inflammatory molecules

Report
A 54-year-old woman presents to her family
physician's office with a 2 week history of
pain and numbness in her left hand
A 19-year-old man, lying flat on a stretcher
and wearing a hard cervical collar, arrives
in the Emergency Room
Do you administer NSAIDs or steroids to
these patients?
Eric Niederhoffer
SIU-SOM
Prostaglandin, Leukotriene, Lipoxin,
and Thromboxane Synthesis
•Pathway overview
•Prostaglandin receptors
•Pathway details
•Differential actions of cyclooxygenases
•COX-1 and COX-2 comparison
•Tissue comparison
•Role of ω-3 fatty acids
Pathway Overview
Anti-inflammatory steroids
Glucocorticoids
NSAIDs
aspirin
Linoleic acid
Zileuton
Arachidonic acid
Prostaglandin H2
synthase
Lipoxygenase
Prostaglandins (PG) Leukotrienes (LT)
Thromboxane A2
synthase
Lipoxygenase
Lipoxins (LX)
Thromboxanes (TXA)
Prostaglandin Receptors
Receptor
Signal Transduction
Distribution
DP1 (PGD2)
AC↑, [cAMP]↑
Platelets, VSM, nervous
tissue, retina, small
intestine, ileum, lung,
stomach, uterus
DP2 (PGD2)
Mobilize intracellular
[Ca2+]
Eosinophils, basophils,
Th2 cells
EP1 (PGE2)
phosphoinositol
turnover↑, [Ca2+]↑
Kidney, lung, spleen,
skeletal muscle, testis
uterus
EP2 (PGE2)
AC↑, [cAMP]↑
Lung, placenta, heart?
EP3 (PGE2)
Most receptors AC↓,
[cAMP]↓, some AC↑ and
[cAMP]↑
Kidney, stomach, uterus,
pancreas, adrenal, testis,
ovary, small intestine,
brain, spleen, colon,
heart, liver, skeletal
muscle, lung, thymus,
ileum
EP4 (PGE2)
AC↑, [cAMP]↑
Small intestine, lung,
thymus, kidney, uterus,
pancreas, spleen, heart,
stomach, brain, ileum,
peripheral blood
mononuclear cells
FP (PGF2)
phosphoinositol
turnover↑, [Ca2+]↑
Corpus luteum, uterus,
stomach, kidney, heart,
lung, eye, liver
IP (PGI2) (IP1, IP2)
AC↑, [cAMP]↑
Platelets, VSM, kidney,
thymus, liver, lung,
spleen, skeletal muscle,
heart, pancreas
phosphoinositol
turnover↑, [Ca2+]↑
Platelets, VSM, thymus,
spleen, lung, kidney,
heart, uterus
[PGI2 = prostacyclin]
TP (TXA2)
http://www.caymanchem.com/app/template/scientificIllustrations%2CIllustration.
vm/illustration/2018/a/z
Pathway Details (PG, TX, LT)
IL-1 (inflammation)
IL-1R
Membrane phospholipids
Phospholipase A2
(or PLC)
Anti-inflammatory steroids
Glucocorticoids
(mediated by lipocortin-Ca2+)
Arachidonic acid
NSAIDS (aspirin)
LTA4
Glutathione
S-transferase
Cyclooxygenase
O2
LTB4 LTC4
PGH2
synthase
PGG2
2GSH
LTD4
PG hydroperoxidase
GSSG
LTE4
PGJ2
PGD2 synthase
TXA2 synthase
PGH2
PGD2
TXA2
PGI2 synthase
PGI2 (PC)
PGE2 synthase
PGF2
synthase
PGF2a
PGE2
Pathway Details (LX)
Arachidonic acid
Epithelia
Endothelia
Monocytes
Aspirin
Airway epithelia
Acyl-COX-2
Leukocytes
15-LOX
15R-HETE
5-LOX
15S-H(p)ETE
LTA4
Leukocytes
Platelets
15R-HETE
5-LOX
15S-H(p)ETE
LTA4
5-LOX
15R-ETT
15S-ETT
15 epi-LXA4 15 epi-LXB4
12-LOX
LXA4
Anti-Inflammatory Effects
http://themedicalbiochemistrypage.org/aspirin.html#
LXB4
Differential Actions
of Cyclooxygenases
Housekeeping
Unwanted
side-effects
Constitutive
PGE2
Bronchodilation
Renal function
TXA2
Platelet function
COX1
NSAIDs
Inducible
Inflammatory
PGI2
Endothelial integrity
Vascular patency
Gastric mucosal
integrity
COX2
PGE2
PGF2a
Proteases
Therapeutic antiinflammatory effects
Inflammation
COX-1 and COX-2
Comparison
Parameter
COX-1
COX-2
Regulation
usually
constitutive
inducible
Range of gene
induction
2 to 4-fold
10 to 80-fold
Rate of gene
activation
24 h
0.5 to 4 h
Effect of
glucocorticosteroids
inhibits
activity*
inhibits
activity*
Relative size of
active site
smaller
larger
Rate of arachidonic
acid consumption
34
nmol/min/mg
39
nmol/min/mg
Effect of aspirin on
COX activity
Inhibited
Affected**
http://elfstrom.com/arthritis/nsaids/actions.html
Tissue Comparison
Brain/nerve Synovial cells Vascular beds
Ar
Ar
Ar
PGH2
PGH2
PGH2
PGD2
PGE2
PGF2a
PGI2
(PC)
PGE2 PGI2
(PC)
PGE2
TXA2
So what would happen if we gave a patient
a large dose of aspirin or Coxib to reduce
inflammation/pain in these tissues?
Role of -3 Fatty Acids
DHA
LPS TNFα
TNFR
Neutrophil
COX/LOX
GPR120
βArr2
TAB1
TLR4
Transcellular
processes
Platelet
TAK1
IKKβ
NFB
COX/LOX
MKK4
JNK
Resolvins
Protectins
anti-inflammatory
Nucleus
Cytokines
inflammatory
Macrophage
Review Questions
• How are prostaglandins, leukotrienes,
lipoxins, and thromboxanes
synthesized (substrates, enzymes,
cofactors)?
• What is the nomenclature for
prostaglandin, leukotriene, lipoxin, and
thromboxane receptors?
• How do NSAIDs work?
• How do steroids work?
• What are important characteristics of
COX-1 and COX-2?
• How do ω-3 fatty acids affect the
inflammatory response?

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