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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
Result of receptor effects downstream:
Inflammation, pain, immunoreg, mitogenesis, plasticity and cell injury
26
Receptor expression
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
27
Therapy via PG
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
Female reprod organ: PG and fxn
PGE2, PGF2a Uterine contraction, oxytocic action
29
Male reproductive organ
PGE2 PGF2a Fertility
30
CV system
PGI2 - Thrombosis PGE2, PGI2 - Arterial vasodilation PGF2 - Venous vasoconstriction PGE2, PGI2 - Patency of fetal ductus arteriosus
31
Respiratory system
PGE2 - bronchodilation PGF2a- bronchoconstriction
32
Renal system
PGE2 PGI1 = Renal blood flow GFR PGE2, PGI2 = renin release PGE2 = Inhibition of ADH
33
GI system
PGE2, PGI2 = cytoprotection
34
Immune system
PGE2, PGI2 = inhibition of T B lymphocyte activation/ prolif
35
CNS
PGE2 = Fever PGD2 = sleep PGE2, PGI2 = Pain
36
Rheumatoid arthritis
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
Inhibiting PG synthesis
Glucocorticoids Inhibit PL --> AA NSAIDs - inhibit COX2/1, AA--> PGG2 NSAIDs - inhibit COX2/1, PGG2 --> PGH2
38
Activating PG formation
Epoprostenol PGI2 Alprostadil - PGE1 Misoprostol - PGE1 analogue Dinoprostone - PGE2 Dinoprost - PGF2a Carboprost - analogue of PGF2a
39
Predominant PG in inflammation
PGE2 and PGI2 Both promote edema and leukocyte influx Enhance blood flow at inflamed region Target for RA Inhibit PGE2 and PGI2 biosynthesis
40
Good PG inhibitors
Inhibition of PGE2 and PGI2 Corticosteroids Nonsteroidal anti-inflammatory drugs
41
Negative + positive effects of PG
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
Corticosteroids + when used
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
Example of corticosteroid
Dexamethasone
44
Additional effects of steroids
lower NOS, lower NO, vasoconstrction Lower adhesion, reduced emigration of leukocytes from vessels Increase endonucleases - induce apoptosis of lymphocytes and eosinophils
45
Corticosteroid mechanism
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
Broad effects of corticosteroids
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
2 major NSAIDs, compare
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
COX enzymes - dual action, which change results in which PG?
Bicyclic endoperoxide - formed in 1st active site C11 Result peroxide C15 (PGG2) Second active site - reduced at peroxide at C15 --> chiral alcohol (PGH2)
49
Early NSAIDS + amino acids + active sites
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
COX2 selectivity
COX2 selectivity - deeper binding pocket Not in COX1 COX2 inhibitor cannot enter the COX1
51
COX2 selectivity vs toxicity
Improved GI side effect Rofecoxib/Vioxx - >270x more selective increase risk of CV effects These issues adhere to all COX2 inhibitors
52
Consequence of COX inhibition: kidney and vasculature
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
RA and NSAIDs, potential new therapeutics
Good, not efficacious for all patients Upstream targeting: goal to reduce cytokines inflammatory activity like TNF-alpha
54
Antibodies for RA
mAbs - preferred for use more homogenous than polyclonal PK/PD more reproducible mAbs raised against inflammatory cytokine - can have therapeutic effects
55
Poly vs mono clonal
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
Ab types
omab - fully mouse ximab - chimeric -zumab - humanized -umab - fully human
57
mAb production
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
Action of infliximab, adalimumab, golimumab
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
Recombinant proteins therapy
Alternate RA treatment - TNF binding domain of receptor TNFR --> to Ab Fc Fusion of Fc increases half-life
60
Etanercept
Chimeric protein binds soluble TNFa, inactivates Fusion/recombinant protein
61
Paracetamol action
1. reducing agent in peroxidase COX site 2. Deacetylation of paracetamol in CNS --> Conjugate with AA --> AM404 --> inhibits endocannabinoid reuptake
62
Dinoprostone, Dinoprost, Carboprost
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
Alprostadil, what for, function, half life
PGE1 second line treatment for ED Injected Vasodilation inhibit platelet aggregation useful for infant congenital heart disease T1/2 - 5-10 min
64
Misoprostol
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
Epoprosteol, action, half life, derivatives
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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