reduces AA turnover and metabolism.
d) Also decreased, but restored with treatment.

Front 113

If a neutrophil could go on a date with smoke, would it?

Back 113

Yes, neutrophils find smoke attractive!

Front 114

What cells defend the lungs against bacterial and viral infections and also promote an inflammatory response that can lead to several lung diseases?

Back 114

Neutrophils

Front 115

Which lungs diseases can result from the inflammatory response of neutrophils?

Back 115

Chronic obstructive pulmonary disease (COPD), severe asthma, cystic fibrosis, and acute respiratory distress syndrome.

Front 116

Activated neutrophils release a)_______ that are proinflammatory and also impair the anti-inflammatory actions of b)______________.

Back 116

a) ROSs

b) Glucocorticoids

Front 117

What do neutrophils secrete that may cause emphysema?

Back 117

Neutrophil elastase and proteinase-3, and matrix metalloproteinases MMP-8 and MMP-9.

Front 118

What do neutrophil elastase and proteinase-3 do?

Back 118

Degrade elastin fibers and stimulate mucus secretion.

Front 119

What do matrix metalloproteinases MMP-8 and MMP-9 do?

Back 119

Break down elastin and collagen.

Front 120

The product of a)_________ degradation by MMP-8 and MMP-9 is a tripeptide b)______.

Back 120

a) Collagen

b) PGP

Front 121

T/F

PGP is a selective neutrophil attractant, but the acetylated form of PGP is a less potent attractant of neutrophils.

Back 121

False!

It is true that PGP is a selective neutrophil attractant, but the acetylated form of PGP is actually an even more potent attractant of neutrophils.

Front 122

Which enzyme can degrade PGP by its intrinsic peptidase activity?

Back 122

Leukotriene A4 hydrolase (LTA4H)

Front 123

________ has two opposite actions that control inflammatory response during acute infection of lungs. What are they?

Back 123

LTA4H

Production of LTB4 and degradation of PGP

Front 124

What mechanism relating to PGP may underlie chronic neutrophilic inflammation in the lungs of smokers?

Back 124

Cigarette smoke extract increases acetylation of PGP and makes PGP resistant to degradation by LTA4H.
Because degradation of the chemoattractant is blocked, neutrophil chemotaxis is increased and prolonged by cigarette smoke.

Front 125

"Why is blood coagulation so complex?"
(straight from slide)

Back 125

It must happen RAPIDLY when needed
It must NOT happen when NOT needed
It must be LOCALIZED

Therefore, there are:
Many levels of regulation
Many redundancies in regulation

Front 126

T/F

Normal endothelium supports platelet adhesion or blood coagulation.

Back 126

False!

Normal endothelium does NOT support platelet adhesion or blood coagulation. It has antithrombotic properties.

Front 127

Normal endothelium produces what to inhibit thrombosis?

Back 127

Prostacyclin or prostaglandin I2 (PGI2)
Nitric oxide, also known as endothelium derived relaxing factor (EDRF)
Heparin sulfate and thrombomodulin

Front 128

What is the action of prostacyclin or prostaglandin I2 (PGI2)?

Back 128

Prevents platelets aggregation

Front 129

What is the action of nitric oxide, also known as endothelium derived relaxing factor (EDRF)?

Back 129

Stimulates smooth muscle relaxation

Front 130

What is the action of heparin sulfate and thrombomodulin?

Back 130

Both inhibit thrombin action

Front 131

During the vascular phase of hemostasis, what occurs?

Back 131

1. Damage to blood vessels and capillaries.
2. An immediate reflex promotes vasoconstriction to prevent blood loss.
3. Exposed collagen promotes the platelets to adhere – platelets activation.

Front 132

What leads to the activation of PLA2 and activation of platelets?

Back 132

Binding of platelets to exposed collagen + Ca2+

Front 133

Activation of PLA2 → release of _________________ → production of ___________________.

Back 133

Arachidonic acid and thromboxane A2 (TXA2)

Front 134

Contents of granules are secreted in response to what?

Back 134

Platelet activation

Front 135

What do granules contain which promotes platelet aggregation, degranulation, and vasoconstriction?

Back 135

TXA2

Front 136

What does prostacyclin (PGI2) cause in endothelial cells? and platelets?

Back 136

Endothelial cells - increased cAMP/vessel smooth
muscle relaxes.

Platelets - increase in cAMP and decreased aggregation

Front 137

What does TxA2 cause in endothelial cells? in platelets?

Back 137

Endothelial cells - increased Ca2+/vessel smooth muscle constricts

Platelets - increase in Ca2+ and increased aggregation

Front 138

Platelet aggregation is controlled by what 3 things?

Back 138

By the balance in production of TXA2 and PGI2
By drugs NSAIDs (aspirin)
By dietary intervention

Front 139

How can platelet aggregation be controlled by NSAIDs (aspirin)?

Back 139

Platelets lack nucleus; cannot replace COX – production of TXA2 is preferentially inhibited.

Front 140

How can platelet aggregation be controlled by dietary intervention?

Back 140

Supplementation of omega-3 reduces production of proinflammatory eicosanoids.