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PCL469 > Prostaglandins/Inflammation > Flashcards

Prostaglandins/Inflammation Flashcards

1
Q

Inflammation in general

A

Essential to alter the immune system of injury/infections
Recruits leukocytes
Aberrant inflammation is detrimental

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2
Q

Cytokines - function

A

Infection: macrophages sense pathogen
release:
Cytokines: modulate immune cell activation
Chemokines: attract specific immune cells
Also: endothelial permeability increases

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3
Q

TLR activation

A

LPS from gram negative bacteria
binds to TLR-4, spec. MD2 part
Clustering of TLRs via their PAMP ligands
TLR signal downstream
IKB destroyed
releases NFKB
Now transcription factor for cytokine genes - activated

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4
Q

Receptor clustering

A

… General mechanism for immune modulation

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5
Q

TLRs and cytokines

A

TLRs + macrophages –> release of immunostimulating cytokines
Inflammatory cytokines act on other cells, initiate inflammation, several mechanisms

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6
Q

5 cytokines

A

IL-1beta
TNF-al
IL-6
CXCL8
IL-12

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7
Q

IL-1beta

A

Activates vascular endothelium,
lymphocytes
Local tissue destruction
Access of effector cells ^^
Effect: Fever, produce IL-6

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8
Q

TNF-alpha

A

Vascular endo
increases vascular permeability
IgG entry
Incr. fluid to lymph node
Effect: Fever
Mobilize metabolites
Shock

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9
Q

IL-6

A

Lymphocyte activation
Ab production
Effect: Fever
acute-phase protein production

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10
Q

CXCL8

A

Chemotactic factor
neutrophil recruiter
Basophil
T cell to site of infection

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11
Q

IL-12

A

NK cells activation
Differentiation of CD4 –> Th1

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12
Q

Macrophages –> phospholipids

A

Immune cell –> release cytokine –> receptor –> activate Phospholipase A2 (macrophage can be activated by same cytokine it produced)

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13
Q

Pathway of PLA2 and therapeutics

A

PL –> Arachidonic acid –> Prostaglandins –> inflammation
Phospholipase: inhibited by Glucocorticoids (dexamethasone)
Cyclooxygenase –> prostaglandins: can be inhibited by NSAIDs (aspirin, ibuprofen)

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14
Q

Eicosanoids and PL damage

A

Membrane damage increases [phospholipid] for PLA2 processing

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15
Q

Pathway from PL –> prosta…

A

PL –> PLA2 –> arachidonic acid –> COX1/2 –> PGG2 –> PGH2 –> prostaglandins, prostacyclin, thromboxanes

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16
Q

Eicosanoid: biosynthesis

A

Major classes: Prostaglandins, leukotrienes, thromboxanes
All from arachidonic acid AA
COX1/2 + prostaglandin synthases –> most biosynthetic transformations

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17
Q

3 parts of conversion to PG-in

A
  1. Cyclization
  2. Adding peroxide bridge
  3. Secondary peroxide acid OOH
    highly potent, reactive, small 1/2 life
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18
Q

Prostaglandin nomenclature

A

Labelled with PG
20 carbons
5 membered ring - dictate A-K
number of double bonds not in ring –> subscript
Stereochemistry at C9, if ketone reduced, alpha/beta

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19
Q

4 Prostaglandin overall structure

A

PGD: C9 is OH, C11 is ketone (flipped than usual)
PGE: ketone is C9; C11 is OH
PGF alpha: C9 and 11 has OH
PGI: prostacyclin: double ring, new one connected with ether

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20
Q

Prostaglandins: local action, 1/2 life, pathological, generally

A

PG biosynthesized, acts locally
Degradation rapid, occurs catabolically and spontaneously
Spatial control over signalling, to limit inflammation to tissue damage
Chronic prod. of PGs: inflammation, disease

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21
Q

Catabolism of prostaglandins:

A

Hydroxyprostaglandin dehydrogenase HPGD
Carbonyl reductase 1: can deactivate PGs
HPGD oxidize OH at C15 –> ketone
CBR1 –> reduced C9 ketone
Some PH unstable and hydrolyze easily
Prostacyclin (PGI2) –> 6ketoPGF1alpha

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22
Q

Eicosanoids: tissue specificity

A

PGs act on every tissue type, numerous effects
Specific effect depend on receptor at tissue

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23
Q

Tissue-specific effects

A

Vessels: PGF2, PGI2, PGE2, PGD2
Platelets: PGE1, PGI2
Intestines: PGE1, PGFalpha
Stomach: PGE2, PGI2
Uterus: PGE2, PGF2
Kidney: PGH2, PGE1
HPA: PGE2, PGE2

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24
Q

Prostaglandin receptors

A

Designated by ring identity by corresponding ligand
PGE2 –> EP (4types)
PGI2–> IP
All GPCR
Alter IC Ca++, cAMP

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25
Q

Result of receptor effects downstream:

A

Inflammation, pain, immunoreg, mitogenesis, plasticity and cell injury

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26
Q

Receptor expression

A

PG rec. expression + Biosynthesis of PGs restricted to certain tissue types
Restricting PG receptor expression
Control over local [active PG] –> regulation over PG signalling
see slide 17

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27
Q

Therapy via PG

A

Modulating PG levels
Overlapping receptor expression on cell types –> various consequences of changing amt of 1 PG in body
Patient can increase PG signalling or inhibit PG biosynthesis

28
Q

Female reprod organ: PG and fxn

A

PGE2, PGF2a
Uterine contraction, oxytocic action

29
Q

Male reproductive organ

A

PGE2 PGF2a
Fertility

30
Q

CV system

A

PGI2 - Thrombosis
PGE2, PGI2 - Arterial vasodilation
PGF2 - Venous vasoconstriction
PGE2, PGI2 - Patency of fetal ductus arteriosus

31
Q

Respiratory system

A

PGE2 - bronchodilation
PGF2a- bronchoconstriction

32
Q

Renal system

A

PGE2 PGI1 = Renal blood flow GFR
PGE2, PGI2 = renin release
PGE2 = Inhibition of ADH

33
Q

GI system

A

PGE2, PGI2 = cytoprotection

34
Q

Immune system

A

PGE2, PGI2 = inhibition of T B lymphocyte activation/ prolif

35
Q

CNS

A

PGE2 = Fever
PGD2 = sleep
PGE2, PGI2 = Pain

36
Q

Rheumatoid arthritis

A

RA -autoimmune, destruction and inflammation of joint tissue
Local inflammation by immune cells - attack autoantigens
Inflammation in synovial membrane –> leukocytes in tissue
T cells activate macrophages –> Cytokines –> osteoclast activation –> break cartilage
Tissue destruction: prostaglandin release: pain, swelling, redness

37
Q

Inhibiting PG synthesis

A

Glucocorticoids
Inhibit
PL –> AA

NSAIDs - inhibit COX2/1, AA–> PGG2
NSAIDs - inhibit COX2/1, PGG2 –> PGH2

38
Q

Activating PG formation

A

Epoprostenol PGI2

Alprostadil - PGE1
Misoprostol - PGE1 analogue
Dinoprostone - PGE2

Dinoprost - PGF2a
Carboprost - analogue of PGF2a

39
Q

Predominant PG in inflammation

A

PGE2 and PGI2
Both promote edema and leukocyte influx
Enhance blood flow at inflamed region
Target for RA
Inhibit PGE2 and PGI2 biosynthesis

40
Q

Good PG inhibitors

A

Inhibition of PGE2 and PGI2
Corticosteroids
Nonsteroidal anti-inflammatory drugs

41
Q

Negative + positive effects of PG

A

PGE2 and PGI2 - pain, fever, immune cell activation –> inflammatory cascades
Also: GI protection of mucosa, CV regulation
Corticosteroids - cannot be safely used long
Modern NSAIDs - more accurate control over local PG

42
Q

Corticosteroids + when used

A

Decrease prod. of cytokines, lower PG
Increased production of IL-10 tho
Decreased recruitment of immune cells
Immunosuppressive, limits use
Used in acute inflammation (anaphylaxis, brain swelling, cyto release syndrome)
RA, lupus IBS MS
Transplant recipients

43
Q

Example of corticosteroid

A

Dexamethasone

44
Q

Additional effects of steroids

A

lower NOS, lower NO, vasoconstrction
Lower adhesion, reduced emigration of leukocytes from vessels
Increase endonucleases - induce apoptosis of lymphocytes and eosinophils

45
Q

Corticosteroid mechanism

A

bind to EC GC receptor
Into cell
bind to NFKB
into nucleus –> transcription of anti-inflammatory cytokines (IL-10, TGF-beta) –> immunosuppression
Also, repress transcription of inflammatory cytokines

46
Q

Broad effects of corticosteroids

A

Extreme changes in transcription
Broad side effects
Not used as chronic treatment
Prevent PLA2 from acting, preventing AA release
Immunosuppresant drugs without side effects need to act narrowly

47
Q

2 major NSAIDs, compare

A

COX1/2
Tissue restricted expression, inducibility - COX2 better target
COX1 constitutively expressed in tissues required for homeostasis- renal, platelet function, gastric mucosal protection
COX2 - for acute and chronic inflammation, pain, fever, limited homeostatic effect

48
Q

COX enzymes - dual action, which change results in which PG?

A

Bicyclic endoperoxide - formed in 1st active site C11
Result peroxide C15 (PGG2)
Second active site - reduced at peroxide at C15 –> chiral alcohol (PGH2)

49
Q

Early NSAIDS + amino acids + active sites

A

Non-specific COX - non-aspirin inhibitors enter active site and physically block AA entry
Ion pair formation with Arg 120
Aspirin - covalently modifies ser529 in active site
Ser529 - acetylated, blocks AA from entering active site

50
Q

COX2 selectivity

A

COX2 selectivity - deeper binding pocket
Not in COX1
COX2 inhibitor cannot enter the COX1

51
Q

COX2 selectivity vs toxicity

A

Improved GI side effect
Rofecoxib/Vioxx - >270x more selective
increase risk of CV effects
These issues adhere to all COX2 inhibitors

52
Q

Consequence of COX inhibition: kidney and vasculature

A

Inhibition of PGE2 and PGI2 synthesis in macrophages
Vasculature: Alter arteriosclerosis plaque formation from COX2 (Atherogenesis): Myocardial infarction, stroke
Kidney: Increase BP
Risk: Myocardial infarction, stroke, hypertension, heart failure

53
Q

RA and NSAIDs, potential new therapeutics

A

Good, not efficacious for all patients
Upstream targeting: goal to reduce cytokines inflammatory activity like TNF-alpha

54
Q

Antibodies for RA

A

mAbs - preferred for use
more homogenous than polyclonal
PK/PD more reproducible
mAbs raised against inflammatory cytokine - can have therapeutic effects

55
Q

Poly vs mono clonal

A

Poly - each Ab is produced by different B cell lineage -from animals
Mono - accessed by cloning specific B cell, fused with immortalized cell line

56
Q

Ab types

A

omab - fully mouse
ximab - chimeric
-zumab - humanized
-umab - fully human

57
Q

mAb production

A

mAb are often first developed in mice
Animal mAb - elicit unwanted immune response in humans
mAb of animal origin are engineered to mostly have human domains

58
Q

Action of infliximab, adalimumab, golimumab

A

Treating TNF-alpha inflammation in RA
anti-TNF-alpha therapy bind to TNF alpha
Do not bind TNGa receptor
Reduced TNFa signalling
Decrease inflammat. cytokine production by immune cells/macrophages
Broadly immunosuppressive - opportunistic infections
Reduce inflammation at arthritic points

59
Q

Recombinant proteins therapy

A

Alternate RA treatment - TNF binding domain of receptor TNFR –> to Ab Fc
Fusion of Fc increases half-life

60
Q

Etanercept

A

Chimeric protein binds soluble TNFa, inactivates
Fusion/recombinant protein

61
Q

Paracetamol action

A
  1. reducing agent in peroxidase COX site
  2. Deacetylation of paracetamol in CNS –> Conjugate with AA –> AM404 –> inhibits endocannabinoid reuptake
62
Q

Dinoprostone, Dinoprost, Carboprost

A

PGE2 PGF2a –> oxytotic agents
Treat Postpartum hemorrhage
Terminate pregancy at any stage - uterine contr.
t1/2 - short, limit usefulness
Synthetic analogues - longer T1/2 - Carboprost
1. Dinoprostone: PGE2 - only one with ketone
2. Dinoprost: PGF2a
3. Carboprost: PGF2a analogue

63
Q

Alprostadil, what for, function, half life

A

PGE1
second line treatment for ED
Injected
Vasodilation
inhibit platelet aggregation
useful for infant congenital heart disease
T1/2 - 5-10 min

64
Q

Misoprostol

A

Synthetic derivative PGE1
Longer 1/2 - + methyl group
Prevent peptic ulceration - oral dosing
Prevent gastric acid production by parietal cells
counteract GI effects of NSAIDs

65
Q

Epoprosteol, action, half life, derivatives

A

Prostacyclin - PGI2
Treat pulmonary hypertension via vasodilation
Prevent platelet aggregation
Short 1/2 life: 3-5 min
Derivatives: Iloprost 30 min
Treprostinil 4H

PCL469 (6 decks)

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