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Block 1 Week 5 > Lipid Mediators > Flashcards

Lipid Mediators Flashcards

1
Q

what does inflammatory response to injury and/or infection cause?

A

1) Redness (rubor)
2) Heat (calor)
3) Swelling (Tumor)
4) Pain (Dolor)

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2
Q

Redness (rubor) due to?

A

due to capillary dilation resulting in increased blood flow

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3
Q

Heat (calor) due to?

A

due to capillary dilation resulting in increased blood flow

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4
Q

Swelling (Tumor) due to?

A

-due to passage of plasma from the blood stream into the damaged tissue

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5
Q

Pain (dolor)

A

-due to tissue destruction, swelling and chemical mediators of inflammation

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6
Q

inflammation process regulation?

A
  • inflammation is regulated by specific molecules

- is carefully choreographed dance between tissue & immune cells triggered by pathogens/iinjury

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7
Q

Chemical Mediators of inflammation?

A

-regulate initiation, progression and resolution of inflammatory response to pathogen and/or injury

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8
Q

What molecules tend to be drug targets for therapeutic regulation of inflammatory process?

A

the chemical mediators of inflammation

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9
Q

chronic inflammation?how prevent it?

A
  • more is not always better if go from acute to chronic have side effects
  • can lead to neutrophils during hole in tissue (abcess) or fibrosis (scaring) & loss of function
  • target key points in the inflammatory cycle to control chronic inflammation
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10
Q

what are the two sources of chemical mediators for inflammation?

A

1) cellular

2) from plasma (the liver)

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11
Q

Two forms of inflamamtion mediators from the cell?

A

1) Preformed proteins: are packaged in vesicles/granules of the cells (like a neutrophil). when activated just have to secrete them
2) Newly synthesized: is slower, have to take time go to nucleus do trxn/trans then can secrete

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12
Q

Plasma/liver mediators follow what two pathways?

A
  • mediators made in Liver (on occasion other organs) then released into plasma.
  • then can do:
    1) Factor XII activation (Hageman factor)
    2) Complement Activation
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13
Q

In what state are Plasma/liver mediators in?

A

-secrete the mediators in inactive form, are quickly activated by enzymes etc. when needed

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14
Q

Do these chemical mediators of inflammation cause damage?

A

-yes; most have potential to cause damage to self

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15
Q

are newly synthesized mediator products in the cell always proteins/peptide?

A

-no; can be lipids, O2 species or many other molecules

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16
Q

What is the source of leukocyte derived mediators? What are some leukocyte derived mediators?

A

1) cytokines
2) Nitric Oxide
3) ROS

source is leukocyte cell and they are newly synthesized as needed

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17
Q

6 reactions that occur in inflammation? how do mediators affect them?

A

1) vasoldialtion
2) vasopermeabilty
3) chemotaxis, leukocyte recruitment & activation
4) fever
5) pain
6) tissue damage

  • specific mediators regulate different steps in inflammation*
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18
Q

vasoldialtion

A

-is about altering smooth muscle function, relaxing smooth muscle to make the vessel wider

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19
Q

vasopermeabilty

A
  • different than vasodilation

- involves making epithelium less leaky, have to make less water tight

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20
Q

chemotaxis

A

-chemoattractants/ that attract/recruit things from to an area of inflammation

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21
Q

fever response

A
  • causes increase in temperature, makes molecular actions go faster & burn through more ATP
  • means body becomes deficient in ATP and pathogens will die from protein denaturation and lack of ATP
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22
Q

3 broad classes of chemical mediators of inflammation?

A

1) Lipid mediators
2) Plasma proteins
3) Cytokines & chemokines

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23
Q

What are lipid mediators?

A

-all lipid mediators are autocoids; but not all autocoids= lipid mediators

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24
Q

Eicosanoids

A

a chemically diverse family of arachidonic acid (AA) derived autacoids

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25
Q

Autacoids

A

-substances that are rapidly synthesized in response to specific stimuli, act quickly at the immediate locality, and remain active only short time before degradation

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26
Q

Lipid Mediator pathway step 1

A

1) cleave arachidonic acid (AA) from plasma membrane

2) can choose between 2 pathways; 5-Lipoxygenase or Cyclooxygenase

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27
Q

arms of the pathway?

A
  • different arms have opposing pathways

ex: vasodilation vs constriction even though are downstream from same source

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28
Q

can all lipid mediator products be made in same cell?

A

-no, each product will be cell type dependent in production because not all enzymes are present in all cells at all times

29
Q

what is arachidonic acid (AA)? what derived from?

A
  • 20 carbon polyunsaturated fatty acid

- derived from dietary sources or by conversion from the essential fatty acid linoleic acid

30
Q

Does AA occur free in the cell?

A
  • NO
  • exists esterified in the plasma membrane
  • must be liberated from the plasma membrane
31
Q

what liberates AA from plasma membrane? When is it liberated? Why?

A
  • Phospholipase A2 releases AA from membrane phospholipids
  • receptor on PM gets bound/ activated, activates PL2A which cleaves AA
  • is regulatory system
32
Q

PL2A four categories based on?

A

1) Structure and size 2) Substrate specificity

3) Calcium requirement 4)Tissue distribution

33
Q

What are the four PL2A categories? Which use Ca?

A

1) Secretory (Ca)
2) Cytoplasmic (Ca)
3) iPLA2 (no Ca)
4) PAF acetyl Hydrolases

34
Q

PLA2 only role cleaving AA from membrane?

A

-no; has many roles and many classes but cleaning AA is one of primary roles

35
Q

PLA2 target for anti-inflammatory therapeutics? steroids?

A
  • no
  • it’s heterogeneity and size of family makes not great target for therapeutic intervention
  • PLA2 involved in too many body processes, would have too many side effects
  • steroids do act here but steroids act everywhere*
36
Q

AA is cleaved from the membrane: Now what?

A

Two pathways

1) Lipoxygenase pathway
2) Cyclooxygenase pathway

  • once decide cannot go back
37
Q

Lipoxygenase pathway

A

-Initial products produced by 3 different lipoxygenases, present in only a few cell types
-5-lipoxygenase is one of the 3; & the primary enzyme in neutrophils
is the primary enzyme in neutrophils

38
Q

5-lipoxygenase and main product?

A
  • made from AA, is the Lipoxygenase pathway
  • primary enzyme in neutrophils, so LOX5 & products are PRO-INFLAMMATORY
  • main product is 5-HPETE
39
Q

5-lipoxygenase in many cell types? what does this tell us?

A
  • very few cells have ability to make them

- means most cells aren’t in danger of making radical pro-inflammatory molecules

40
Q

5-HETE

A
  • main product of 5-lipoxygenase; is intermediate to final products of LOX-5 pathway
  • converted into a family of compounds called leukotrines
41
Q

5’-LOX –> 5-HETE; now what?

A

2 separate pathways

1) Cysteinyl LTs
2) LTA4 hydrolase

42
Q

Cysteinyl LTs (CLTs)

A

-made of LTC4, LTD4 & LTE4
-1000x more potent in inducing bronchospasm than histamine
-involved in many chronic inflamm disorders in body
(inflamm bowl disease & asthma)

43
Q

why are antihistamines only partially helpful in severe allergic reactions?

A

-if reactions include CLTs then only dealing with one half of the problem (histamine) not other part

44
Q

LTA4 hydrolase

A

-product of 5-Lox pathway
-powerful chemotactic agent, recruits leukocytes
to areas of inflammation

45
Q

Leukotrienes associated with

A
  • leukotrienes= major family of compounds that were converted from HETE-5
  • Leukotrienes associated with:
    1) Asthma
    2) Inflammatory Bowel Disease
    3) Glomerulonephritis
46
Q

A) what does 5-Lox pathway make x2?

B) what cell type makes them?

A

1) 5-LOX–>5-HETE–>
Leukotrienes (LT)
(vasoconstriction)

2)5-LOX–>5-HETE–> 12-LOX–> Lipoxins (vasodilation)

B) leukocytes

47
Q

When have AA, what determines the end product we get?

A

-actual product get is dependent on enzymes present in the specific cells & tissue

48
Q

Transcellular leukotriene biosynthesis?

A
  • adds another layer of regulation in 5-LOx pathway
  • sequesters different synthetic steps in separate cells
  • is how make Lipoxin
49
Q

Lipoxin transcellular biosynthesis mechanism?

A

1) AA liberated, activate 5-HETE –>5-LOX pathway in neutrophil, can make LTA4
2) attract platelets, when have sufficient quantities where plates & neutrophil touching, LTA4 can be moved into platlet
3) once in platelet, can synthesize 12-LOX
4) 12-LOX makes anti-infammatory Lipoxins

50
Q

why can’t synthesize 12-LOX in neutrophil? Why can’t synthesize in platelet by itself?

A
  • it makes Lipoxins which are anti-inflammatory, neutrophils are pro-inflammatory
  • neutrophil lacks the enzymes to make 12-LOX; platelet lack machinery to 5-LOC so can’t make LTA4
  • FOR REGULATION
51
Q

What is the process of Transcellular Leukotriene Biosynthesis used for?

A

-to produce Lipoxins and stop the inflammatory reaction

52
Q

Lipoxin actions

A

1) Inhibit leukocyte recruitment
2) Inhibit neutrophil chemotaxis and adhesion
3) May be negative regulators of leukotriene synthesis

53
Q

how do you block lipoxin production?

A

-blocking cell:cell adhesion blocks lipoxin production

54
Q

how cycloxygenase pathway initiated?

A

by two diff enzymes that regulate 2 diff pathways

1) Cox-1: constitutively expressed
2) Cox-2: inducibly expressed

55
Q

how cycloxygenase pathway lead to?

A

-production of prostaglandins

56
Q

What is COX?

A

-also known as prostaglandin H synthase, - a heme-containing enzyme that catalyzes two sequential enzymatic reactions

57
Q

two sequential enzymatic reactions of COX?

A

1) the bis-oxygenation of AA leading to production of PGG2 (COX reaction) 2) reduction of 15-hydroperoxide of PGG2 leading to formation of PGH2 (hydroperoxidase reaction)
* then separate into 2 diff pathways

58
Q

Normal functions mediated by cycle-oxygenase (COX)?(5 big ones)
what drives these processes?

A

1) Angiogenesis
2) Ovulation
3) Implantation
4) Wound healing
5) Temp Regulation

prosteglandins

59
Q

How are prostaglandins synthesized?

A
  • in a cell-type specific manner, not made in all cells all the time
  • dependent on enzymes present in specific tissue type
60
Q

How do prostaglandins function?

A
  • paracrine and autocrine mechanisms

- many produce effects by acting through distinct GPCRs

61
Q

How can same prostaglandins produce a different effects?

A
  • depends on what GPCR is in the specific tissue

- tissue can expresses receptors linked to activating or inhibiting intracellular signaling pathways

62
Q

How target specific prostaglandin pathways therapeutically?

A
  • use Prostanoid Agonists
    1) agonists drugs will have ligands that bind receptors and cause opposite to occur
    2) inducers: have ligands that bind receptors and induce something to prohibit pathway
63
Q

3 outcomes of the COX (cyclo-oxygenase) pathway?

A

AA–> Cycloendoperoxides
1) thromboxane (COX-1); vasoconstricting
2) prostacyclin (COX-2):
vasodilation
3) Prostaglandins; 2 types, do both constriction & dilation

64
Q

Why hard to target COX or 5-lox pathway therapeutically?

A

-because have so many roles in many different pathways nearly impossible to target the single one you want

65
Q

What does Asprin/NSAID block?

A
  • COX pathway

- COX-1 10-100X more than Cox 2

66
Q

How block the entire process (COX & LOX)?

A

-steroids that block PLA2 which prevents cleavage of AA from the membrane

67
Q

How block entire LOX pathway?

A
  • Lipoxigenase inhibitors
68
Q

How block just leukotriene production?

A

-Leukotriene receptor agonists

Block 1 Week 5 (8 decks)

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